Sex and Gender Differences in Obesity: Biological, Sociocultural, and Clinical Perspectives

Abstract

Sex and gender differences significantly influence the prevalence of obesity, patterns of fat distribution, metabolic health outcomes, and responses to treatment. While women generally exhibit a higher overall prevalence of obesity, men are more susceptible to visceral fat accumulation, which increases the risk of cardiovascular disease (CVD), type 2 diabetes, and other obesity-related complications. This review examines the biological, genetic, and sociocultural foundations of sex-based differences in obesity. Estrogen plays a crucial role in regulating subcutaneous fat deposition and brown adipose tissue (BAT) activity in women, whereas men tend to accumulate more visceral fat and demonstrate reduced BAT thermogenic function. Genetic investigations, including genome-wide association studies, have identified sex-specific loci associated with central adiposity and fat metabolism. Additionally, emerging research indicates distinct gut microbiome profiles between obese men and women. Sociocultural and psychosocial factors, such as gender norms, body image perception, and healthcare-seeking behavior, also influence the risk and management of obesity. Women are more inclined to seek treatment and participate in structured weight-loss programs, while men often face under diagnosis due to stigma and limited healthcare access. These sex-based differences are evident in comorbidities, with women being more vulnerable to obesity-related cancers and mental health disorders, whereas men experience an earlier onset of CVD and diabetes. Despite these distinctions, most obesity interventions lack gender-specific considerations. This review underscores the necessity for sex- and gender-tailored strategies in the prevention, diagnosis, and treatment of obesity. A more nuanced understanding of these differences can improve clinical outcomes and inform policy development for equitable obesity care.

INTRODUCTION

The World Obesity Atlas 2023 reports that 14% of men and 18% of women over the age of 20 years are classified as obese, with this gender disparity expected to persist [1]. A recent analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 further corroborates that obesity prevalence is consistently higher among women than men across all super-regions, with the gender gap being more pronounced in low- and middle-income countries [2]. Despite these findings, there remains a paucity of research dedicated to developing sex- and gender-specific strategies for obesity prevention and treatment.

While obesity prevalence is higher in women and is a significant risk factor for non-communicable diseases (NCDs), NCD prevalence is lower in women than men [3]. This discrepancy is thought to be linked to sex-specific patterns of fat distribution, with men accumulating more visceral adipose tissue (VAT) and women having more subcutaneous fat deposits [4]. Additionally, the higher activity of brown adipose tissue (BAT) in women may contribute to their lower prevalence of NCDs [5].

The influence of sex hormones, particularly estrogen, is the most widely accepted explanation for these differences. However, emerging evidence from genome-wide association studies (GWAS) suggests that genes located on both sex chromosomes and autosomes also play a role in sex-specific differences in obesity phenotypes and related disease morbidities.

Moreover, sociocultural factors experienced by men and women, which have been relatively underexplored in research, must be considered to fully understand the disparities in the prevalence of obesity. A study investigating the relationship between obesity and education by gender found that the association between lower education levels and obesity was stronger in women than in men [6]. The prevalence of overweight and obesity is further exacerbated among women in developing countries compared to those in developed countries [7].

This review synthesizes recent studies on the biological and sociocultural factors contributing to gender differences in obesity prevalence. It aims to provide essential information for the development of gender-specific obesity management policies and proposes directions for future research.

BIOLOGICAL BASIS OF SEX DIFFERENCES IN OBESITY

Compared to men, women have a higher percentage of body fat and tend to store it differently, with more adipose tissue accumulating in the hips and thighs. Furthermore, the activity of BAT is higher in women than in men, and the aforementioned characteristics contribute to the increased risk of metabolic disorderrelated health problems in men compared to women [8]. By understanding the molecular mechanisms underlying these differences and their impact on metabolism, we can optimize the prevention and treatment of obesity and related NCDs based on sex- and gender-specific characteristics.

1. Why women and men have different proportions of subcutaneous and visceral fat?

Body fat tissue not only serves as the body's most efficient energy storage system but also acts as an endocrine organ, producing hormones and hormone-like substances that influence various metabolic processes.

