Adipocytokine profiles in maternal obesity: The impact of lipoinflammation on serum, breastmilk, and infant metabolic development

Abstract

Adipocytokines are proteins with systemic metabolic effects, and additional adipocytokines have been identified. Adipocytokines are present in the serum, and obesity-mediated inflammation can alter their expression. Breast milk also contains adipocytokines that may influence infant metabolism and growth. Nonetheless, the relationship between circulating and milk adipocytokines during maternal inflammation and their effects on infant development remain unclear. We conducted a comprehensive literature review of studies published between 2000 and 2024 in PubMed to analyze the associations between obesity-mediated inflammation and adipocytokines in maternal serum and breast milk and to explore their potential effects on infant growth and metabolic health. We focused on updated evidence for the legacy adipocytokines leptin, adiponectin, TNF-α, and IL-6 and the emerging adipocytokines chemerin, neuregulin-4, and betatrophin. The results indicated that although obesity-mediated inflammation affected circulating adipocytokines, their levels were not consistently reflected in breast milk. Leptin, chemerin, and betatrophin were more influenced by lipoinflammation than adiponectin, IL-6, and TNF-α. Neuregulin-4 was present in milk, and its serum levels decreased during gestational diabetes. Some adipocytokines were correlated with infant growth; however, the evidence remains inconclusive. Importantly, no adverse metabolic or growth outcomes were linked to changes in milk adipocytokine profiles. These findings support the promotion of breastfeeding as part of infant health strategies, even in the context of maternal lipoinflammation.

Highlights

● Maternal lipoinflammation alters serum but not always milk adipocytokines.

● Local regulation of milk adipocytokines may protect infant metabolic health.

● Breastfeeding supports infant health despite maternal metabolic alterations.

Introduction

Obesity is a chronic complex disease characterized by an excessive accumulation of adipose tissue (AT) and is a growing global health issue. In 2022, one in eight individuals was obese, 43% of adults worldwide were overweight, and over 37 million children aged < 5 yr were overweight (1). Infant obesity increases the risk of developing obesity and noncommunicable diseases (NCDs) later in life (1). Fortunately, obesity and related NCDs can be prevented through cost-effective interventions such as breastfeeding.

Exclusive breastfeeding for the first 6 mo provides a full supply of nutritional and non-nutritional bioactive components that are dynamic and support growth, immune development, and metabolic health (2,3,4,5,6). These benefits persist throughout breastfeeding after complementary feeding begins. Protein-based components, such as hormones and cytokines, are part of the bioactive profile of breast milk, and some can be referred to as adipocytokines, as they can be secreted by maternal AT (7). Examples include leptin and adiponectin, which regulate food intake, energy expenditure, and infant AT development, as well as cytokines like IL-6 and TNF-α that contribute to immune maturation and metabolic regulation through lipid and glucose metabolism (2, 4, 5, 7, 8). Adipocytokines in breast milk have been hypothesized to influence infant energy homeostasis and metabolic programming, although their endocrine activities in infants remain unclear.

Epidemiological studies have shown that breastfeeding is associated with reduced risk of childhood obesity (5, 9). However, this protective effect may be confounded by maternal BMI. One study did not adjust for maternal BMI, acknowledging that it was a potential confounder (9), whereas others found that the association was attenuated after adjusting for maternal BMI (5). Nevertheless, these studies did not evaluate milk adipocytokines, leaving a gap in our understanding of their contributions to infant metabolic programming.

Overweight and obesity can be classified using the BMI (1). Increased BMI can trigger AT remodeling, leading to a chronic low-grade inflammation known as “lipoinflammation” (10). This involves adipocyte hypertrophy, immune cell infiltration, AT hypoxia, and dysregulated adipocytokine secretion, with increased proinflammatory IL-6, leptin, and TNF-α levels and reduced anti-inflammatory adiponectin levels (10). However, changes in milk are not fully mirrored, and adiponectin levels can increase in some cases (11). Other serum and milk studies on mothers with pre-pregnancy obesity have reported a similar effect (12), suggesting a regulatory mechanism modulating adipocytokine transfer that may protect infant health.

