Sex Differences in the Impact of Obesity on Immunity

Abstract

The prevalence of obesity has increased significantly worldwide in the past few decades and is anticipated to rise further in the future. Obesity, characterized by excessive fat accumulation and chronic low-grade inflammation, dysregulates innate and adaptive immune responses, thereby increasing the risk of infectious diseases, cardiovascular diseases, and cancers. Males and females differ considerably in patterns of fat distribution, adipose tissue inflammation, and adipocytokine production, resulting in substantial sex-specific differences in metabolic health outcomes during obesity. Despite growing evidence of its importance, biological sex remains underprioritized in preclinical, clinical, and epidemiological obesity-related research. In this review, we explore the impact of biological sex on obesity-associated immune dysregulation and its consequences for a range of health outcomes, including infectious diseases, vaccine-induced immunity, autoimmune diseases, cancer, and cardiometabolic risk. We highlight recent findings from animal models and human studies to discuss the mechanistic roles of sex steroids and chromosome complements in shaping fat distribution, adipose inflammation, gut microbiota composition, and systemic inflammation, which collectively drive sex differences in obesity-associated immune responses. Greater consideration of biological sex in obesity research is essential to better understand disease risk, develop targeted interventions, and improve care.

1. Introduction

Obesity, defined as having a body mass index (BMI) greater than or equal to 30 kg/m², refers to an excessive accumulation of adipose tissue in the body that negatively impacts the health and well-being of both men and women. The obesogenic environment, created by multiple factors such as changes in food habits (e.g., increased consumption of energy-dense processed foods), changes in work habits and sedentary lifestyles, high stress, and genetics, is driving the global rise in obesity. Since the 1990s, the prevalence of obesity has doubled among adults, while it has quadrupled among children and adolescents (1). In 2022, 2.5 billion adults (≥ 18 years) were overweight (i.e., BMI ≥ 25 kg/m²), and 890 million were living with obesity globally, while over 390 million children and adolescents (5 – 19 years) were overweight. If the current trend continues, by 2035, over half of the world’s population is estimated to be living either with overweight or obesity, and the annual economic costs will exceed $4 trillion (2). In the U.S., at least 1 in 5 children, 1 in 3 adolescents, and 2 in 3 adults are estimated to develop obesity by 2050 (3). These alarming forecasts of obesity and associated comorbidities underscore a global public health crisis.

Adipose tissue acts as both an endocrine and immunological organ, beyond its conventional role as an energy reservoir. In healthy-weight individuals, immune cells residing in the adipose tissue, such as M2 macrophages, group 2 innate lymphoid cells (ILC2s), eosinophils, and dendritic cells (DCs), predominate and maintain an anti-inflammatory environment (4). These immune cells promote insulin sensitivity and regulate immune homeostasis through a coordinated network of cytokines and adipokines. Obesity induces adipocyte hypertrophy and hyperplasia, resulting in hypoxia, oxidative stress, and adipocyte death, which triggers upregulation of chemokines, recruitment of monocytes, and their differentiation into pro-inflammatory M1 macrophages (4). Increased secretion of inflammatory adipokines (e.g., leptin) and cytokines (e.g., TNF-α, IL-6, IL‑1β), and reduced secretion of adiponectin further shifts the adipose tissue microenvironment from anti-inflammatory to a chronically inflamed state characterized by accumulation of M1 macrophages, natural killer (NK) cells, ILC1s, and CD8⁺ T-cells and B-cells. Obesity also promotes accumulation of inflammatory T helper (Th) 1 and Th17 cells and reduces regulatory T (Treg) cells and Th2 cells, further amplifying adipose tissue inflammation (4).

Sex as a biological variable (SABV) refers to the fundamental biological differences between males and females, including genetic (XX/XY chromosome), hormonal (estrogen/testosterone), gonadal (ovaries/testes), and anatomical differences, while gender refers to the sociocultural norms and roles associated with being male and female. Biological sex significantly influences the risk and progression of obesity due to inherent differences in hormonal profiles, genetic predispositions, and the composition of gut microbiota, which collectively drive variations in fat distribution, adipose tissue inflammation, and secretion of adipokines and inflammatory mediators (5). Men typically accumulate more visceral adipose tissue (VAT) around abdominal organs, whereas premenopausal women accumulate more subcutaneous adipose tissue (SAT), particularly in the gluteal-femoral region. Visceral adiposity strongly predicts metabolic disease, while lower body fat is protective. These differences are largely driven by sex hormone signaling within the adipose depots (5).

SABV also shapes baseline immunity, infection outcomes, and vaccine responses (6). The X chromosome in females carries more protein-coding and immune-related genes than the Y chromosome, which partly contributes to sex differences in immunity, while sex hormones, estrogen and progesterone in females and testosterone in males, directly modulate immune cell function by acting through their receptors, further influencing sex differences in immunity. In general, estrogen enhances antibody production, antiviral and antibacterial defenses, and vaccine-induced immunity. However, its effects are context-dependent; for example, it promotes immune tolerance in physiological states, such as pregnancy, while enhancing pro-inflammatory adaptive immune responses in autoimmune diseases (6). Testosterone generally exerts anti-inflammatory effects, suppressing antibody production and Th1/Th17 responses while promoting Treg differentiation. On the other hand, progesterone has anti-inflammatory effects and promotes immune tolerance mostly during pregnancy (6).

This review integrates current evidence on the influence of biological sex on obesity-associated immune dysregulations and sex-specific differences in health outcomes, including autoimmune disease, infectious disease risk, vaccine-induced immunity, cancer, and cardiometabolic risk. We discuss the mechanistic contributions of sex chromosomes and sex hormones to adipose tissue distribution, microbiome composition, systemic inflammation, and downstream disease outcomes. Finally, we highlight the critical knowledge gaps and emphasize the need for sex-stratified research approaches to better understand sex-dependent metabolic and immune trajectories in obesity and its associated diseases.

2. Sex Differences in Immune Responses in Normal-Weight Individuals

Biological sex influences both innate and adaptive immunity. These differences arise from sex chromosome-encoded genes, sex steroid receptor signaling, and epigenetic regulation of immune cells (6). For example, in adult women, the spontaneous apoptosis of neutrophils is significantly delayed compared to men, and administration of estradiol and progesterone at physiological doses further delays neutrophil death in both sexes (7). In contrast, monocyte counts and pro-inflammatory cytokine production, including TNF-α and IL-6, are higher in men, indicating functional differences between sexes (8). The NK cell numbers are typically higher in males, but their effector function is greater in females (9). In the mouse model, this difference persisted even after gonadectomy, indicating that it is not solely dependent on sex steroids. The X-linked epigenetic regulator, Utx/Kdm6a, which escapes X inactivation and is expressed at higher levels in female NK cells, is identified as a key contributor to greater NK cell function in females (9). Production of type I interferons (IFNs) by antigen-presenting cells, including the plasmacytoid DCs, is higher in females than in males, which enhances protection against infections but also increases risk of reactogenicity (10). Likewise, ILCs also differ between males and females. Androgens typically suppress ILC2 function in males, whereas reduced androgen signaling results in greater activation in females, with production of more inflammatory cytokines such as IL-5 and IL-13, contributing to a higher risk of non-allergic asthma in females (11). Testosterone-mediated ILC2 inhibition also diminishes the activation and function of DCs and hence contributes to sex differences in adaptive immunity (12).

Females typically mount stronger adaptive immune responses than males. The CD4/CD8 ratio is higher in adult females than in males, which is mostly due to the greater numbers of CD8 T-cells in males. Females also exhibit higher B-cell numbers and functions and better T-cell activation and proliferation (6). Estrogen enhances B-cell development and antibody production in females, while testosterone has an inhibitory function. Androgens, particularly testosterone, decrease antibody production, T-cell numbers and activation, while enhancing anti-inflammatory cytokines by antigen-presenting cells and promoting neutrophil recruitment. However, these neutrophils exhibit an immunosuppressive N-2-like phenotype, which is inefficient and has reduced antimicrobial capacity, thus impairing the overall ability to kill bacteria and prolonging the inflammatory process in males (13).

3. Adipose Tissue Biology and Immune Function

Adipose tissue is a dynamic organ crucial for energy storage as fat droplets, thermoregulation, endocrine signalling via secretion of leptin and adiponectin, and immune homeostasis. In healthy-weight individuals, adipose tissue accounts for 10 – 20% of body weight in men and 25 – 30% in women, which changes with age and metabolic status (14). White adipose tissue (WAT) stores energy in the form of triglycerides and secretes adipokines, such as leptin, adiponectin, and resistin, which regulate appetite, insulin sensitivity, glucose homeostasis, and inflammation (4). It primarily exists as SAT, located under the skin, and VAT, surrounding abdominal organs. In contrast, brown adipose tissue (BAT), located in the interscapular region, neck, and around vessels, mediates thermogenesis. WAT exhibits substantial plasticity via browning, where white adipocytes differentiate into beige cells that acquire BAT-like features in response to cold or adrenergic stimulation (4).

In healthy-weight individuals, WAT is enriched with anti-inflammatory cells, such as M2 macrophages, Tregs, ILC2s, invariant natural killer T (iNKT) cells, and NK cells that maintain tissue homeostasis, suppress inflammation, and coordinate metabolic functions (4). SAT and VAT exhibit distinct immune landscapes, indicating depot-specific immune functions. VATs also contain fat-associated lymphoid clusters, which contain diverse immune cells, including B- and T-cells, macrophages, DCs, iNKT cells, and ILC2s, and act as a lymphoid organ (15). Adipocytes and stromal-vascular cells secrete hundreds of adipokines, including adiponectin and leptin, which act locally and systemically. Adiponectin acts as an anti-inflammatory molecule and suppresses macrophage activation, while leptin enhances monocyte/macrophage, neutrophil, and NK-cell activity and promotes CD4 T-cell proliferation and IL-2 production (16).