Women generally have a higher proportion of subcutaneous fat, while men tend to accumulate more visceral fat, making them more susceptible to metabolic imbalances (Fig. 1). The increased accumulation of subcutaneous adipose tissue (SAT) in women is thought to support efficient lipid mobilization, particularly during periods of high-energy demand such as lactation [9]. These differences become especially pronounced with the onset of puberty [10]. The excessive accumulation of total body fat and VAT is closely associated with the development of metabolic disorders, including insulin resistance, metabolic syndrome, fatty liver disease, and hypertension. In contrast, the expansion of SAT is well known to have a protective effect, helping to reduce insulin resistance and the risk of type 2 diabetes [11].

Fig. 1. Distribution of body fat in males and females. Males predominantly accumulate visceral adipose tissue (VAT), which contributes to an increased metabolic risk. In contrast, females tend to accumulate subcutaneous adipose tissue (SAT), which is associated with improved insulin sensitivity. These patterns are influenced by variations in sex hormone profiles, such as estrogen and testosterone, as well as sex-specific genetic regulation of adipose tissue. EFEMP1: EGF containing fibulin-like extracellular matrix protein 1, GRB14: growth factor receptor-bound protein 14, NID2: nidogen 2, RSPO3: R-spondin 3, VEGFA: vascular endothelial growth factor A.

1) Estrogen in sex-specific fat distribution

The primary factor driving sex-specific differences in fat distribution is estrogen [12], and this has been proven in studies comparing premenopausal and postmenopausal women. After menopause, the SAT to VAT ratio decreases, highlighting the impact of estrogen on fat distribution. An earlier study using dual-energy X-ray absorption measurements in non-obese healthy women indicated that postmenopausal women (n=70) had 20% more fat mass than premenopausal women (n=61) [13]. Another study showed that the number of years since menopause was positively correlated with fat tissue mass, body fat percentage, abdominal fat percentage, and the ratio of abdominal fat to total body fat [14]. Furthermore, postmenopausal women showed increased lipid accumulation in the liver and muscle compared to premenopausal women, accompanied by a decline in insulin sensitivity. This phenomenon was closely linked to previously discussed ectopic lipid deposition [15].

The effects of hormones on fat distribution have been well demonstrated in various animal studies. Ovariectomy (OVX) led to a significant increase in total body fat, with pronounced accumulation in the VAT compared to non-ovariectomized controls. However, when 17β-estradiol was administered to ovariectomized animals, a reduction in total body fat and an increase in SAT were observed [16]. OVX-induced estrogen depletion led to adipocyte hypertrophy in both visceral and SATs. However, supplementation with 17β-estradiol in OVX mice mitigated adipose tissue fat accumulation, partially through the regulation of adipose differentiation-related proteins, with a more pronounced effect in VAT than in SAT [17]. In addition, clinical studies have shown that subcutaneous and visceral preadipocytes from women exhibit a greater proliferative response to 17β-estradiol stimulation than those from men. Notably, neither estrone nor dihydrotestosterone has demonstrated sex- or site-specific effects on preadipocyte proliferation rates [18].

Endogenously produced estrogens include estrone, estriol, and estradiol, with estradiol exhibiting the highest biological activity. Estradiol binds to estrogen receptors (ER)α and ERβ with similar affinities, subsequently inducing epigenetic regulation and gene expression changes that mediate its effects across various tissues. In particular, estrogen-ERα signaling has been shown to differ significantly between SAT and VAT, as well as between men and women. Previous studies indicate that lipoprotein lipase, an enzyme essential for lipid storage by processing circulating fatty acids and triglycerides (TG), exhibits higher activity in SAT in women, whereas in men, its activity is more prominent in VAT [19]. Since ERβ counteracts the effects of ERα, a higher ERα/ERβ ratio in abdominal visceral fat helps restrict fat accumulation in this depot, whereas a lower ERα/ERβ ratio in gluteal fat creates a more favorable environment for adipose storage in overweight to obese premenopausal women [20]. In male mice, the relative deficiency of ERα in visceral fat predisposes them to a greater accumulation of visceral fat. Furthermore, the deletion of ERα from adipocytes in both sexes leads to increased adiposity, specifically in the visceral fat depot [21]. The anti-obesity effects of β-ligands result from indirect peroxisome proliferator-activated receptorγ antagonistic actions through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor γ [22]. In female SAT, this effect has been reported to be associated with an increase in antilipolytic α-adrenergic receptors [23].