This review examines the current evidence on how maternal lipoinflammation affects human milk adipocytokines, focusing on whether maternal serum adipocytokine variations are reflected in milk and their potential impact on infant growth and metabolism. We explore four key “legacy” adipocytokines (namely, leptin, adiponectin, IL-6, and TNF-α) involved in immunity and energy balance, as well as three emerging adipocytokines (namely, chemerin, neuregulin-4, and betatrophin).

Methods

We conducted a literature search of articles published from 2000 to 2024 in the PubMed database. The search terms were “breastfeeding,” “human milk,” “breast milk,” “overweight,” “obesity,” “maternal serum,” “maternal obesity,” “adipose tissue,” “white adipose tissue,” “hormones,” “peptides,” “cytokines,” “adipokines,” “adipocytokines,” “novel adipokines,” “novel adipocytokines,” “inflammation,” “lipoinflammation,” “adipose tissue inflammation,” and “fat inflammation.” Based on the initial results, we refined our queries by incorporating terms such as “leptin,” “adiponectin,” “IL-6,” “TNF-α,” “chemerin,” “neuregulin-4,” and “betatrophin.” This strategy yielded 152 peer-reviewed studies that included experimental and epidemiological evidence of adipocytokines in breast milk and maternal serum in the context of obesity-mediated inflammation.

Study selection and eligibility criteria

Studies were included if they met the following criteria: (1) original peer-reviewed research in humans; (2) assessment of maternal adiposity or metabolic status (such as BMI, overweight/obesity, gestational diabetes, fat distribution, metabolic syndrome, or lipoinflammation-related disorders); and (3) quantitative measurement of adipocytokines in maternal serum and/or breastmilk. Studies were excluded if they were case reports or conference abstracts, lacked full-text access, or did not quantify adipocytokines in milk or blood samples. Priority was given to studies with a clear methodology, sufficient sample size, and simultaneous evaluation of both serum and breast milk markers.

Data collection

Two reviewers independently screened the titles and abstracts of the initial 152 articles for relevance. The reference lists of selected papers were manually screened to identify additional relevant studies. After excluding studies with low applicability, 89 articles were selected for full-text review, and the following data were extracted: maternal condition (BMI or metabolic diagnosis), biological samples analyzed (serum and breast milk), adipocytokines measured, and relevant infant outcomes including anthropometry, body composition, and metabolic markers.

The final dataset was organized thematically using the individual adipocytokines. For each adipocytokine, studies were grouped and discussed according to 1) the effect of maternal lipoinflammation on serum levels, 2) the presence and regulation of adipocytokines in breast milk, and 3) potential associations with infant growth or metabolic outcomes.

Leptin

Leptin is primarily released by white AT and regulates energy balance by suppressing food intake and increasing energy expenditure (13). In infants, milk leptin may influence growth and appetite, suggesting its role in early endocrine and metabolic regulation (11, 13). In obesity, increased AT elevates leptin production, which contributes to leptin resistance, reducing its anorexic effects, increasing appetite, and potentially weight gain (13). Leptin has proinflammatory properties that can promote TNF-α and IL-6 production in AT macrophages, potentially amplifying lipoinflammation (11, 14). In breast milk, leptin contributes to infant appetite regulation and energy balance, and its dysregulation in maternal inflammation influences the endocrine homeostasis of infants (13, 14).

Leptin is produced by mammary epithelial cells and secreted in milk, with additional contributions from the maternal circulation (13). This may explain the positive correlation between milk leptin levels and maternal BMI at multiple time points. Higher serum and colostrum leptin levels have been reported in obese women than in mothers with normal weight (11), and these differences persist at 2 wk (15), 2 mo (12), and 4 mo postpartum (15). Previous studies have only evaluated milk and reported that leptin levels continue to correlate with maternal BMI at both 1 (16) and 4 mo postpartum (17) (Table 1). Although milk leptin decreases during lactation, its levels remain higher in obese mothers than in those with normal weight (18), reflecting sustained regulation mediated by maternal adiposity. Future studies should evaluate whether the maternal metabolic state beyond BMI, such as insulin resistance, dyslipidemia, or MeTS, can further influence serum and milk leptin levels.

