Body fat can be classified into essential fat and storage fat. Storage fat refers to the fat accumulated in adipose tissue and is primarily composed of triacylglycerols [1]. Essential fat, on the other hand, is found in lipid-rich tissues, including the liver, heart, lungs, central nervous system in both men and women. In women, additional essential fat in found in the mammary glands and pelvic region. Reference values indicate that men have approximately 12% storage fat and 3% essential fat, whereas women generally have around 15% storage fat and 12% essential fat [2]. Storage fat constitutes around 86% of total body fat and is the most variable component among individuals [1]. Body fat can also be categorized based on its location, such as trunk fat and appendicular fat, the latter being found in the arms and legs [3].

Functionally, mammals, including humans, possess different types of adipocytes—white, beige, and brown adipocytes—distributed throughout various regions of the body. WAT is the predominant form of fat in adults [4]. It can be further divided into three main anatomical categories: SAT, VAT, and ectopic fat [5, 6]. Ectopic fat, which accumulates in organs such as muscles, pancreas, liver, and heart [7], is typically present in small quantities and is beyond the scope of this review. This manuscript will primarily focus on SAT and VAT. Additionally, WAT can be further subdivided into three groups based on its depth relative to the skin: superficial SAT, deep SAT, and VAT [8]. Additionally, specific terminology is often used to describe fat in particular anatomical regions, such as abdominal SAT [9].

VAT surrounds intra-abdominal organs, including abdominal and intra-abdominal fat [10, 11]. This encompasses fat surrounding internal organs, such as epicardial fat, perivascular fat, and fat surrounding gastrointestinal structures [6, 7]. VAT is a component of android fat, which also includes abdominal SAT.

Excessive accumulation of VAT is now recognized as adiposopathy due to its strong association with increased risks of insulin resistance, type 2 diabetes, and cardiovascular diseases [5, 12, 13, 14, 15, 16, 17, 18, 19]. For example, individuals with Crohn’s disease or intestinal tuberculosis exhibit significantly higher ratios of VAT to SAT or total fat [20]. VAT plays a key role in the secretion of pro-inflammatory cytokines, including interleukin-6 (IL-6), as well as hormones like leptin and adiponectin, particularly in the context of systemic inflammation [21, 22]. Reducing VAT through interventions such as fasting has been shown to alleviate low-grade chronic inflammation linked to excessive visceral adiposity [23]. Additionally, VAT is closely associated with conditions such as sleep apnea, certain tumors, and other disorders [11].

SAT lies just beneath the skin and is distributed across various body regions, including the thighs, hips, and gluteal region. It is further classified into deep and superficial SAT. SAT distribution varies by anatomical site, age, and sex [24, 25, 26]. Unlike other types of fat, SAT plays protective roles by shielding delicate organs (such as the eye) and cushioning body areas exposed to high mechanical stress (such as the heel and toe pads) [13]. Additionally, it contributes to the sexually dimorphic appearance of human faces [27]. Prior to menopause, women tend to accumulate more SAT, which may offer protection against the adverse effects of obesity and metabolic syndrome [12]. However, with aging, SAT can infiltrate the dermal layer, impairing skin elasticity and promoting wrinkle formation [28]. Additionally, SAT can adapt to changes in nutrient status, age, and sex [26, 29]. As a result, SAT is often considered a beneficial tissue, with its subcutaneous accumulation generally being less harmful, particularly in female [6].

However, SAT is not always beneficial. Excessive SAT, for instance, can contribute to biomechanical disorders associated with increased fat mass, such as ulcers, immobility, and sleep apnea. Moreover, when caloric intake exceeds the storage capacity of SAT, excess energy may be redirected toward VAT accumulation [11]. The benefits of SAT can also vary by anatomical location. In humans, upper-body SAT is responsible for most systemic free fatty acids (FFAs) and is more insulin-resistant than lower-body SAT [6, 15].