2) Genomics in sex-specific fat distribution

The primary factor influencing sex-based differences in fat distribution is the role of sex hormones, particularly estrogen. However, the observation that differences in fat accumulation emerge before the onset of secondary sexual characteristics suggests the involvement of mechanisms other than sex hormones [24,25]. Notably, recent studies using obese mouse models have reported that variations in the number of X and Y chromosomes contribute to sex-specific differences in obesity-related traits. Independent of gonadal steroids, the number of X chromosomes has been shown to contributes to sex-specific differences in obese mice [26]. Additionally, in men with the XYY karyotype, a trend toward increased central adiposity has been observed [27].

As mentioned earlier, the distribution of body fat, rather than total fat mass, plays a crucial role in determining metabolic outcomes. VAT accumulation is associated with an increased risk of cardiovascular disease (CVD), diabetes, and insulin resistance. In contrast, SAT appears to lower these risks. Consequently, there is broad consensus that women have greater protection against these conditions than men [28]. Recently, significant efforts have been made to map the genetics of beneficial adipose traits and explore the underlying mechanisms driving sex-specific genetic links to central obesity and fat distribution.

GWAS based on large-scale single-nucleotide polymorphism combined with metabolic traits, including MRI data, reported 14 alleles associated with higher adiposity but a favorable metabolic profile [29]. Many of these alleles were associated with a lower SAT to VAT ratio. However, few studies have reported sexual dimorphism in central obesity loci. Among various anthropometric traits used to assess obesity, those exhibiting clear sexual dimorphism (greater in women than in men) in heritability scores include the waist-to-hip ratio (WHR), WHR adjusted for body mass index (BMI) (WHRadjBMI), WC adjusted for BMI (WCadjBMI), and HIP adjusted for BMI (HIPadjBMI) [30]. A genome-wide interaction meta-analysis provided evidence for sex-specific genetic influence on central obesity and fat distribution. A meta-analysis of data from the GIANT consortium revealed that seven loci (near RSPO3, VEGFA, GRB14, LYPLAL1, HOXC13, ITPR2-SSPN, and ADAMTS9) showed a stronger association with WHRadjBMI in women than in men [31]. Among 44 loci identified with sex-specific effects, 28 exhibited stronger effects in women, 5 showed greater effects in men, and 11 displayed opposite effects between sexes. A meta-analysis incorporating GWAS data from 57 cohort studies and Metabochip data from 44 cohorts (n=210,088) identified 49 genes significantly associated with WHRadjBMI [32]. Of these, 19 genes (PLXND1, NMU, F AM13A, MAP3K1, HMGA1, NK X2-6, SFXN2, MACROD-1VEGFB, CMIP, BCL2, SNX10, LYPLAL1, GRB14-COBLL1, PPARG, ADAMTS9, TNFAIP8-HSD17B4, VEGFA, RSPO3, and HOXC13) exhibited stronger effects in women, while a single gene showed stronger effects in men. Other studies indicated that the association of rs3791679 near EFEMP1 with WCadjBMI was stronger in men, whereas the association of rs1982963 near NID2 with WHRadjBMI was stronger in women among individuals of East Asian ancestry [33]. A recent meta-analysis of GWAS for body fat distribution in 694,649 individuals of European ancestry identified 63 signals in 346 loci associated with WHRadjBMI, with one-third of the signals being sexually dimorphic [34]. Heritability and variant effects are generally stronger in women than in men. Genetic association with body fat distribution was measured using bioelectrical impedance analysis in 362,499 individuals from the UK Biobank [35]. Among 98 independent associations, 37 associated variants were stronger in females. Genes and pathways associated with these loci in women’s body fat distribution have been linked to mesenchymal-derived cells, extracellular matrix deposition, and remodeling, as well as female endocrine tissues. These findings suggest potential mechanisms that influence the distribution of adipose tissue, specifically in women. The most recent GWAS of body fat percentage based on UKBiobank data found 195 and 174 loci, with only 38 loci common to both sexes [36]. These large GWAS suggest a broad, but still poorly defined, causal genetic program for central obesity and related CMD, and importantly for observed sex differences in fat distribution phenotypes.