Chronic nutrient surplus leads to adipocyte hypertrophy and hyperplasia, hypoxia, and elevated free fatty acids. It drives lipoinflammation, a chronic, low-grade inflammation characterized by the induction of proinflammatory cytokines, such as TNF-α, IL-6, and MCP-1, and the recruitment of proinflammatory immune cells (4). It shifts the adipose tissue microenvironment towards a pro-inflammatory state characterized by accumulation of neutrophils, M1 macrophages, Th1 and Th17 cells. Accumulation of triglycerides in non-adipose organs (e.g., liver, pancreas, heart, muscles) disrupts cellular function and promotes insulin resistance. Obesity increases CD4⁺ and CD8⁺ T-cells in adipose depots, while suppressing the number and function of Tregs. The T-cells that infiltrate the adipose tissues exhibit an activated pro-inflammatory phenotype, producing IFN-γ, IL-17, TNF, and Granzyme B (17). VAT Tregs are adapted to the lipid-rich adipose environment and express several key transcription factors, such as peroxisome proliferator-activated receptor gamma (PPARγ), GATA binding protein 3, suppression of tumorigenicity 2 (ST2), and basic leucine zipper transcription factor, crucial for their phenotype, stability, and potent immunosuppressive function. In healthy-weight individuals, these Tregs maintain glucose homeostasis and insulin sensitivity by restraining local inflammation, while in obesity, their numbers and function decline with increased abundance of pro-inflammatory Th17 cells (4). B-cell subsets, B-1 and B-2, also reside in adipose tissues and exert their metabolic effects. B-1 cells and regulatory B-cells inhibit inflammation via IL-10 and natural IgM antibody production, while B-2 cells, which are increased during obesity, promote inflammation and insulin resistance via inflammatory cytokine and IgG antibody production (17).

4. Sex Differences in Obesity-Associated Immune Dysregulation

4.1. Adipose Tissue Characteristics

Obesity induces a chronic pro-inflammatory environment in WAT, especially in VAT, where expanding adipocytes drive macrophages towards a pro-inflammatory M1 phenotype and secrete cytokines and chemokines promoting recruitment of more monocytes, neutrophils, and T-cells that amplify local inflammation through IL-6, IFN-γ, and TNF-α production (Figure 1) (4). The NLRP3 inflammasome, which acts as a sensor for metabolic stress from excess fat deposition and adipocyte death, further promotes the release of pro-inflammatory cytokines IL-1β and IL-18, linking adipose tissue inflammation to insulin resistance, chronic inflammation, and increased risk of cardiometabolic diseases (18).

Figure 1: Obesity-associated immune dysregulations between males and females.

Males preferentially accumulate visceral adipose tissue (VAT), whereas females accumulate more subcutaneous adipose tissue (SAT). During obesity, male adipose tissue exhibits heightened inflammatory immune remodeling, characterized by greater neutrophil activation, cytokine production, and NLRP3 inflammasome activation, while females have higher natural killer (NK) cell activity and lower inflammatory responses. In males, stronger Th1/17 cell response and reduced regulatory T (Treg) cell function contribute to adipose tissue inflammation and insulin resistance, while Tregs are better maintained in females, protecting against inflammation. Overall, females display reduced adipose inflammation, in part due to estrogen-mediated protection. The figure was generated at biorender.com.

Biological sex has a strong influence on adipose tissue distribution, inflammation, and metabolic risk. Women typically have more subcutaneous fat, particularly superficial subcutaneous fat, while adult men with obesity have significantly higher VAT that correlates strongly with inflammatory cytokines and metabolic dysfunction (5). In men, adipose tissue inflammation, the size of the adipocytes, and macrophage content are strongly associated with insulin resistance and metabolic syndrome, while such interactions are weaker in women during obesity. In women, adipose tissue inflammation and metabolic syndrome correlate more with the reduced anti-inflammatory adiponectin levels, rather than increased pro-inflammatory responses (19).

During high-fat diet (HFD)-induced obesity, male rodents exhibit stronger systemic inflammation, more M1-like macrophage polarization in VAT, and elevated TNF-α and IL-1β cytokines, whereas females maintain higher M2-like macrophage proportions (20). The accumulation of more pro-inflammatory macrophages in male mice is driven by leptin, free fatty acid, and its receptor GPR120 in macrophages, which promotes TNF-α production, whereas female macrophages produce the anti-inflammatory cytokine IL-10 (21). In a mouse model of HFD-induced obesity, female mice display an earlier accumulation of Th1/17 cells that decreases with adiposity, while males exhibit delayed but sustained accumulation of pro-inflammatory Th1/17 immune cells and enhanced NLRP3 inflammasome (22). In females, there is an increased lipolysis, driving adipose tissue remodeling and lipid clearance that limits inflammatory activation compared to males with obesity (23).

Experimental SAT removal in mice indicates that the more SAT distribution in females is a key factor protecting them from obesity-induced neuroinflammation, whereas males, who naturally carry less SAT and more VAT, are more predisposed to proinflammatory responses (24). Moreover, the Resistin-like molecule α (RELMα), elevated in females than in males, also maintains M2 macrophages and eosinophils and protects females from weight gain and inflammation. Its absence leads to weight gain and inflammatory macrophages, which are reversed with RELMα treatment or eosinophil transfer (25). Ovariectomy increases inflammation and weight gain in females, while loss of androgen hormones improves metabolic and inflammatory responses in males, suggesting a protective effect of estrogen in females (26). However, with aging, females exhibit a shift in adipose tissue inflammation characterized by elevated VAT CD8⁺ T cells, increased IFN-γ and TNF-α, and decreased anti-inflammatory Tregs, potentially contributing to the higher risk of cardiovascular diseases in middle-aged women (27).

4.2. Innate Immunity

During obesity, Toll-like receptors (TLRs), including TLR2 and TLR4, are overexpressed in visceral fat, where they recognize fatty acids and danger-associated molecular patterns (DAMPs) to activate NF-κB and AP-1 pathways, promoting pro-inflammatory cytokine production (28). CD14, a co-receptor for TLR2 and TLR4, enhances lipid-induced inflammatory signaling, and in humans, genetic variation in CD14 leads to increased BMI and altered lipid metabolism (29). NOD-like receptors (NLR), particularly NLRP3 inflammasome, detect danger signals activating caspase-1 to secrete IL-1β; and ablation of Nlrp3 prevents inflammasome activation and improves insulin-signaling, indicating its strong contribution to obesity-associated metabolic alterations (30). In men, NLRP3 and IL-1β correlate positively with adipocyte size, indicating that larger adipocytes drive greater inflammasome activation (31). Likewise, in the diet-induced obesity (DIO) model, male mice show increased CD11b⁺ myeloid cell numbers in VAT, accompanied by significant inflammasome activation compared with females (22).

A meta-analysis indicates that absolute neutrophil counts in the routine blood examination, rather than the neutrophil-to-lymphocyte ratio (NLR), are a more reliable and stable parameter for obesity-associated inflammation (32). Men with obesity exhibit stronger neutrophil-driven inflammation than women, with significantly increased neutrophil counts and activation as indicated by elevated expression of Elane, the neutrophil elastase, and myeloperoxidase (i.e., Mpo) genes. Women, on the other hand, show higher lymphocyte count and enriched NK cell activity (33). Sex differences in systemic pro-inflammatory responses are illustrated in additional human and animal model studies, where boys with obesity or male rodents display a pro-inflammatory metabolic profile in phagocytes and heightened systemic inflammation compared with girls or female rodents, respectively (34, 35).

Obesity is associated with reduced NK cell frequencies, cytokine production, and cytotoxicity, indicated by impaired receptor expression, modulation of mechanistic target of rapamycin (mTOR) pathways, and defective metabolism (36). NK cells from individuals with obesity exhibit reduced expression of key metabolic genes involved in glycolysis and downstream targets, impairing cellular metabolism required for effective NK cell training, metabolism, and activation (37). In the mouse model, HFD-induced NK cell expansion increases adiposity, adipose tissue inflammation, and insulin resistance, while its depletion improves them, indicating its direct role in metabolic alterations and insulin resistance (38). Mouse model studies also indicate that obesity suppresses NK cell cytotoxicity and antiviral functions by reducing granzyme and IFN-γ production (39). It is associated with the suppression of NK cell mitochondrial function by the expansion of IL-10-producing Tregs in HFD-treated mice, an effect that can be reversed by switching mice back to a control diet (39). Obesity also expands a distinct population of NK cells expressing IL-6 receptor α (IL-6Rα) and other myeloid lineage genes, resulting in reprogramming of NK cells to drive inflammation and insulin resistance (40). Despite these, sex differences in NK cell function during obesity are largely unknown.

Prolonged HFD treatment increases macrophage and DC numbers in the spleen of mice; reprograms their metabolism towards fatty acid oxidation, increasing reactive oxygen species and lipid peroxidation; and impairs antigen uptake, co-stimulatory molecule expression, and antigen presentation by DCs to T helper cells (41). Both in humans and mouse models, obesity drives the accumulation of specific DC phenotypes in adipose tissues that promote pro-inflammatory Th-17 polarization and contribute to insulin resistance (42, 43). Moreover, DCs are required for obesity-associated inflammation, as young male mice lacking DCs accumulate fewer macrophages in adipose tissues, do not develop HFD-induced weight gain, and lack metabolic dysfunction (44). Conventional type 1 DCs (cDC1s) and conventional type 2 DCs (cDC2s) maintain adipose tissue and systemic metabolic homeostasis through Wnt/β-cathenin and PPAR-γ signaling pathways, respectively (45, 46). These separate but complementary signaling pathways can be disrupted by HFD treatment, driving adipose tissue inflammation and metabolic disease. cDC1s, in particular, drive DIO and hyperlipidemia via iNKT cell activation (46). Sex difference is reported in DC accumulation and function in the adipose tissues, where males with obesity display higher numbers of DCs with greater pro-inflammatory cytokine production capability (Figure 1) (47). In males, androgens control DC numbers in gonadal adipose tissue, while the role of sex steroids appears minimal in females (26).