Table 1. Comparison of adipocytokine levels in maternal serum and breastmilk in the context of obesity-related lipoinflammation.

Leptin receptors in the gastric and intestinal epithelia indicate potential absorption and systemic actions (19). However, the results of studies on the metabolic responses of infants to breast milk leptin have been inconsistent. For example, at 1 mo postpartum, no differences in weight gain were detected in exclusively breastfed infants of mothers with obesity or normal weight, despite higher milk leptin levels in the obesity group (16). In contrast, other studies suggest a protective effect, with higher breast milk leptin levels being associated with lower fat mass at 4 mo (20), lower weight and lean body mass (18), and lower BMI Z-scores and weight-for-length z-scores (WLZ) at 4 mo and 1 yr postpartum (17). Future studies should evaluate not only how maternal lipoinflammation affects leptin concentration and volume but also quantify milk intake for more accurate interpretations of leptin exposure and its impact on growth and metabolic programming.

Adiponectin

Adiponectin, an anti-inflammatory adipocytokine with insulin-sensitizing properties, not only modulates lipid and glucose metabolism (21) but also suppresses proinflammatory cytokines such as TNF-α and IL-6, mitigating obesity related inflammation (14, 21). Circulating levels of adiponectin are reduced in individuals with obesity, type 2 diabetes, and pregnant women with a high BMI, contributing to systemic metabolic dysfunction (21, 22). This suppression is exacerbated by TNF-α and IL-6, which further inhibit adiponectin expression, reinforcing the proinflammatory loop (14).

In breast milk, adiponectin is primarily present in its high-molecular-weight form, which is the most metabolically active form, and primarily originates from maternal circulation, with potential local synthesis within mammary epithelial cells (23, 24). However, unlike leptin, which clearly reflects maternal BMI, milk adiponectin levels show inconsistent associations. One study reported lower serum but higher colostrum levels in mothers with obesity than in those with normal weight (11) (Table 1). Other studies found similar milk (17) or serum and milk adiponectin levels across different BMI groups (15). In contrast, one report observed lower adiponectin levels in overweight and obese groups at 2 mo postpartum (25) (Table 1). Nevertheless, the overall effect of maternal metabolic status appears limited, as a systematic review showed that only one out of nine studies identified a clear association between maternal BMI and breast milk adiponectin levels (23). While direct evidence supporting the regulation of adiponectin in milk remains limited, a proposed mechanism suggests that lower prolactin levels in obese individuals can increase local adiponectin synthesis in mammary AT (23).

The relationship between breast milk adiponectin and infant growth appears to be nonlinear and time-dependent. One study reported an inverse correlation between WLZ in breastfed infants, suggesting a protective effect against early adiposity (24). A previous study (18) observed an inverse correlation with fat mass at 4 mo; however, by 2 yr of age, higher adiponectin levels were positively associated with weight and fat mass, suggesting delayed or compensatory growth. Another study also observed a time-dependent effect, with adiponectin being initially associated with lower WLZ in the first 6 mo, followed by higher weight-for-age Z-scores (WAZ) by 24 mo (26). Other studies found no association at 4 or 12 mo postpartum (17), indicating variability in both exposure timing and outcome measures.

Collectively, the literature suggests that milk adiponectin regulates early weight gain and supports compensatory growth, indicating a dynamic, time-dependent effect on infant development. However, none of these studies evaluated maternal lipid inflammatory status or actual milk intake; therefore, it remains unknown whether this modulates the relationship between milk adiponectin levels and infant metabolic or growth outcomes.

TNF-α

TNF-α is a proinflammatory cytokine primarily secreted by macrophages within AT (7, 14). It has autocrine, paracrine, and endocrine-like activities in distant organs such as the liver, pancreas, and muscle (14). TNF-α contributes to systemic metabolic dysregulation by promoting lipolysis, suppressing insulin signaling and altering adipocytokine expression including increased leptin and IL-6 and reduced adiponectin (14, 27).