2. Why do women exhibit higher brown adipose tissue activity than men?

Body fat tissue is primarily classified into white adipose tissue (WAT) and BAT. WAT stores fat in the form of TG within a single large droplet inside white adipocytes, which can be used when energy is required. In contrast, BAT is composed of brown adipocytes that contain multiple small TG droplets rather than a single large droplet. Notably, brown adipocytes have a high mitochondrial density and utilize uncoupling protein 1 (UCP-1) to facilitate heat production [37]. The distribution of BAT and WAT in humans is similar in both men and women, with BAT primarily located in the supraclavicular region [38]. However, women have a greater amount of BAT with higher activity per unit of weight (Fig. 2) [39]. Additionally, UCP-1 expression is more pronounced in women than in men [40]. In high-fat diet-fed animals, female mice exhibited greater vascularization in perigonadal WAT than male mice. Additionally, browning of the tissue was observed, which was associated with an increase in UCP-1 expression [41]. Moreover, when a high-fat diet was provided instead of a low-fat diet, complex I and II respiration in BAT mitochondria increased in female mice. However, this adaptation has not been observed in male mice [42]. As an increase in BAT was associated with improvements in blood glucose, TG, and high-density lipoprotein (HDL) cholesterol [43], differences in BAT volume may be one of the factors contributing to the sex-specific differences in the incidence of type 2 diabetes and CVD.

Fig. 2. Sex-specific disparities in brown adipose tissue (BAT). Distinct sex-related differences in BAT are observed, wherein androgens inhibit BAT activity, whereas estrogen enhances both BAT activity and the browning of white adipose tissue. These differences are influenced not only by hormonal factors but also by genetic elements, including the increased expression of the X-linked gene KDM5C in females and the male-specific effects resulting from the deletion of the GHSR gene. AMPK: AMP-activated protein kinase, ANP: atrial natriuretic peptide, AR: adrenergic receptor, BNP: B-type natriuretic peptide, CXCL14: C-X-C motif chemokine ligand 14, FFA: free fatty acids, GHSR: growth hormone secretagogue receptor, H3K4: histone 3 lysine 4, KDM5C: lysine demethylase 5C, miR: microRNA, UCP-1: uncoupling protein 1.

BAT adipocytes contain β-adrenoreceptors (β1-AR, β2-AR, and β3-AR), that enhance adenylyl cyclase activity, and α2-AR, which inhibits it. The balance between these receptors plays a crucial role in determining UCP-1 expression [44]. Female rodents have lower α2-A expression compared to males, resulting in a reduced α2-A/β3-AR ratio. This leads to superior mitochondrial function, making catabolic metabolism more efficient [45].

1) Estrogen and brown adipose tissue

Previous studies have examined the role of estrogen in enhancing BAT activity. Estrogen promotes WAT browning by increasing UCP-1 expression in WAT through the secretion of arterial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [46,47]. Several studies have found that premenopausal women have higher blood levels of ANP and BNP than men. This difference is thought to contribute to sex-specificity in BAT accumulation and energy metabolism [10]. Activation of the ERα in adipocytes has been found to enhance the expression of beiging-related genes. Furthermore, restoring ERα in ERα knockout mice stimulated AMP-activated protein kinase (AMPK) and adipose tissue TG lipases, increasing the availability of free fatty acids (FFA), which in turn promoted UCP-1 activation [48]. Notably, when excess energy was provided through a high-fat, high-carbohydrate diet, the increase in BAT temperature was more pronounced in women than in men [49]. When estrogen was administered to OVX mice on a high-fat diet, an increase in STAT3 mRNA, which is involved in brown adipocyte differentiation within the VAT, was observed. Additionally, there was an upregulation of UCP-1 protein, along with its regulatory genes dio-2 and adreβ3 mRNA, as well as CPT-1b expression, a BAT-specific enzyme involved in fatty acid oxidation [50]. Furthermore, ERα was observed to modulate DRP-1, a key regulator of mitochondrial remodeling, and downregulate the expression of genes involved in mitochondrial biogenesis, such as Pgc1b, Nrf1, and Polrmt [51]. Meanwhile, several miRNAs regulated by estrogen have been identified as playing a role in brown adipogenesis. Examples include miRNA-196a and miRNA-455, which are present in both WAT and BAT [52].