4.3. Adaptive Immunity

During obesity, there is a marked reduction in circulating Treg cells in humans, accompanied by an increase in CD4⁺ effector memory T cells, indicating loss of immunoregulation and a heightened pro-inflammatory T-cell state (48). HFD treatment in mice also leads to a substantial reduction of Treg cells in VAT, which is governed by local plasmacytoid DCs-induced IFN-α that downregulates PPARγ, a key transcription factor for Tregs (49). VAT contains two distinct Treg populations: ST2⁺ Tregs that require IL-33 and PPARγ, and are associated with tissue repair, metabolic homeostasis, and regulation of type 2 immunity; and CXCR3⁺ Tregs that depend on T-bet and IFNγ for their development and function and suppress Th1 immunity and inflammation. In mice, sexual dimorphism is observed in the distribution and function of Treg cells in VAT. Normal-weight males contain a larger number of Treg cells than females in VAT, with high expression of the IL-33 receptor (ST2), the maturation marker KLRG1, and chemokine receptor CCR2. Consistently, production of immunosuppressive cytokine IL-10 is higher in male VAT but not in females. Treatment of male wild-type mice with estrogen reduced Treg cells in VAT, while treatment of females with testosterone increased them, indicating that sex hormones regulate Treg population and function in VAT (50). Following HFD treatment, male VAT Tregs undergo a rapid decline and lose transcription factors, IL-33 responsiveness, and their regulatory ability, predisposing them to greater metabolic risk (50). In mice, obesity selectively reduces ST2⁺ Tregs in male mice, contributing to adipose tissue inflammation and insulin resistance, but the CXCR3⁺ Tregs in females remain stable, protecting against inflammation (Figure 1) (51).

In both humans and mice, obesity leads to the production of inhibitory soluble factors in the stromal vascular fraction that exhaust CD4 and CD8 T-cells, making them unable to respond to stimulation by limiting upregulation of their activation markers (52). CD4⁺ T cells may retain an obesity memory, as the adoptive transfer of helper T-cells from male mice with obesity accelerates weight regain in recipients (53). During obesity, adipose tissue is shifted from a Th1-dominant to a Th17-dominant environment. Accumulation of CD11c⁺CD1c⁺ DCs in humans, and CD11c^highF4/80^low DCs in mice, led to differentiation of CD4 T-cells to Th17 rather than regulatory T cells, indicating the significant role played by DCs in shaping adaptive immunity during obesity (42). Impaired fatty acid oxidation is also a key metabolic driver inducing proinflammatory Th17 activity in obesity. For example, in individuals with type 2 diabetes (T2D), impaired fatty acid transport and β-oxidation, combined with exposure to long-chain fatty acylcarnitines, promote Th17-associated cytokine production, which can be improved by reducing the expression of CPT1A, which is the key enzyme that transports long-chain fatty acids into the mitochondria for β-oxidation (54).

B-cell changes during obesity mirror many of the defects seen in chronological aging. For example, exposure of B cells to saturated fatty acid palmitate triggers metabolic reprogramming, upregulating T-bet, a transcription factor that drives autoimmune antibody production, and promotes synthesis of self-reactive antibodies (55). Individuals with obesity also exhibit an increased frequency of double-negative (IgD⁻CD27⁻) B cells, strongly correlated with self-reactive antibodies (56). Obesity further dysregulates B-cell mitochondrial activity, characterized by reduced ATP production, weakened oxidative phosphorylation, and increased mitochondrial oxidative stress (57). Obesity impairs B-cell responses both in young and elderly individuals following influenza vaccination. People with obesity have a weaker antibody response, reduced numbers of switched memory B cells, decreased expression of activation-induced cytidine deaminase and E47 transcription factors, and increased pro-inflammatory cytokine production (58). Sex differences in B-cell responses during obesity, particularly following infection and vaccination, are discussed later.

5. Sex Differences in obesity-associated infectious disease risk

In general, obesity is associated with an increased risk of severe outcomes of infectious diseases in both sexes. The mechanisms include alteration in the innate and adaptive immune system, imbalanced crosstalk between the immune system and adipose tissues, impaired chemotaxis, dysregulated macrophage dynamics and cytokine production, reduced vitamin D levels, decreased pulmonary volumes and compliance, and obesity-associated comorbidities such as diabetes and hypertension (59).

5.1. Sex Differences During Viral Infection

During the COVID-19 outbreak, male sex was associated with severe outcomes, including intensive care unit admission and death (60). Disease severity in males is likely associated with increased inflammatory cytokines, induction of non-classical monocytes, and lower antibody and T-cell-mediated immunity (61). Retrospective and cross-sectional studies from around the world showed that individuals with obesity had a higher risk of developing disease severity, hospitalization, admission to the intensive care unit, requirement of invasive mechanical ventilation, and mortality. A recent meta-analysis of prospective studies showed that obesity increased the risk of death in patients with COVID-19 by 52% (62). Another systematic review and meta-analysis also observed that compared to patients with normal weight, patients with obesity had 32% increased risk of death (63).

Dos Reis et al. carried out an observational, cross-sectional study in Brazil to understand the sex differences in COVID-19 outcomes in individuals with obesity, and observed a marked effect of obesity on COVID-19 deaths in men, but a modest effect in women (64). Another study in Mexico observed that obesity, regardless of biological sex, increased COVID-19 severity, and males, irrespective of obesity status, had worse outcomes (65). Guerson-Gil et al. observed that in men, COVID-associated deaths are significantly associated with BMI ≥35, while in females, such an association was observed only in severe obesity (BMI ≥40) (66). However, in kidney transplant recipients with overweight and obesity, female patients required supplemental oxygen and had unfavorable COVID-19 outcomes compared to normal weight controls, and such an effect was less prominent in male patients (67). Likewise, in a K18-hACE2 transgenic mouse model of DIO, Lee et al. observed that females with obesity had an increased susceptibility, greater viral burden, and interferon production compared to males (68). These findings highlight sex- and obesity-specific vulnerabilities in COVID-19 and underscore the complex interactions between sex and obesity that necessitate tailored clinical risk assessments.

Sex differences in the impact of obesity on viral pathogenesis are also observed during West Nile virus (WNV) infection. In a mouse model of DIO, obesity exacerbates the WNV infection-induced mortality rate in females than in males, which is associated with higher virus titers in the central nervous system and reduced virus-neutralizing antibody production in females with obesity (69).

During influenza virus infection, adult females, particularly of reproductive age, experience higher rates of influenza-related hospitalizations, more severe symptoms, and long-lasting illness compared to age-matched males, as observed in epidemiological data and animal model studies (70). Mouse models show that females suffer worse outcomes due to heightened inflammatory immune responses and greater pulmonary tissue damage, despite having similar viral replication levels as males (71, 72). Sex hormones appear to mediate these differences, as elevated levels of testosterone and the tissue-repair protein amphiregulin are associated with better outcomes in males, while high doses of estradiol reduce severe outcomes in females. Likewise, obesity is an independent risk factor for severe outcomes of seasonal and pandemic influenza virus infections, increasing the risk of severe disease and death (73). Individuals with obesity shed the influenza A virus (IAV) for a longer duration, experience a delay in virus clearance, and are at a higher risk of complications, including pneumonia and secondary bacterial infections. Obesity also contributes to the evolution of viruses through mutations (73).

Despite evidence of sex differences in influenza virus pathogenesis in non-obese hosts, sex difference studies during obesity are rare both in humans and animal models. To better reflect the status of inclusion of animals of either sex or segregation of data by biological sex, we reviewed articles relevant to IAV pathogenesis studies in animal models of DIO (Table 1). 28 publications used mouse and ferret models of DIO to investigate influenza virus pathogenesis during obesity. Of which, 19 included only males with obesity, 3 had only females with obesity, 3 did not clearly indicate animal sex, and 3 had animals of both sexes, with only 1 study stratifying data by biological sex (Table 1). This depicts the gaps existing in the exploration of the sex-specific impact of obesity on influenza virus pathogenesis.

Table 1:

Influenza pathogenesis studies in animal models of diet-induced obesity (DIO)