In breastmilk, TNF-α is produced by macrophages and other immune cells within the mammary gland, with potential contributions from mammary epithelial cells (10, 28). Although circulating TNF-α levels are increased in obesity and lipoinflammation related metabolic complications (7, 29), studies show that this is not consistently reflected in milk. For instance, significantly higher serum TNF-α was observed in mothers with obesity compared to those with normal weight, but this was not reflected in colostrum (11). Comparisons of both milk and serum at 2 wk, 2 mo, and 4 mo postpartum revealed no significant differences in TNF-α concentrations between BMI groups (12, 15). This pattern persisted in milk samples, even when analyzed for up to 9 mo of lactation (30). The limited correlation between serum and milk TNF-α levels suggests the presence of local regulatory mechanisms in the mammary glands that may protect infants from maternal inflammation.

Milk volume may also impact milk composition, as one study reported that mothers with low milk production had significantly higher TNF-α levels (31). However, none of the reviewed articles controlled for milk volume, highlighting the need to account for milk volume when evaluating TNF-α and other adipocytokines in milk.

While studies on milk TNF-α primarily focus on its role in infant immunity (3), some research has explored its impact on growth and metabolic programming (12, 30). In one study, TNF-α positively correlated with infant weight and % fat mass. However, this was lost after BMI stratification, with the negative correlations of milk TNF-α with weight and % fat mass observed only in infants from normal-weight mothers (12). These results suggest that maternal obesity may blunt infant responsiveness to milk TNF-α, possibly due to prenatal metabolic adaptation (12). In contrast, another longitudinal study found no association between milk TNF-α and infant growth from 0.5 to 9 mo postpartum (30).

Although no clear adverse effects on metabolic or growth outcomes were identified, further research is needed to explore if maternal lipoinflammation alters the immune or metabolic functions of TNF-α in human milk, and how this can impact early life metabolic programming.

IL-6

IL-6 is a multifunctional adipocytokine mainly secreted by AT macrophages with both pro- and anti-inflammatory effects (7, 32). IL-6 regulates metabolic homeostasis and glucose metabolism. High IL-6 levels during liver inflammation promote insulin resistance and inflammation (14). Leptin can induce IL-6 and TNF-α production, and high IL-6 levels can suppress adiponectin, contributing to a feedback loop that sustains a chronic inflammatory state (14). Conversely, IL-6 has anti-diabetic, regenerative, and anti-inflammatory effects, including the induction of IL-10 (14, 28).

In breast milk, IL-6 likely originates from immune and mammary epithelial cells (28), and its levels increase in individuals with obesity and metabolic syndromes (29). However, milk IL-6 levels poorly correlate with maternal systemic inflammation, supporting the hypothesis of local mammary regulation (see section “Mechanisms regulating milk adipocytokines and their impact on infant programming”). For example, previous studies reported that in the first two days (11) and at 4–8 wk postpartum (12), maternal serum IL-6 levels were significantly increased in overweight or obese mothers, whereas milk levels remained unaffected. Other studies found similar IL-6 levels in blood and milk across normal-weight, overweight, and obese groups at 2 wk, 4 mo (15), and 9 mo postpartum (30) (Table 1).

Previous studies have reported conflicting evidence regarding maternal BMI, milk IL-6 levels, and infant body composition (12, 20, 33). In one study at 4–8 wk postpartum, higher milk IL-6 was negatively correlated with infant length, weight, head circumference, and percent fat mass, but only among infants of normal-weight mothers. Given that no associations were observed in infants born to overweight or obese mothers, it has been suggested that infants exposed to maternal obesity could exhibit metabolic adaptations that change their sensitivity to milk adipocytokines (12). A separate study demonstrated that higher IL-6 ingestion correlated with accelerated weight gain up to 7 mo of age, irrespective of maternal BMI (20). In contrast, another study (33) found no relationship between milk IL-6 and infant body composition at 1 or 6 mo postpartum. Taken together, these findings suggest that milk IL-6 may influence infant growth; however, such effects likely depend on the maternal metabolic context and infant programmed sensitivity to inflammatory signals shaped by early life exposure.