Unlike estrogen, androgens are known to suppress BAT activity [53]. Meanwhile, a recent human study found that women exhibit a greater thermogenic response to cold exposure and meal challenges than men [49].

2) Genomics in sex-specific BAT activity

Similar to the distribution of body fat, differences in the quantity and function of WAT and BAT between sexes are determined not only by sex hormones but also by genetic differences, including the presence of the XY chromosome. A recent study demonstrated that KDM5C, an X escape gene, is more highly expressed in individuals with XX chromosomes (i.e., females) [54]. This gene regulates H3K4 methylation and UCP-1 gene expression in BAT, thereby enhancing thermogenic activity, which helps explain the sex differences in BAT activity. In contrast, deletion of the ghrelin receptor (GHSR) gene led to reduced food intake only in male rats, along with an increase in thermogenesis observed exclusively in males. This suggests that GHSR functions as a male-specific gene that influences sex differences in BAT activity [55]. A recent cohort study of infants in their first year of life revealed that posterior cervical BAT exhibited greater activity in girls than in boys. Moreover, BAT activity was inversely related to adiposity parameters only in girls. This study also identified a positive correlation between serum CXCL14 levels and BAT activity in the posterior cervical and supraclavicular regions. Additionally, neonatal BAT demonstrated elevated CXCL14 expression [56]. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone released in response to metabolic stress, helping to restore metabolic balance in WAT, BAT, liver, and muscle, while also regulating food intake through taste modulation. Notably, in diet-induced obese mice, FGF21 injection resulted in lower WAT mass in females than in males, accompanied by reduced blood glucose, cholesterol, and insulin levels. Furthermore, increased expression of Dio2 in BAT and of Pparg, Lpl, and Lipe in WAT has been observed exclusively in females, underscoring the role of these genes in metabolic homeostasis [57]. Analysis of 732 study participants in the SOS Sub-Pair study revealed that metabolic efficiency per unit of adipose tissue was significantly higher in women than in men. This difference was linked to the elevated expression of genes associated with mitochondrial function in adipose tissue, indicating a pronounced mitochondrial gene signature in women. Notably, the expression of UCP-1, a key brown adipocyte marker, was found to be five times higher in women than in men [58].

SEX DIFFERENCES IN OBESITY AND GUT MICROBIOME

It remains unclear whether differences in the composition or proportions of specific microbes or microbial communities influence sex differences in obesity or whether biological differences in male and female obesity drive changes in the gut microbiota. Kaliannan et al [59] conducted a series of experiments to explore the mechanisms underlying sex differences in obesity and susceptibility to metabolic syndrome. Their study revealed that the gut microbiota mediates the effects of estrogen, contributing to sex-specific variations in obesity and metabolic syndrome markers. Estrogen has been found to reduce Proteobacteria levels and suppress bacterial lipopolysaccharide synthesis. However, a study examining sex-specific differences in obesity after depleting the gut microbiota with antibiotics in male and female mice fed a high-fat diet found that sex-specific obesity traits persisted even after microbiome depletion [60]. This suggests that gut bacteria are not causally linked to sex differences in obesity. A cross-sectional study using 96 men and 116 women found that there are sex-specific microbiome signatures contributing to obesity, despite males and females having similar gut microbiome characteristics, including overall abundance and diversity. The genera Bacteroides, Absiella, Holdemanella, and Gemmiger were positively associated with android fat ratio in men, whereas Bacteroides, Paraprevotella, Clostridium_IV, and Gemmiger had negative associations with android fat ratio in women [61].