Animal model	Virus	Key observations	Ref.
Ferrets	H1N1, H3N2, H9N2, Influenza B	Irrespective of the virus strain, disease severity is greater in male ferrets with obesity. They have dysregulated antiviral responses in lungs and are more likely to transmit the influenza virus than non-obese ferrets.	(74)
Ferrets	H9N2	The neutered male ferrets exhibit a unique class of obesity-specific genetic variants generated after influenza virus infection, indicating the potential role of obesity in influenza virus evolution.	(75)
Mouse	H1N1	In female BALB/c mice with DIO, influenza infection causes more severe disease, and influenza virus replication is also observed in the thoracic adipose tissue.	(76)
Mouse	H1N1	Thermoneutral housing (30 °C) induces severe obesity and metabolic disease in female C57BL/6 mice, as in males. In 5 days of follow-up after a lethal dose of H1N1 IAV infection, there is no difference in disease severity between male and female DIO mice.	(77)
Mouse	H1N1	Influenza virus infection increases airway inflammation, fibrosis, and elastance in DIO male and female mice (data not stratified by sex). Mice with obesity exhibit increased arachidonic acid levels in bronchoalveolar lavage (BAL) fluid and phospho-p38 MAPK levels in the lungs. Treatment with dilmapimod, a p38-specific inhibitor, protects mice with obesity from IAV-induced disease severity.	(78)
Mouse	H1N1	The mitochondrial pyruvate carrier inhibitor drug, MSDC, improves glucose tolerance and total blood cholesterol; promotes lung inflammation resolution; and recovery from influenza virus infection in male C57BL/6 DIO and genetically obese mice.	(79)
Mouse	H1N1	In male C57BL/6 mice, DIO alters CD8+ T cell metabolism, with 30% lower basal oxygen consumption rate, 24.9% lower basal extracellular acidification rate, 47.5% lower maximal mitochondrial respiration, and 61.6% lower spare respiratory capacity compared to non-obese mice at 10 days post-infection with IAV.	(80)
Mouse	H3N2	Type I (i.e., IFN-α and IFN-β) and Type III (i.e., IFN-λ) interferon responses are impaired in the lungs of DIO male C57BL/6 mice. Mice with obesity have reduced expression of interferon regulatory factor 7 in the lungs after infection with the influenza virus.	(81)
Mouse	H1N1	Male C57BL/6 DIO mice have altered CD4+ T cell metabolism, and treatment with metformin, a drug that inhibits T cell oxidative metabolism, protects them from influenza infection-induced mortality.	(82)
Mouse	H1N1	Infectious viruses are detected in the hearts of DIO male and female C57BL/6 mice (data not stratified by sex) at higher levels, compared with non-obese mice following infection with low or high doses of influenza virus up to 6 days post-infection. Antiviral and inflammatory responses in the hearts are reduced in mice with obesity, indicating a potentially increased risk of influenza-associated cardiac complications in obesity.	(83)
Mouse	H1N1, H3N2	Influenza viruses derived from hosts with obesity have increased replication kinetics in vitro and a greater virulence in vivo in DIO male C57BL/6 and genetically obese mice.	(84)
Mouse	H1N1	DIO male C57BL/6 mice have reduced type I interferon response and increased M1 macrophage phenotype in the lungs associated with higher viral titers and increased mortality following influenza virus infection.	(85)
Mouse	H3N2, H1N1	During the secondary influenza virus infection, DIO male C57BL/6 mice have reduced memory T-cell response and altered T-cell metabolism, which is not reversed by weight loss.	(86)
Mouse	H1N1	During influenza virus infection, type I interferon response is delayed in DIO female C57BL/6 mice, and prostaglandin E2 levels are increased in the lungs. Treatment with paracetamol, a weak prostaglandin synthesis inhibitor, improves antiviral response in the lungs and the survival rate.	(87)
Mouse	H1N1, H3N2, Influenza B virus	In DIO male C57BL/6 mice, obesity increases mortality from secondary Streptococcus pneumoniae infection following primary influenza virus infection. Even vaccination cannot protect against coinfection.	(88)
Mouse	H1N1	Male C57BL/6 DIO mice exhibit lower B cell frequency and reduced transcripts of early lymphoid commitment markers in the bone marrow, lower antibody titers, and increased disease severity after influenza virus infection. Supplementation with docosahexaenoic acid, an essential fatty acid that improves these outcomes by elevating levels of specialized proresolving lipid mediators (SPMs).	(89)
Mouse	H1N1	Male BALB/c DIO mice exhibit increased neutrophil extracellular traps (NETs) formation in the lungs at 6 days post-infection with a lethal dose.	(90)
Mouse	H1N1	Exercise improves cytokine and chemokine production in the BAL fluid, IFN-α gene expression, antibody production, and CD8+ T cell responses, and reduces disease severity in the DIO male C57BL/6 mice.	(91)
Mouse	H1N1	Virus-infected DIO male C57BL/6 mice exhibit reduced numbers of macrophages and Tregs in the lung airways, and altered metabolites associated with lipid metabolism, fatty acid-related pathways, and nucleotide metabolism.	(92)
Mouse	H1N1, H3N2	DIO does not influence the generation of memory CD8+ T cell response after primary infection with the H1N1 virus and their ability to respond to a secondary challenge with the H3N2 virus.	(93)
Mouse	H1N1	Distinct metabolic alterations in lipids, ketone bodies, nucleotides, amino acids, etc., are observed between virus-infected male C57BL/6 DIO and non-obese mice in tissues and biofluids.	(94)
Mouse	H1N1	During a heterologous secondary IAV challenge, DIO male C57BL/6 mice produce significantly lower levels of non-neutralizing but cross-reactive antibodies, have higher viral titers, and produce more numbers of less responsive Tregs.	(95)
Mouse	H1N1	DIO female C57BL/6 mice have higher serum leptin and lower adiponectin levels, and treatment with anti-leptin antibody improves the survival rate, following influenza virus infection, to 80% compared to 40% in the control group.	(96)
Mouse	H1N1, H3N2	Following H1N1 and H3N2 IAV infection, increased mortality is observed in the DIO male C57BL/6 and genetically obese mice. They exhibit delayed resolution of lung inflammation. Mice with obesity require a higher dose of oseltamivir for complete protection.	(97)
Mouse	H1N1	DIO male C57BL/6 mice have higher morbidity and mortality after infection with the 2009 pandemic H1N1 virus. However, no such difference is observed after infection with seasonal H1N1 or 1918-like swine H1N1 virus.	(98)
Mouse	H3N2, H1N1	In DIO male C57BL/6 mice, secondary influenza virus infection (i.e., H3N2 followed by H1N1) causes increased morbidity and mortality; reduced interferon responses in the lungs; increased pulmonary viral titers and pathology; and diminished effector memory T cell responses.	(99)
Mouse	H1N1	DIO C57BL/6 mice exhibit delayed mononuclear cell infiltration and reduced DCs in the lungs after influenza virus infection. DCs in mice with obesity have comparable antigen uptake and migration ability but reduced antigen presentation than those from the non-obese mice.	(100)
Mouse	H1N1	DIO C57BL/6 mice display higher mortality, reduced pulmonary expression of antiviral cytokines, and reduced NK cell cytotoxicity compared to non-obese controls.	(101)

In the ferret model of DIO, neutered and descented males or ovariectomized females are used, which only represent the genetic contributors of sex differences and cannot represent the contributions of sex steroids (74, 75). Moreover, female ferrets do not develop obesity after the diet treatment, indicating limitations of investigating the interaction of obesity and biological sex in ferret models (74). Mouse models of DIO are commonly used for influenza virus pathogenesis studies, and both in males (77, 97–99) and females (76, 77) obesity is associated with more severe disease. Mouse model studies have shown that during influenza virus infection in hosts with obesity, interferon responses are impaired (81, 85); macrophages and Treg responses in the lung airways are reduced or delayed, but neutrophil extracellular traps (NETs) formation is increased (90, 92, 100); B-cell numbers and antibody responses are reduced (89); T-cell metabolisms and memory responses are negatively impacted (80, 82, 86); outcomes of secondary bacterial and influenza virus infection are worse (88, 99); and viruses may even replicate in extrapulmonary tissues such as thoracic adipose tissue and heart (76, 83). However, the inclusion of animals of only one sex in these studies, or the lack of segregation of data by sex, limits our understanding of sex differences in these outcomes.

Alarcon et al. used thermoneutral housing (30 °C) conditions to induce equivalent obesity in male and female mice (77). Following infection with a lethal dose of IAV, obesity exacerbated disease pathogenesis in both males and females, and sex difference was not observed. However, analysis was performed only up to 5 days post-infection and lacked temporal analysis following infection with a low-dose infection (77). In our yet to be peer-reviewed work, we did temporal analysis of sex differences in IAV pathogenesis following infection with a high- and low-dose of IAV in a mouse model of DIO. Our findings suggest that biological sex difference, as observed in non-obese hosts, persists during obesity where females experience greater influenza disease severity associated with delayed and persistent inflammatory responses in the lungs. This highlights the necessity of sex-inclusive study designs to better understand how biological sex differences impact virus pathogenesis in hosts with obesity.

5.2. Sex Differences During Bacterial and Other Infections

During bacterial infection, sex differences occur in pathogen recognition, innate immune responses, and adaptive immunity (102). Likewise, sex differences are also evident in fungal diseases, where males are disproportionately affected than females (103). Obesity also influences the outcomes of bacterial and fungal pathogenesis. However, the interaction of obesity and biological sex during bacterial, fungal, and other infections is understudied.

During Escherichia coli infection, mice with obesity display higher leukocyte accumulation, cytokine production, and severe lung injury, despite having comparable bacterial counts, indicating that obesity may be detrimental during certain bacterial infections (104). Following Klebsiella pneumoniae infection, HFD-treated mice have reduced intra-alveolar neutrophils, which exhibited decreased bacterial phagocytosis and killing, indicating that DIO impairs pulmonary Klebsiella clearance and augments blood dissemination by reducing neutrophil killing (105). These studies, however, only used male mice with obesity. Entrup et al. investigated the effects of obesity on Pseudomonas aeruginosa pneumonia in a mouse model of DIO using both male and female mice. DIO increased bacterial burden in both sexes; however, compared to female mice, males with obesity had higher bacterial burden, reduced ability of alveolar macrophages in phagocytosis and bacterial killing, which was mediated by obesity-associated upregulation of prostaglandin E2 (PGE2) in males (106).

The impact of obesity on sepsis is not clear. While some studies indicate an increased risk, others suggest the protective role of obesity on sepsis outcomes (107, 108). A recent systematic review and meta-analysis of murine sepsis studies suggested mixed effects with no survival benefit due to obesity (108). Despite the mixed results, studies that segregated data by patients’ gender indicate that, compared to male patients, female patients with obesity have a higher mortality risk (109, 110). A similar obesity paradox has been documented for pneumonia, where several epidemiological studies report a measurable protective effect of obesity against pneumonia-related deaths (111).

5.3. Sex Differences in Vaccine-Induced Immunity and Protection

Obesity also impacts vaccine-induced immune responses. While a few studies suggest no effect (112), several studies indicate that individuals with obesity have reduced antibody responses to COVID-19 vaccines and accelerated waning of virus-neutralizing antibodies (113, 114). In a mouse model of DIO, which only used male mice, the SARS-CoV-2 mRNA vaccine exhibited lower antibody titers, reduced CD8⁺ T-cell activation, and protection from lung infection against virus challenge (115). In another experiment, which only used female mice with DIO, Chen et al. showed that T- and B-cell-mediated adaptive immunity is impaired, leading to lower vaccine efficacy (116). These findings suggest that obesity harms the adaptive immunity of both sexes following COVID-19 vaccination. Interestingly, data that segregate antibody responses between males and females with obesity indicate that increased adiposity is associated with decreased antibody responses in men but not in adult women (117, 118). Likewise, a mouse model study using both males and females showed that after immunization with the SARS-CoV-2 mRNA vaccine, female mice with obesity produce higher neutralizing antibody levels against the original virus as well as the Omicron variant than the males (119). These data highlight the importance of considering biological sex during COVID-19 vaccine development and safety and efficacy studies.