Chemerin

Chemerin is a proinflammatory adipocytokine predominantly secreted by the liver and adipocytes from white AT and is involved in adipocyte metabolism, glucose homeostasis, and adipogenesis (34, 35). Its endocrine and paracrine activities in obesity and lipoinflammation conditions have led to its classification as a hormone-like adipocytokine (36, 37). Chemerin may contribute to immune protection in newborns through its antimicrobial activity and its role in immune cell recruitment (38). Chemerin is enhanced by TNF-α and IL-1β and may reinforce inflammation by promoting IL-6 and TNF-α release (35, 36). Its levels are linked to systemic inflammation, insulin resistance, and disrupted glucose transport (34, 35). It can also modulate insulin sensitivity and lipid storage in adipocytes (36).

Chemerin levels are increased in patients with obesity, type 2 diabetes, cardiovascular disease, and metabolic syndrome (34, 35). Higher levels in milk compared to blood suggest local mammary secretion (38), Two studies reported that mothers with GDM, compared to normoglycemic peers, had significantly higher chemerin levels in both serum and colostrum, transitional (38), and mature milk (38, 39). The levels remained elevated at 6 wk postpartum in both the serum and milk of mothers with GDM, whereas they decreased significantly in normoglycemic mothers (39). This persistent increase may be due to the reduced methylation of the chemerin promoter (39). In contrast, another study (40) found no difference in colostrum chemerin levels between mothers with GDM and normoglycemic mothers. However, serum chemerin levels were not assessed, limiting the interpretation of the influence of systemic levels on milk concentration. These findings suggest that milk chemerin levels may not directly mirror the maternal metabolic status and could be regulated locally within the mammary gland, with epigenetic mechanisms potentially contributing to its concentration in milk.

Only one study has evaluated the association between milk chemerin and infant growth in the context of maternal inflammation. In that study (39), chemerin levels in the colostrum and mature milk from mothers with GDM were positively correlated with infant weight at 6 wk postpartum, suggesting that milk chemerin may contribute to infant postnatal growth. Nonetheless, whether it exerts endocrine effects in infants or simply reflects the maternal inflammatory and metabolic status remains to be determined.

Betatrophin

Betatrophin is a proinflammatory adipocytokine primarily produced by the liver and AT from brown, visceral, and subcutaneous fat (29, 41, 42). It regulates lipid metabolism, glucose homeostasis and insulin activity (42, 43), and its increased in insulin resistance, MeTS, and type 2 diabetes (42, 43). It correlates with TNF-α, suggesting that inflammation stimulates its expression (42, 43) and preclinical studies report an inverse relationship with anti-inflammatory adiponectin (44).

Betatrophin is present in human breast milk, with levels exceeding those in maternal blood and local synthesis possibly occurring in connective breast tissue (45). Betatrophin levels are higher in colostrum but decline during lactation. Mothers with GDM show significantly elevated betatrophin levels in the serum and colostrum, transitional, and mature milk, compared to normoglycemic mothers (45), suggesting that maternal metabolic status may shape milk composition.

While it remains unclear whether milk betatrophin influences infant growth during maternal inflammation, pediatric studies have provided some insights. One study (46) reported no significant differences in serum betatrophin or metabolic markers, including glucose and lipid profiles, among children with normal weight, obesity, or obesity with non-alcoholic fatty liver disease. In contrast, another study (47) found higher serum betatrophin levels in obese insulin-resistant children and adolescents than in their metabolically healthy obese peers and a negative correlation with BMI in insulin-sensitive individuals, but not with BMI z-scores that account for age. These findings suggest that age and insulin sensitivity may influence betatrophin levels, although evidence of their direct effects on infant growth is lacking.

Neuregulin-4

Neuregulin-4 (NRG4) is an anti-inflammatory adipocytokine primarily secreted by brown and beige AT, with lower expression in white AT (21, 34). It modulates insulin sensitivity, lipid metabolism, and systemic energy balance (21). NRG4 protects gut epithelial integrity by preventing apoptosis triggered by bacterial infections, suggesting its potential role in the developing intestine (48). NRG4 reduces proinflammatory macrophage activity, suppress TNF-α and IL-1β expression and promotes adiponectin secretion (49, 50). Conversely, TNF-α can suppress NRG4 expression in AT, potentially reducing its metabolic and anti-inflammatory functions during inflammatory stress (51).