GENDER INFLUENCES ON OBESITY

1. Sociocultural and behavioral factors

Obesity patterns are heavily influenced by sociocultural norms and gender roles. Research indicates that women with traditional gender role attitudes are more likely to become obese due to reduced economic opportunities and limited workforce participation, whereas men remain largely unaffected [62]. Cultural norms also play a significant role in shaping dietary preferences [63]. Men tend to favor animal-based proteins that are culturally associated with masculinity and muscle development [64]. In contrast, women often choose healthier options, such as vegetables, influenced by health awareness and societal pressure to maintain a certain weight [65]. These gender-based preferences are also evident in children, with girls showing a preference for fruits and vegetables, while boys lean towards meat and high-fat foods, exhibiting stronger appetite responses and reduced sensitivity to feelings of fullness [66]. Social connections also play a significant role in obesity outcomes. A long-term study highlighted marital status and social relationships as crucial factors [67]. These findings indicate that individuals who experienced divorce or widowhood faced a higher risk of obesity. Interestingly, women who became single during the study period were less likely to develop obesity than those who remained married. Moreover, the study revealed that poor social connections over time were strongly associated with an increased obesity risk, particularly among men. Infrequent interactions with friends and weaker social ties further increased this risk, with the effects being more pronounced in men than in women.

2. Treatment-seeking behavior and healthcare accessibility

Gender disparities significantly affect access to healthcare and weight loss resources for obesity. Men and women face different challenges owing to societal norms, healthcare provider biases, and systemic barriers. Research shows that women are more likely to seek obesity treatments, such as bariatric surgery, accounting for 80% of patients [68]. This disparity stems from cultural beliefs, social pressure to meet ideal body standards, and healthcare provider prejudice. Conversely, men encounter stigma and insufficient outreach, reducing their likelihood of pursuing such interventions [69]. Weight-related stigma plays a crucial role in healthcare accessibility, with individuals often avoiding medical care because of fear of judgment. Women report higher rates of discrimination in healthcare settings, leading to delayed treatment, whereas men frequently internalize societal expectations of self-reliance, making them less likely to access medical help [70]. In developing countries, women encounter significant barriers to healthcare, including limited education, financial difficulties, and cultural restrictions. These systemic challenges often lead to delayed diagnosis and treatment, worsening obesity-related health risks in women. To reduce these disparities, gender-specific strategies such as targeted education programs, policy reforms, and culturally inclusive healthcare practices are essential. Improving equal access to weight loss resources can ultimately enhance health outcomes for both men and women.

3. Psychosocial factors

Psychosocial factors play a pivotal role in shaping dietary habits and influencing treatment outcomes across genders. Several studies have shown that women tend to engage in more frequent snacking and meal skipping, which is often driven by societal pressure related to weight control [65,71]. One study revealed that women who maintain regular and structured eating habits tend to have better health outcomes, whereas women who eat impulsively and men who eat irregularly are more likely to have higher body fat percentages [72]. Furthermore, gender differences in body image perception are apparent, with girls experiencing a notable increase in body dissatisfaction during early adolescence, whereas boys tend to show a decrease. These disparities were strongly connected to lack of parental support, negative emotional states, and self-reported dietary restraint but not to ideal body internalization, BMI, or eating disorders [73]. For both men and women, uncontrolled and emotional eating were key factors connecting perceived stress to dietary risks. However, higher sleep quality was found to reduce this connection only in females. Similarly, emotional eating influenced the relationship between perceived stress and BMI, with improved sleep quality weakening this association exclusively in females, indicating gender-specific psychological effects on body weight [74].

SEX AND GENDER DIFFERENCES IN OBESITY-RELATED COMORBIDITIES

The global rise in obesity represents a substantial health challenge, primarily due to its strong association with obesity-related comorbidities, including CVD, type 2 diabetes, mental disorders, and cancer (Fig. 3) [75]. Recent studies reveal significant sex differences in the prevalence and outcomes of these obesity-related comorbidities [76]. These disparities are driven by complex interactions among biological, metabolic, and behavioral factors.