Emerging evidence suggests that obesity impacts humoral responses in a sex-dependent manner even after vaccination against tick-borne encephalitis (TBE). After the booster dose, neutralizing antibodies peak in both groups, i.e., healthy-weight individuals and those with obesity, and reach similar levels. However, the subsequent decline in neutralizing antibodies at 6 months is significantly greater in individuals with obesity, which is associated with higher BMI and their insulin and leptin levels. When antibody data were analyzed by sex, males with obesity showed a stronger and more rapid early boost compared to females with obesity, associated with a lower testosterone level in males with obesity (120). In a mouse model, after TBE virus vaccination, IgG and neutralizing antibodies are lower in mice with obesity, driven by a significantly lower response in males with obesity compared to non-obese males (121).

During influenza vaccination, non-obese adult females of reproductive age produce higher antibody responses and are better protected from subsequent influenza virus challenge compared with adult males (122–128). In the mouse model, sex differences in antibody responses are evident up to 4 months post-vaccination, indicating a long-term effect, and extend to diverse mutants (126, 127). While both hormonal and genetic factors contribute to better influenza vaccine-induced immunity in adult non-obese females than in males, our recent study indicates that this difference is likely driven primarily by sex steroids (127). Influenza antibodies are positively associated with estradiol concentration in females and negatively associated with testosterone levels in males; the sex difference disappears with the removal of gonads and is reproduced once sex steroids are replenished (123, 124). Moreover, adult females have a larger number of germinal center (GC) B cells, higher expression of Tlr7 and Aicda genes, and superior somatic hypermutation frequencies in B-cells, contributing to better immunity (125–127).

A recent systematic review suggested that obesity is not associated with impaired early induction of antibody response, evaluated within a month post-vaccination, to H1N1 influenza vaccines (129). However, despite having comparable antibody responses in the beginning, individuals with obesity have a rapid decline in antibodies within a year compared to healthy-weight individuals (130). Individuals with obesity are also at two-fold higher risk of developing influenza-like illnesses, despite vaccination, compared to healthy-weight controls (131). This is linked to obesity-associated impairment in B- and T-cell activation following influenza vaccination (131, 132). Mouse model studies, which provide a more controlled environment, have shown that obesity impairs humoral and T-cell responses to influenza vaccines (133, 134). Moreover, even higher dose vaccination or the addition of adjuvants does not improve protection in mice with obesity (134).

To gain better insights into the consideration of biological sex differences following influenza vaccination in hosts with obesity, we reviewed articles relevant to influenza vaccination studies in mouse models (Table 2). Most prior studies used only male mice (88, 133, 138–141), with a few using only females with obesity (137). In recent studies, both males and females with obesity have been considered (135, 136), allowing direct comparison of data between the sexes (135). Studies using exclusively male C57BL/6 mice have shown that after influenza vaccination, obesity reduces antibody production and protection compared to non-obese mice (133, 138, 140, 141). One study reported that adding alum or squalene adjuvants increased antibody responses in genetically obese mice, yet this enhancement does not improve protection (134). Another study found that E. coli outer membrane vesicles, as an adjuvant in male C57BL/6 mice, increase antibody response and improve protection (139). In contrast, a study using exclusively female CD-1 mice showed that vaccine-induced antibody responses are comparable between mice with or without obesity, although disease severity after infection is greater in females with obesity (137). Honce et al. examined how the timing of the diet switch affects influenza vaccine efficacy in a DIO mouse model (136). They showed that DIO impairs the functional memory T-cell development following influenza vaccination, and that weight loss before but not after vaccination improves influenza vaccine efficacy (136). Importantly, this beneficial effect of pre-vaccination diet switch is observed in both sexes with obesity (136).

Table 2:

Influenza vaccine study in mouse models of obesity.

Animal model	Vaccine strains	Key findings	Ref.
Mouse	H1N1	Female C57BL/6 DIO mice develop higher antibody responses and are better protected than male mice with obesity. There is no difference in splenic B- and Tfh-cells between males and females with obesity.	(135)
Mouse	H1N1	Influenza vaccination fails to protect male and female DIO C57BL/6 mice by impairing the generation of functional memory T-cell responses. Weight loss before vaccination, but not post-vaccination, improves influenza vaccine efficacy in both sexes with obesity.	(136)
Mouse	H1N1	After a prime-boost vaccination with an H1N1 HA-based vaccine and subsequent homologous virus challenge, DIO female CD-1 mice lose significantly greater body mass compared to non-obese mice on a control diet. However, antibody responses before or after the virus challenge are comparable between females with or without obesity.	(137)
Mouse	H1N1	DIO male C57BL/6 mice produce significantly lower IgG antibodies following influenza vaccination than the controls. Oral supplementation of vitamin A improves antibody responses and protection by reducing lung virus titers in males with obesity.	(138)
Mouse	Trivalent (H1N1, H3N2, influenza B)	In DIO male C57BL/6 mice, use of Escherichia coli outer membrane vesicles as an adjuvant improved trivalent influenza vaccine-induced antibody and cell-mediated immune responses, and increased survival rate after homologous and heterologous virus challenges.	(139)
Mouse	H1N1, H3N2, influenza B	After a sublethal dose infection with H1N1, H3N2, or influenza B viruses and subsequent Streptococcus pneumoniae secondary bacterial infection, DIO male C57BL/6 mice experience increased mortality. Subsequent studies, which included only genetically obese mice, indicate that vaccinations do not protect mice with obesity against secondary bacterial infection.	(88)
Mouse	H7N9, H1N1	The addition of alum and squalene adjuvants increases both neutralizing and non-neutralizing antibody responses in genetically obese mice, with breadth and magnitude lower than in non-obese mice. However, it is not sufficient to protect mice with obesity. Increasing the vaccine dose and passive immunization with vaccinated non-obese sera also do not improve protection in mice with obesity.	(134)
Mouse	H1N1	Lipopolysaccharide-induced IL-6 and TNF-α levels are lower in macrophages of DIO male C57BL/6 mice. After influenza vaccination, mice with obesity produce lower antibody responses than non-obese mice.	(140)
Mouse	H1N1	DIO male C57BL/6 mice produce lower levels of virus-neutralizing antibodies compared to non-obese mice. Mice with obesity also exhibit higher MCP-1 levels in serum and adipose tissue, low levels of virus-specific effector memory CD8+ T cells, and increased inflammation in the lungs after virus challenge.	(133)
Mouse	H1N1	DIO male C57BL/6 mice generate lower levels of antibody responses after vaccination with the 2009 H1N1 split virus vaccine. They have more severe pulmonary pathology and a reduced survival rate following virus challenge.	(141)

Despite these insights, direct comparisons of antibody responses and protection following influenza virus vaccination and challenge between males and females with obesity have been lacking. In our recent study (135), we addressed this gap using an H1N1 IAV vaccination and challenge model. We observed that following vaccination, males but not females with obesity exhibit reduced antibody responses. Although obesity negatively impacts protection in both vaccinated male and female mice, the impairment is more severe in males, as reflected by greater morbidity, inability to clear infectious virus from the lungs, and heightened pulmonary inflammation (135). Interestingly, B-cells and T follicular helper (Tfh)-cells are comparable between males and females with obesity, suggesting that antibody production by B-cells is specifically impaired in males with obesity (135). Overall, these findings highlight the necessity of considering both obesity and biological sex in preclinical, clinical, and epidemiological studies of influenza vaccination.

6. Sex Differences in Obesity-Associated Autoimmune Diseases

Obesity increases the risk of autoimmune diseases. A recent systematic review and meta-analysis reported a 41% higher overall incidence of autoimmune diseases in individuals with obesity compared to normal-weight individuals (142). Obesity increases the risk of rheumatoid arthritis (RA) by 30%, psoriasis by 18%, multiple sclerosis (MS) by 49%, and Crohn’s disease/ulcerative colitis by 35%. The prevalence estimates are also higher for RA (11%) and psoriasis (35%) in individuals with obesity (142). A large population-based study in the Danish National Birth Cohort, which only included women, also showed that obesity leads to a 3-fold increased risk of sarcoidosis and a 2-fold increased risk of type 1 diabetes mellitus. Adult women with obesity also had an increased risk of psoriasis, RA, and Crohn’s disease (143).

Autoimmune diseases exhibit a strong sex difference in normal-weight individuals. Women are disproportionately affected by systemic lupus erythematosus (SLE), Takayasu’s arteritis, Sjögren’s disease, thyroiditis, Graves’ disease, RA, MS, and celiac disease (144). In contrast, men are disproportionately affected by type 1 diabetes, Crohn’s disease, Ankylosing spondylitis, myocarditis, and primary biliary cholangitis (144). Sex hormones are the major contributors to these differences. Estrogen enhances both B- and T-cell-mediated immune responses than testosterone, which increases both the risk for autoimmune diseases and a heightened response to obesity-induced inflammation (144). Estrogen also downregulates the expression of the autoimmune regulator (AIRE), weakening central tolerance and activating autoreactive T-cells, while androgens upregulate AIRE expression and promote immune tolerance (145).

Obesity influences the risk of RA differently in men and women. While obesity is a risk factor for RA in both sexes, the positive association of BMI with RA is stronger for women than for men, indicating that obesity largely contributes to the rise of RA cases in women (146). In a Swedish case-control study, women with obesity had 60% higher odds of developing anti-citrullinated protein antibody (ACPA)-negative RA than normal weight women, whereas men with obesity had 40% reduced odds of developing ACPA-positive RA than normal weight men (147). Further, long-term obesity (≥10 years) is associated with a 35% increased risk of developing RA in women (148).