NRG4 is present in human breast milk (48); however, its origin and the influence of the maternal metabolic status on milk levels remain unknown. Similar to adiponectin, circulating NRG4 levels are reduced in overweight, obese, and MeTS individuals (52), and women with GDM have lower NRG4 serum levels than normoglycemic pregnant women (53, 54). A similar reduction has been described for serum adiponectin in the context of maternal lipoinflammation; however, serum levels are not consistently reflected in milk and may even increase under these conditions (11, 23). Whether NRG-4 follows a similar pattern requires further investigation. These discrepancies underscore the need for further studies to evaluate whether NRG4 is locally regulated within the mammary glands.

To date, no study has evaluated whether milk NRG4 could influence infant growth or metabolism. This remains an important area of investigation because NRG4 plays endocrine-like roles in lipid metabolism and insulin sensitivity, suggesting that it could have implications for infant growth and metabolic programming.

Mechanisms regulating milk adipocytokines and their impact on infant programming

During metabolic stress, some pro and anti-inflammatory milk adipocytokines such as adiponectin, IL-6 and TNF-α often show weak or inconsistent correlations with circulating levels. This discrepancy suggests that the mammary glands play an active regulatory role in shaping milk composition. The proposed mechanisms include selective epithelial transport, transcriptional regulation, local cytokine signaling or modulation of tight junctions within the mammary tissue. These processes may respond to maternal lipoinflammation-related comorbidities, shaping milk into a profile different from that of the maternal state. In addition, this mechanism may regulate other milk components, including immune-related proteins and other bioactive compounds.

Milk adipocytokines may also influence long-term outcomes. The proposed mechanistic hypotheses include the regulation of hypothalamic appetite circuits, AT development, gut immune maturation, and epigenetic modifications. Despite growing evidence supporting these mechanisms, a direct causal link among maternal lipoinflammation, mammary regulation, and infant programming remains to be fully established. Further research is required to clarify how selective filtering works and how it may influence metabolic health.

Conclusion

This review summarizes the current evidence on the effects of obesity-mediated lipoinflammation on maternal serum adipocytokine levels, its impact on breast milk adipocytokine composition, and the potential metabolic implications for infants.

Lipoinflammation increases circulating leptin, TNF-α, IL-6 chemerin and betatrophin, while decreasing adiponectin and NRG4. However, these alterations were not consistently mirrored in breast milk, suggesting the presence of local regulatory mechanisms, potentially within the mammary gland, that attenuate the transfer of proinflammatory signals to the infant. These may involve tight junction control, selective transport from the blood, epigenetic regulation, or local cytokine production, or epigenetic regulation which may regulate inflammatory cues while maintaining immunometabolic signals.

This is clinically relevant as it reinforces that breastfeeding, even in the context of maternal obesity or lipoinflammation-related disorders, continues to offer adequate metabolic, endocrine, and immune support during early development.

Studies examining infant growth and metabolic programming in the context of inflammation are limited and provide mixed findings, even for legacy adipocytokines. However, some reports have suggested potential protective effects against obesity risk through reduced early weight gain or metabolic adaptations that could allow lower responsiveness to adipocytokines in infants of mothers with obesity. It should be noted that most studies have only quantified milk adipocytokine concentrations without considering actual milk intake, which limits conclusions about actual infant exposure and metabolic effects.

Physiological studies on emerging adipocytokines, such as betatrophin, chemerin, and NRG4, are limited; however, available data indicate immunometabolic functions that could influence endocrine and metabolic development.

One limitation of this review is that most of the included studies assessed maternal status using BMI alone, with little consideration of insulin resistance, dyslipidemia, or other metabolic traits. This reflects a broad gap in the available literature, restricting the possibility of more accurate clinical interpretations. Identifying how maternal lipoinflammation modifies milk adipocytokines, how they can be regulated within the mammary gland, and the precise effect of milk adipocytokines in modulating early metabolic regulation represents a crucial gap in pediatric endocrinology.

Conflict of interests

None declared.