Fig. 3. Sex-specific associations between obesity and major comorbidities. Obesity is implicated in various chronic conditions, exhibiting distinct patterns between males and females. Obese males are at an elevated risk for coronary heart disease (CHD), hypertension, and cancers of the colorectal, kidney, and esophagus, and they tend to develop type 2 diabetes at a lower body mass index (BMI) and an earlier age. Conversely, obese females demonstrate a heightened risk for heart failure (HF) and cancers of the endometrium, ovary, and breast, and they are more likely to develop diabetes at a higher BMI with increased insulin resistance. Furthermore, depression and anxiety are more prevalent among obese females compared to their male counterparts. CVD: cardiovascular disease, VAT: visceral adipose tissue.

1. Cardiovascular disease

Obesity is a well-established risk factor for CVD; however, its impact differs between men and women. While men have a higher absolute CVD risk, sex differences in lipid profiles influence cardiovascular outcomes [77]. Women with obesity tend to have lower HDL and higher TG levels than non-obese women, thereby increasing the risk of CVD [78]. In contrast, obese men are more likely to develop hypertension and dyslipidemia at an earlier age, leading to a higher prevalence of coronary heart disease (CHD) during early adulthood [79]. Obesity has also been identified as a significant risk factor for heart failure (HF). An analysis of 5,881 participants from the Framingham Heart Study revealed that each 1-unit increase in BMI was associated with a 5% higher incidence of HF in men and a 7% increase in women [80]. These sex-based disparities in cardiovascular risk factors are also evident in adolescents. Boys with obesity tend to exhibit greater arterial thickness and early signs of atherosclerosis, whereas girls are more prone to developing metabolic syndrome, which further compounds their long-term CVD risk [81].

2. Type 2 diabetes

Men tend to develop type 2 diabetes at a lower BMI, but accumulate higher levels of visceral fat, which is strongly associated with insulin resistance. The inverse relationship between BMI and age at diagnosis is more pronounced in women than in men, suggesting that younger women with type 2 diabetes tend to have significantly higher BMIs than their male counterparts [82]. Additionally, at the time of diagnosis, women exhibit higher levels of insulin resistance, as measured by HOMA-IR, than men. Despite their higher BMI, women with type 2 diabetes are diagnosed at an older age than men, further emphasizing the delayed onset of the disease in women relative to their weight status [83]. The later onset of type 2 diabetes in women may be linked to the regulatory role of estrogen in maintaining insulin sensitivity before menopause. However, following menopause, a decline in estrogen levels contributes to increased insulin resistance, which may contribute to disease progression [84].

3. Mental health

Obesity is significantly associated with mental health disorders, including depression and anxiety. Studies indicate that individuals with obesity have a significantly higher prevalence of depression and anxiety than those with normal weight. Depression severity is positively correlated with increasing obesity levels [85]. A systematic review and meta-analysis confirmed a significant association between obesity and anxiety disorders. This association is observed in both men and women, but the risk is notably higher in females, possibly due to social and psychological stressors. Furthermore, severe obesity (BMI >35 kg/m²) exacerbates mental health risks, particularly in women [86]. Women with obesity are at a significantly higher risk for depression than men, largely due to body image dissatisfaction and social stigma. Emotional eating is a common coping mechanism among obese women, whereas men tend to engage in externalizing behaviors, such as substance use [87]. Biological mechanisms, including hormonal differences and inflammatory responses, may contribute to the sex disparities in obesity-related mental health problems. Psychological factors, such as self-esteem and perceived discrimination, play a critical role in mediating this relationship. Addressing body image concerns and societal stigma is crucial for mitigating mental health burdens in obese individuals [88].