Women are disproportionately affected by SLE, and obesity adds to the inflammatory burden. One study showed that women with obesity have an 85% increased risk of developing SLE compared to women with normal BMI (149). Obesity further exacerbates inflammation, reduces quality of life, and causes greater physical decline in SLE patients (150). Vitamin D deficiency, which is more common in individuals with obesity than in normal-weight individuals and in patients with SLE, may contribute to the increased risk in women with obesity (151). Though SLE is more common in females, the disease manifestation, such as organ damage, is more severe in males. Zhang et al. used a mouse model to explore the impact of an HFD on SLE pathogenesis and reported sex-specific differences (152). Females on HFD exhibited an early onset of skin rashes with higher skin pathology, whereas males on HFD developed more severe disease as indicated by splenomegaly, proteinuria, elevated anti-dsDNA levels, and nephritis (152).

Childhood or adolescent obesity significantly increases the risk of developing MS later in life, and the impact of obesity is greater in females than in males (153). A recent study shows that women with obesity exhibit higher serum protein signatures associated with Th1, IL-17, and MS signaling pathways compared to men (154). Consistently, in the mouse model of experimental autoimmune encephalomyelitis (EAE), females with obesity exhibit elevated Th1/IL-17 inflammatory responses in the central nervous system (CNS), which are associated with enhanced EAE severity. These mice also exhibit increased baseline serum IFN-α and enhanced expression of STAT1 and IFN-γ production by CD4⁺ T cells. Moreover, these Th1 responses are dependent on adiposity in female mice, as they are abrogated by gonadectomy or knocking down the type I IFN receptor in T-cells, indicating that the exacerbation in MS/EAE autoimmunity is driven by excess fat deposition that triggers type I IFN signaling and skews T-cells towards a pro-inflammatory Th1 phenotype (154).

Overweight and obesity are associated with higher Psoriasis Area and Severity Index (PASI) scores, longer disease duration, and a significantly higher prevalence of metabolic comorbidities such as fatty liver, dyslipidemia, hyperuricemia, impaired liver function, and dysglycemia (155). The impact of obesity on psoriasis severity is greater in men than in women (156). Likewise, obesity increases the risk of developing hypothyroidism by 86% and Hashimoto’s thyroiditis by 91% (157). Risk patterns exhibit sex differences, where higher BMI in women is associated with a higher risk of hypothyroidism and Hashimoto’s thyroiditis, while it is associated with elevated thyroid peroxidase antibodies (TPOAb) in men (158).

7. Sex Differences in Obesity-Associated Cancer Risk

A US-based study suggested that the proportion of cancers attributable to overweight and obesity ranges between 3.9 – 6% among men and between 7.1 – 11.4% in women (159). Obesity leads to an imbalance in adipokines by increasing leptin and decreasing adiponectin. Since leptin promotes cell growth and adiponectin exerts anti-proliferative and anti-inflammatory effects, this imbalance favors cellular proliferation, angiogenesis, and immune evasion (160). Obesity-associated alterations in adipose tissues, such as hypoxia and stress, gut microbial dysbiosis, and chronic low-grade systemic inflammation, further contribute to increased risk of cancer (160).

Certain cancers occur predominantly in one sex, and yet, obesity influences their outcomes. For example, obesity increases the risk of developing breast cancer by 26% in post-menopausal women, while it exerts a protective effect pre-menopause (161). This is likely mediated by differences in sex steroids; obesity reduces estrogen exposure by disrupting menstrual cycles pre-menopause, while adipose tissues produce estrogen, increasing cancer risk post-menopause (161). However, sex steroids are not the sole players, as in mice, even after hormone depletion by ovariectomy, obesity accelerates tumor growth, indicating the role of adipose tissue in breast cancer development (162). Parallel to mouse studies, a recent large-scale human study showed that obesity accelerates molecular aging in tumors, promoting expression of genes associated with inflammaging-like phenotypes and driving estrogen-positive breast cancers (163).

In women, obesity at ages 18 – 21 years increases the risk of endometrial cancer by 185% while adult obesity increases it by 26%, and weight loss reduces the risk (164). In mouse models, obesity exacerbates endometrial cancer, and HFD treatment drives tumor growth and expression of ERα in tumor cells of estrogen receptor-positive endometrial cancer (165, 166). Likewise, in men, obesity is associated with poor prognosis of prostate cancer and reduced treatment effectiveness, with more severe side effects (167). Studies in transgenic mouse models also exhibit prostate cancer acceleration during obesity mediated by enhanced growth factors and inflammatory signaling (168).

Gastric cancer incidence, mainly caused by Helicobacter pylori infection, is higher in men than in women, and following H. pylori infection, men develop more severe inflammation in the stomach lining than women (169). In the mouse model, DIO significantly increases H. felis-induced gastric cancer, suggesting a synergistic effect of obesity and Helicobacter infection in enhancing gastric carcinogenesis (170). In hepatocellular cancer, the risk of incidence and mortality is 2 – 3 times greater in men than in women with obesity (171). Likewise, overweight and obesity increase the risk of colorectal cancer in both sexes, yet the risk is higher in men than in women (172). Mouse model studies replicate human observations, where HFD treatment enhances colon tumors and associated gene expression in males (173). Female sex hormones may offer partial protection in women, as colorectal cancer risk is inversely associated with post-menopausal hormone therapy (174). Bidirectional interaction between gut microbiota and sex hormones is also possible in mediating colorectal cancer risk. Sex hormones influence gut microbiota composition and function, while gut microbiota impact sex hormone production through different bacterial enzymes (175).

8. Sex Differences in Cardiometabolic and Cardiovascular Risk in Obesity

Obesity increases the risk of cardiometabolic and cardiovascular diseases (CVD). More than two-thirds of deaths linked to high BMI are due to CVDs (176). Risk of cardiometabolic multimorbidity, specifically T2D, coronary heart disease, and stroke, increases 2-fold in overweight individuals to between 5 and 15-fold in individuals with obesity (177). Obesity is also the strongest risk factor for hypertension, which is the major contributor to obesity-associated CVD (178). Likewise, obesity increases the risk of developing dyslipidemia by 2 to 3 times (179). A US-based study reported obesity as a contributor of 21% cases of myocardial infarction, 16% of stroke, 38% of heart failure, and 19% of CVD (180).

VAT, accumulated during obesity, is associated with a greater risk of endothelial dysfunction and cardiometabolic risk (181, 182). It increases the production of pro-inflammatory adipocytokines such as leptin and resistin, while reducing the synthesis of anti-inflammatory adiponectin and omentin. Such changes induce endothelial dysfunction, leading to vasoconstriction, and promote atherosclerosis by increasing vascular smooth muscle cell migration and proliferation, as well as the inflammatory polarization of macrophages (181). It disrupts normal cellular function and increases lipotoxicity and oxidative stress, leading to a state of chronic inflammation, dyslipidemia, endothelial dysfunction, and hypertension. Hyperinsulinemia, as a compensatory mechanism to perturb glucose and fat metabolism, directly damages blood vessels and promotes atherosclerosis and other CVDs (182). Additionally, the reduced anti-inflammatory adipocytokines and hyperinsulinemia also reduce nitric oxide production, further enhancing vascular dysfunction. Insulin also inhibits lipoprotein lipase activity in adipocytes, increasing free fatty acid production, which leads to lipid deposition in vascular endothelium, heart, and other tissues (182).

Biological sex plays a complex role in how obesity influences the risk and severity of cardiometabolic diseases. Women have less VAT accumulation than men, however, they exhibit a stronger association between VAT and cardiometabolic risk compared to men (183). Consequently, while men generally exhibit a higher prevalence of certain metabolic conditions, women often face a greater subsequent risk of CVD outcomes, a phenomenon referred to as cardiometabolic paradox (184). For example, men with obesity have a higher prevalence of metabolic syndrome (MetS, 67%) than women with obesity (45%), particularly at a younger age (< 40 years) (185). Likewise, obesity is more strongly associated with dyslipidemia development in men than in women. While men with obesity had 2.7-fold higher odds of dyslipidemia than men without obesity, it is 1.5 times higher among women (186). In contrast, the obesity-associated relative risk of CVD is higher in women (64%) than in men (46%) (187). Sex differences are also evident in T2D, with men typically diagnosed at a younger age and with lower BMI, while in women T2D is associated with higher BMI and a greater obesity burden (188). Notably, a relatively small increase in VAT is associated with a substantially increased insulin resistance and risk of T2D in women compared to men (189). Collectively, these findings highlight that body fat distribution, rather than BMI alone, appears to be the key mediator of sex differences in cardiometabolic disease risk during obesity.

The risk of cardiometabolic diseases changes with age, particularly in females. For example, non-alcoholic fatty liver disease (NAFLD) is more prevalent in men than in women during pre-menopause, and the risk increases for women after menopause (190). Even in morbidly obese NAFLD patients, male gender is a strong predictor of advanced fibrosis, which is associated with unfavorable outcomes (191). The lower risk of NAFLD and cardiovascular disease in young adult women may be attributed to sex hormones and the pattern of adiposity. Abdominal obesity is a significant risk factor for CVD and increases in women after menopause. In premenopausal women, estrogen is protective and regulates liver metabolism and inflammation, which is lost after menopause (192).

9. Sex Differences in Gut Microbiome in Obesity

Gut microbiome plays a significant role in food digestion, nutrient synthesis, and energy metabolism; glucose, lipid, and other metabolic regulation; intestinal integrity and control of inflammation; and hormonal signaling, influencing the host’s metabolic health and disease (193). It differs between males and females, leading to sex-dependent changes in gastrointestinal inflammation, systemic immune responses, and varying susceptibility to inflammatory conditions (194). The composition and function of the gut microbiome are also altered during obesity, which directly impacts obesity-associated chronic inflammation and insulin resistance (193).

Sex differences in gut microbiota are better characterized in non-obese hosts and are evident throughout the lifespan (195). Sex difference is observed as early as the first 30 days of life, where male infants show a lower alpha diversity, less abundance of Clostridiates, and more abundance of Enterobacteriales (196). Sex difference is also observed in the gut microbiome of infants (3 – 4 months) born to mothers suffering from asthma, where male infants have fewer Lactobacillus in the gut than females (197). Pre-pregnancy overweight in mothers further reduces the abundance of Lactobacillus in male infants (197).

The gut microbiome changes significantly with the onset of puberty and in adulthood. Yuan et al. observed that the abundance of Clostridiales is reduced, and the abundance of Betaproteobacteria is elevated with the onset of puberty in humans (198). Studies in the mouse models have more clearly shown that sex-specific differences in gut microbiome become evident at puberty and increase with adulthood, and female mice exhibit higher alpha diversity (199, 200). In healthy adults, young adult women (20 – 45 years) have greater alpha diversity in comparison to men of the same age range. Such a difference is less pronounced in middle-aged adults and disappears around 60 years of age (201). Men with higher testosterone and women with higher estradiol exhibit greater gut microbial diversity. Testosterone in men correlates with Acinetobacter, Dorea, Ruminococcus, and Megamonas, whereas estradiol in women is associated with a Bacteroidetes-enriched and Firmicutes-depleted microbiota, including Slackia and Butyricimonas (202). Sex differences in gut microbiome are reversed by castration of male mice, suggesting the significant influence of androgens in gut microbiome (200). Moreover, transfer of male gut microbiota to naïve female mice significantly changes the recipient’s gut microbiota and boosts testosterone levels, indicating a crucial bidirectional link where gut microbes influence sex hormones and vice versa (199).

Gut microbiota also influences disease susceptibility in a sex-dependent manner. In a non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), female mice are more susceptible to disease than males, but such a difference disappears in germ-free conditions (199). Transfer of cecal contents from male mice protects females against T1D, associated with increased testosterone levels and abrogated after blocking androgen receptor activity, indicating direct effects of gut microbiota in modulating not only the sex hormones but also the progression of autoimmunity (199). Androgen-dependent effect in gut microbiota is also observed in another study where castration in males reverses the sex difference. Certain microbial lineages having higher abundance in males, potentially through androgen-associated expansion, protected them against T1D (200).

Sex difference is also observed in the gut microbiome of children with obesity. For example, a cross-sectional study on 188 Iranian elementary school children (aged 7–12 years) observed that Firmicutes is significantly higher, and the Bacteroidetes to Firmicutes ratio (B/F) is significantly reduced in children with obesity compared to normal weight children (203). This is mostly driven by differences in girls, who have significantly higher Firmicutes, reduced Bacteroidetes, and significantly lower B/F ratio, whereas boys only exhibit significantly higher Firmicutes levels (203).

Premenopausal and non-obese women differ from men in beta diversity and are enriched in beneficial taxa, including Christensenellaceae and short-chain fatty acid (SCFA)-producing species, while men are enriched in Prevotellaceae, Pasteurellaceae, and Clostridium species (204). Postmenopausal women exhibit gut microbiota shift towards a male-like profile. In premenopausal women, the gut microbiome contains a higher abundance of genes involved in steroid biosynthesis and metabolic pathways. However, obesity disrupts these sex-linked features, abolishing differences in beta diversity, taxonomy, functional pathways, and hormone-microbiota correlations (204).

Many human studies consistently show that individuals with obesity have a lower relative abundance of Bacteroidetes and a higher abundance of Firmicutes, leading to a higher Firmicutes/Bacteroidetes (F/B) ratio (205). A meta-analysis observed that adults with obesity have a lower relative abundance of Bifidobacterium and Eggerthella, and a higher relative proportion of Acidaminococcus, Anaerococcus, Catenibacterium, Dialister, Dorea, Escherichia-Shigella, Eubacterium, Fusobacterium, Megasphera, Prevotella, Roseburia, Streptococcus, and Sutterella in adults with obesity compared to non-obese adults (205). These microbial changes are mostly linked to increased energy harvest and metabolism, where Firmicutes and carbohydrate-fermenting genera extract calories more efficiently from food; reduced gut barrier function and increased inflammation, whereas lower Bifidobacterium levels impair gut barrier integrity; and increased bile acid and lipid metabolism (205).

A study in Chinese adults observed that higher BMI is associated with reduced Bacteroidetes, including Alistipes, Bacteroides, and Odoribacter, and increased Firmicutes, particularly Blautia, Dorea, and Prevotella abundance (206). Importantly, distinct sex-specific microbial signatures are observed, where females are enriched in Bacteroides, Parabacteroides, Clostridium, and Akkermansia, and show higher representation of microbial pathways involved in carbohydrate, glycan, and energy metabolism. In contrast, males display enrichment in microbial pathways related to nucleotide metabolism and cofactor/vitamin biosynthesis, suggesting differences in microbial functional capacity between sexes (206). Another larger study with 551 Chinese adults showed that underweight individuals exhibit higher alpha diversity than other BMI groups. When stratified by sex, females maintain this BMI-associated alpha diversity pattern, whereas males show no significant alpha diversity differences across BMI categories. Males with obesity exhibit an enrichment of Fusobacteria, while females with obesity show higher Actinobacteria abundance. Functional analysis reveals increased butyrate-acetoacetate CoA-transferase in individuals with obesity, suggesting enhanced energy accumulation, and elevated PhoH-like ATPase in males, indicating a male-specific tendency to harvest energy (207).

Animal models also reflect sex differences in the gut microbiome during obesity. For example, during HFD treatment, Bridgewater et al. observed that while 27 operational taxonomic units (OTUs) increased and 14 decreased in females, only 12 increased and 20 decreased in males in response to HFD treatment; nine of the OTUs decreased, and only the Lachnospiraceae increased in both sexes (208). In another study, male and female C57BL/6 mice showed distinct differences in both obesity outcomes and gut microbiota features after HFD treatment up to 17 weeks. Akkermansia was notably higher in females, particularly on HFD, which may be linked to their relative resistance to obesity, whereas males on HFD had higher levels of taxa like Peptococcus that have been associated with increased adiposity (209).

10. Contributors to sex differences in obesity

10.1. Hormonal regulation

Sex hormones are key regulators of immunometabolism and play significant roles in mediating sex differences in health and disease during obesity. Estrogen is critical for maintaining healthy adiposity both in males and females. Estrogen includes estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). Premenopausal women have markedly higher E2 levels than postmenopausal women and men. After the menopause, E2 levels decline sharply in women and are replaced by E1, while E3 and E4 are predominantly associated with pregnancy and fetal development (210). Estrogens mediate their effects through the estrogen receptor α (ERα), ERβ, and G protein-coupled receptor 1 (GPER-1), distributed in adipocytes, immune cells, and various organs. On the other hand, androgens refer to different male hormones, including testosterone, dehydroepiandrosterone (DHEA), and dihydrotestosterone (DHT), and they exert their physiological effects through androgen receptors (AR) (211).

Expression of hormone receptors differs between males and females. For example, in the C57BL/6 mouse model, males have significantly higher VAT but lower expression of ERα and ERβ in VAT compared to females (212). The lower receptor expression is associated with active autophagy and obesity-associated metabolic dysregulation in males. Deletion of the ERα and induction of estradiol signaling removes sex differences in adiposity, indicating the direct role of estrogen-mediated regulation (212). Mechanistically, ERα signaling prevents adipocyte dysfunction. For example, estrogen reduces adipose tissue inflammation and fibrosis by binding to ERα and upregulating the expression of prolyl hydroxylase 3 (Phd3), which in turn breaks down hypoxia-inducible factor 1 alpha (HIF-1α) that otherwise promotes adiposity and metabolic dysfunction (213). Likewise, ERα signaling activates the mTOR, which inhibits the activity of unc-51-like autophagy activating kinase (ULK1), a protein crucial for initiating autophagy, leading to suppression of autophagy and resultant VAT accumulation (212).

Estrogen has a protective role in adipose tissue. Estrogen promotes a less inflammatory adipose environment by inhibiting NF-κB signaling, reducing proinflammatory cytokine production, and promoting M2-like macrophages in VAT (214, 215). Estrogen also controls Treg distribution in adipose tissue, making females more protected from obesity-associated inflammation than males. In females with obesity, Tregs are maintained in VAT while decreasing in males, with studies showing that ovariectomy reduces the Treg numbers and estrogen replacement in females restores them (216).

Reduced estrogen levels in women increase the risk of visceral adiposity, and this can be reversed following estrogen supplementation (210). Obesity also alters estrogen balance. During premenopause, estrogen fluctuates and can dip, but postmenopause, while ovarian synthesis decreases, adipose tissue becomes the main estrogen source via aromatization, converting androgens into estrogens, which causes a higher overall increase in estrogen activity (210). ERα is central to estrogen’s anti-inflammatory effects in adipose tissue. ER-α signaling inhibits adipogenesis, whereas ER-β promotes browning. Consequently, females who have higher estrogen levels preferentially accumulate SAT, while males more readily develop VAT due to lower ER-α activity and circulating estrogen (210).

Low testosterone is both a cause and consequence of obesity. Testosterone is negatively associated with obesity development in men, and hormone therapy decreases adiposity (217). Men accumulate more VAT than women, due to lower ERα expression or signaling in VAT, and a differential AR expression pattern, which is higher in VAT. Testosterone inhibits adipogenesis and creates an anti-inflammatory environment by reducing leptin, TNF-α, IL-6, and IL-1β production, and maintaining Tregs, ILC2, and Th2 cells (217). Testosterone deficiency enhances inflammatory markers, adiposity, and obesity.

Gonadal hormones drive sex differences in adipose tissue accumulation. ERα knockout in rodents leads to adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose intolerance in both sexes (218). Likewise, ovariectomy increases VAT accumulation in females, while estrogen supplementation abolishes it (219). In men, low-level androgen is strongly correlated with increased VAT, a key feature of metabolic syndrome, creating a cycle where low testosterone promotes belly fat, and excess fat further lowers testosterone, impacting metabolism and insulin sensitivity (211). Likewise, male mice that lack AR signaling in the adipocytes exhibit a human T2D-like phenotype, with visceral adiposity, insulin resistance, and metabolic dysfunction following HFD treatment (220). Testosterone supplementation in castrated male mice inhibits the accumulation of VAT and SAT, while DHT selectively prevents SAT expansion, indicating differential regulation of obesogenesis by androgens (221). In women, hyperandrogenism in polycystic ovary syndrome (PCOS) promotes abdominal fat accumulation by antagonizing the protective androgen effects (222). Together, these findings show that male- and female-derived sex steroids distinctly regulate adipose tissue and metabolic outcomes.