4. Cancer

A study using the US Cancer Statistics database revealed that excess body weight was responsible for approximately 37,670 new cancer cases in men and 74,690 in women each year between 2011 and 2015 among individuals aged 30 and older. The proportion of cancers linked to excess weight varied by type, with the highest percentages observed in liver or gallbladder cancer (51% in women and 48.8% in men) and endometrial cancer (49.2% in women). Additionally, esophageal adenocarcinoma accounted for 30.6% of obesity-related cancers in men [89]. On a global scale, research published in 2019 found that approximately 3.9% of all cancer diagnoses in 2012 were associated with excess body weight, with a greater burden observed in women [90]. Women face a higher risk of obesity-related cancers, such as endometrial, ovarian, and postmenopausal breast cancers, whereas men are more affected by colorectal, kidney, and esophageal adenocarcinoma [91,92]. Women with a BMI between 30 and 34.9 kg/m² have an 18% higher risk of developing cancer compared to those with a BMI under 25 kg/m², with the risk escalating to 62% for women with a BMI of 40 kg/m² or higher [93]. In men, a BMI of 30 to 34.9 kg/m² is associated with a 9% increase in cancer risk, rising to 52% for those with a BMI of 40 kg/m² or more. These disparities may be attributed to differences in fat distribution, hormonal profiles, and metabolic factors. For instance, adipose tissue contributes to estrogen production, which is linked to an increased risk of breast, endometrial, and ovarian cancers in women [94,95,96,97]. Conversely, in men, obesity is associated with elevated insulin and insulin-like growth factor-1 levels, which may promote the development of colorectal and kidney cancer [98].

IMPLICATIONS FOR PREVENTION AND TREATMENT

Sex differences in obesity have significant implications for both prevention and treatment strategies, necessitating a personalized approach to obesity management. Biological factors, such as hormones and genetics, as well as behavioral distinctions between men and women contribute to sex differences in obesity prevalence, comorbidities, and treatment responses.

Preventive strategies must consider sex-specific social and psychological factors, as women are more often encouraged to adopt weight-loss behaviors [99], whereas men tend to avoid support services because of perceived misalignment with their identity or lifestyle [100].

In terms of treatment, lifestyle interventions, including diet, physical activity, and behavioral support, are fundamental. While women are more than twice as likely to participate in structured weight management programs, men tend to rely on self-directed approaches [101]. This difference may be attributed to higher levels of weight dissatisfaction among women, in addition to societal perceptions that women are more motivated to engage in weight control [102]. Sex differences have also been observed in response to lifestyle interventions. For instance, previous studies suggest that men may achieve greater weight loss than women through dietary interventions such as very-low-energy, low-carbohydrate, and low-fat diets [103,104,105]. Another study demonstrated that women are more frequently observed to succeed in maintaining weight loss than men [106].

As with lifestyle intervention studies, most pharmacological clinical trials do not report outcomes separately by sex, largely because most participants are women. Nonetheless, sex differences persist in the treatment response. Recent evidence indicates that women may experience greater weight reduction than men after one year of pharmacotherapy. This is supported by key trials involving obesity medications such as semaglutide, sibutramine, and liraglutide [107]. Moreover, adverse event profiles differ between sexes, with women being more likely to experience gastrointestinal side effects, potentially affecting adherence [108].

Bariatric surgery is indicated for obese individuals with BMI ≥35 kg/m² with comorbidities or BMI ≥40 kg/m² [109]. Several cohort studies have reported that approximately 80% of patients undergoing bariatric surgery are female [110,111,112]. However, this sex difference does not appear to be associated with patient interest in weight loss surgery, but rather with disparities in access to healthcare [76,113]. Differences in postoperative outcomes between the sexes have also been reported. A meta-analysis found that men who underwent surgery tended to experience greater reductions in BMI, which may be explained by their higher preoperative BMI compared to women. In contrast, women show a higher percentage of excess weight loss [114]. In addition, women tend to have lower satisfaction and poorer psychological outcomes. Conversely, men exhibit worse physiological outcomes with lower rates of comorbidity improvement [110].

CONCLUSIONS

Sex and gender differences play a significant role in influencing obesity and its associated health risks (Fig. 4). Although women exhibit higher rates of obesity, men are more susceptible to severe metabolic complications due to variations in fat distribution and hormonal profiles. Additionally, sociocultural factors and access to healthcare further contribute to these disparities. Understanding these distinctions is crucial for the development of effective gender-sensitive prevention and treatment strategies.

Fig. 4. Biological and sociocultural determinants of sex- and gender-related disparities in obesity. Both biological factors, such as sex hormones, chromosomes, and genomics, and sociocultural factors, including gender roles, dietary practices, and stigma, contribute to the observed differences in obesity patterns and associated risks between sexes. These disparities underscore the necessity for gender-sensitive approaches in the prevention and treatment of obesity.