10.2. Genetic and epigenetic regulation

The human X chromosome (~165 Mb, ~800 genes) is three times larger than the Y chromosome (~60 Mb). Although X-chromosome inactivation (XCI) balances gene expression, some genes escape XCI, contributing two copies of X-linked genes in females than in males, and subsequent sex-biased immune regulation (6). The escape from XCI could result in higher expression of various X-linked genes in females, contributing to sex differences in obesity and metabolic diseases (223). In humans and normal animal models, distinguishing the effects of sex steroids and chromosomal sex is difficult. Therefore, the four core genotype (FCG) mouse model is mostly used, in which mice with four different sexes are generated: XX or XY females with ovaries and XX or XY males with testes, enabling investigation of the effects of sex hormones by comparing gonadal males and females, and the effects of sex chromosomes by comparing XX and XY mice (223).

The FCG mouse model study, accompanied by other mouse models, shows that X chromosome dosage is the key driver of higher adiposity and weight gain, rather than the Y chromosome (224). During HFD treatment, XX mice gain higher body weight and develop greater adiposity and metabolic dysfunction, irrespective of the gonadal sex (224). Various genes that escape XCI, including Kdm5c, Ddx3x, Kdm6a/Utx, Eif2s3x, and Usp9x, are associated with mediating adipose inflammation and metabolic dysfunction during obesity (225). In humans, Kdm5c expression in adipose tissue correlates with BMI (226). In the mouse model, female adipose tissue and a variety of other organs have higher expression of Kdm5c than in males. Reducing the dose of the Kdm5c gene normalized body weight, food intake, and the process of adipocyte differentiation. Mechanistically, it influences chromatin accessibility and regulates genes related to the extracellular matrix, which are essential for the expansion of adipose tissue. Thus, Kdm5c contributes to sex differences in adipose tissue inflammation and obesity (226).

Utx or Kdm6a, which is a histone demethylase, is also strongly associated with obesity development and acts as an epigenetic regulator that influences fat storage, inflammation, and energy balance. Myeloid-specific knockout of Kdm6a in mice improves energy expenditure and thermogenesis, and eliminates HFD-induced obesity (227). Mechanistically, Kdm6a knockout downregulates the Inositol-requiring enzyme 1 alpha (Ire1α), which regulates macrophage polarization to M1 phenotype, driving accumulation of M2 macrophages and IL-10 synthesis (227). Kdm6a also regulates the expression of cryptochrome 1 (Cry1) in the hypothalamus, promoting leptin resistance and obesity (228). The higher expression of Kdma6 in XX females than in XY males is also linked to sex differences in autoimmunity (229). It displays sexual dimorphism in CD4 T cells, and its deletion reduces EAE severity by shifting Th1 to Th2 immunity and reducing neuroinflammation (229). Other X-linked genes, such as Ddx3x, are implicated in lowering lipid accumulation; Eif2s3x enhances adipogenicity, and Usp9x improves glucose metabolism (225). Likewise, emerging evidence suggests that several putative escape genes, including Xist, Ogt, 5-Htrc, and Tnmd, exert their own unique effects in mediating metabolic alterations during obesity (225). Moreover, several autosomal genes exhibit sex-dependent differential expression, which can also exert significant effects on sex differences observed during obesity (225).

The microRNAs (miRNAs) are also involved in mediating obesity pathophysiology, and several of them exhibit sex differences. Among Hispanic adolescents (13 – 17 years), miR-24–3p, miR-361–3p, and miR-3605–5p are downregulated and miR-486–5p and miR-199b-3p are upregulated in the blood samples of females with obesity (230). These miRNAs are linked to PI3K-Akt, AMPK, TGF-β, and lipolysis signaling pathways, which regulate energy balance, adipose tissue function, and metabolic health (230). Another recent study also shows that several miRNAs, including miR-148a-3p, miR-503–3p, miR-34a-5p, and miR-199a-3p, are significantly downregulated in patients with obesity compared to those who are overweight (231). Additionally, males preferentially downregulated miRNAs associated with insulin sensitivity and vascular risk, while females had a prominent loss of miR-503–3p, a regulator of adipogenesis and angiogenesis (231). Many other miRNAs are upregulated (e.g., miR-29a, miR-138–5p, miR-378a), while others are downregulated (e.g., miR-143, miR-126) during obesity and influence adipose inflammation, macrophage polarization, and insulin resistance (232).

Long noncoding RNAs (lncRNAs) also regulate adipocyte development and function, influencing epigenetic, transcriptional, and post-transcriptional levels (233). Males and females with obesity show distinct transcriptional profiles of lncRNAs in SAT (234). The differentially expressed lncRNAs are associated with pathways such as MAPK, Wnt, and glycosylation, indicating sex-specific regulation of adipose inflammation and immune responses. A recent study shows that lncRNA29RIK increases the susceptibility to HFD-induced obesity by promoting lipopolysaccharide-induced caspase activation, amplifying IL-1β-driven inflammation and pyroptosis of macrophages (235).

Conclusion

Obesity is more prevalent in females, and they also have a higher total body fat percentage than males. However, females accumulate more SAT, whereas males store more VAT. Male VAT exhibits a more pronounced pro-inflammatory immune profile, characterized by M1-like macrophage polarization, inflammasome activation, accumulation of Th1/Th17 cells, and loss or functional impairment of Tregs, accompanied by increased local and systemic levels of adipocytokines, such as TNF-α, IL-6, IL-1β, and leptin. Because VAT is a major driver of obesity-associated immune and metabolic dysregulation, the expansion of SAT in females is considered relatively metabolically protective, supported by estrogen and adiponectin-mediated promotion of M2-like macrophage polarization, preservation of Treg function, and anti-inflammatory immune responses.

Sex differences in obesity-associated infectious disease risk and metabolic dysregulations are largely dependent on differential adipocyte biology and systemic chronic low-grade inflammation. For example, the low VAT and high SAT accumulation contribute to a relatively lower cardiovascular disease risk in premenopausal females compared with males. However, loss of estrogen-mediated protection after menopause increases the metabolic disease risk in females and is accompanied by greater sensitivity to visceral adiposity. While both BMI and VAT predict cardiometabolic diseases in males, VAT is a stronger predictor in females. It also highlights that body fat distribution, rather than BMI alone, is equally important in mediating sex differences.

Sex differences are driven by sex steroids and genetic and epigenetic factors that impact insulin resistance. Gonadal hormones directly influence the pattern of adipose tissue distribution, its inflammation, and immune cell activation. Likewise, emerging evidence demonstrates significant contributions of genes that escape XCI (e.g., Kdm5c, Kdm6a), and epigenetic regulators such as microRNAs and lncRNAs in contributing to sex differences. The use of FCG and similar mouse models has also helped in teasing apart the contribution of gonadal sex versus chromosomal complement in mediating sex differences during obesity. Studies indicate that gut microbiome composition differs between males and females with obesity, and there is a bidirectional link between gut microbes and sex hormones. However, how these differences translate into infectious diseases, autoimmune disease risk, and other metabolic outcomes remains poorly understood and warrants further investigation.

Obesity increases the risk and severity of various autoimmune diseases. In healthy-weight individuals, females generally exhibit a higher prevalence of autoimmune diseases, partly because estrogen enhances adaptive immune responses and modulates central tolerance. Although it remains underexplored, emerging evidence suggests that obesity can exacerbate autoimmune disease risk and severity in a sex-specific manner. For example, obesity may increase the risk of RA and SLE in females, but it may cause greater SLE severity in males. Likewise, the risk of developing MS and certain thyroid disorders may be higher in females, and that of psoriasis may be greater in males. Obesity also increases the risk of several cancers in a sex- and age-dependent manner. However, substantially more research is needed to clarify these differences in a context-dependent manner, and particularly considering occasionally protective associations of obesity observed in adult females.

In non-obese settings, sex differences have been most extensively investigated in the context of viral infections and autoimmunity, with influenza virus pathogenesis and vaccine efficacy serving as the prominent examples. Yet, our review highlights a substantial gap in understanding sex differences in influenza pathogenesis and vaccine responses in the population with obesity. This limitation extends to other viral infections, such as COVID-19. Many studies either include only one sex, lack balanced sample size, or do not stratify data by biological sex and gender.

Practical limitations in animal models may also further contribute to these gaps in preclinical research. For instance, female mice on HFD do not consistently develop obesity to the same extent as males, leading to a bias toward the exclusive use of male mice. Although thermoneutral housing can enhance obesity development in female rodents, its effects on physiological and immune responses require context-specific consideration. Likewise, ferrets used in infectious disease research are often neutered, limiting their utility for studying the combined effects of sex steroids and genetic factors. Additionally, the preclinical DIO studies relying on inbred strains may not adequately capture the genetic diversity present in human populations with obesity. Cross-bred populations, such as the collaborative cross, may provide a useful platform to address such limitations by incorporating genetic diversity.

As discussed, available evidence demonstrates that males and females with obesity differ in infectious disease risk, vaccine-induced immunity, autoimmune disease risk, and cardiovascular outcomes. Sex differences in gut microbial composition, sex steroid signaling, and genetic and epigenetic regulation of immune cells play crucial roles in shaping immune responses during obesity. These factors vary between males and females, throughout their lifespan, further complicating immune and metabolic outcomes in obesity. Despite increased inclusion of both sexes in research in recent years, sex-specific immune effects of obesity in infectious and non-infectious diseases remain poorly characterized. Therefore, preclinical, clinical, and epidemiological studies should prioritize balanced inclusion of males and females and segregation of data by sex and gender. Integration of genetic, microbial, and hormonal perspectives in scientific research will enable the identification of mediators of sex differences in obesity-associated metabolic dysfunctions. These approaches are essential for developing personalized therapeutic strategies and improving care for the growing global population living with obesity.

Data availability statement

No data was generated in this study.