Emerging research suggests that, rather than acting as a passive storage site for excess energy, WAT is considered a dynamic and diverse organ, dispersed throughout the body and capable of sensing and responding to various physiological signals from its microenvironment. It, in turn, functionally and morphologically adapts to changes in physiological status. The plasticity of WAT is further evident in the sexual dimorphism of fat mass between females and males [12, 30, 31, 32], as well as in the differences in fat distribution observed between perimenopausal and postmenopausal women [33]. Therefore, WAT is now considered as a heterogeneous organ with a remarkable degree of plasticity [34, 35]. Understanding the factors that drive WAT heterogeneity, including its prenatal and postnatal genetic influences, hormonal status, and regional variations, is essential for gaining deeper insights into the characteristics of this newly recognized organ, as well as the pathological consequences of postmenopausal obesity.

Beyond fat redistribution, it is important to recognize that the characteristics of VAT, as outlined in Table 1, may reflect its roles extending beyond merely being a marker of adiposopathy or an indicator of obesity-related metabolic complications. Adiposopathy, defined as the pathological dysfunction of adipose tissue, is often a primary cause of metabolic syndrome. In fact, these characteristics are often oversimplified to the idea that “obesity protects obesity” [57, 58, 94]. This concept is particularly evident in the expansion of VAT.

VAT has a higher density of glucocorticoid and ARs compared to SAT. Moreover, VAT adipocytes exhibit increased activity of 11$\beta$-HSD1, an enzyme that converts cortisone to cortisol within the tissue [71]. This process enhances local glucocorticoid exposure, influencing a wide array of metabolic, anti-inflammatory, and immunosuppressive mechanisms, thus supporting both normal VAT and systemic processes [56, 95]. For example, increased glucocorticoid-signaling enables VAT adipocytes to respond more sensitively to environmental stressors by mobilizing FFAs and becoming more responsive to adrenergic stimulation. While this local amplification of glucocorticoid signaling aid in adaptation to stress, it also contributes to side effects, such as the development of insulin resistance [71, 96].

Another key factor is that VAT is considered a primary driver of adiposopathy, largely due to the release of adipokines that regulate both adaptive and acquired immune responses, contributing to the development of metabolic and immune diseases [11, 19]. For instance, increased leptin secretion from adipose tissue suppresses appetite and promotes energy expenditure, thereby contributing to the maintenance of energy balance and the mitigation of lipodystrophy. Paradoxically, leptin also stimulates the renin-angiotensin system (RAS), which plays a role in regulating fluid balance, but can lead to hypertension [97], systemic sclerosis, and other disorders [98].

In addition, adipose tissue secretes a combination of pro-inflammatory cytokines (such as leptin, interleukin-1 beta (IL-1$\beta$), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, tumor necrosis factor $\alpha$ (TNF$\alpha$), and resistin) and anti-inflammatory cytokines (such as adiponectin) [99]. This complex cytokine profile is part of the “obesity paradox”, where the same biological processes can exert both protective and harmful effects. For example, the altered ratio of ERs (ER$\alpha$/ER$\beta$) in the context of estrogen deficiency further complicates the immune and metabolic responses, thereby contributing to the multifaceted health impacts of obesity [91, 99, 100].

Another notable paradox is that, during menopause, adipose tissue becomes the primary source of estrogen, with VAT often referred to as a “third ovary”—a concept central to the “obesity paradox” [94]. Although the total amount of estrogen produced after menopause is significantly lower than during a woman’s reproductive years [12], this shift has crucial implications. Estrogen derived from adipose tissue can help mitigate certain cardiovascular risks, but it also promotes further adipose tissue expansion, thereby contributing to obesity. This, in turn, increases the risk of developing estrogen-sensitive breast cancer, highlighting the complex role of adipose-derived estrogen in both protective and harmful processes [101, 102].

Consistent evidence suggests that VAT may not be the primary cause of metabolic complications [5, 15, 103]. Several loci on human chromosomes have been identified that paradoxically exert beneficial cardiometabolic effects, either by promoting favorable fat distribution or by having no adverse cardiometabolic impacts at all [104]. Additionally, individuals with metabolic syndrome often exhibit a borderline negative correlation with abdominal SAT mass [105]. The paradox may stem from the underlying fat mass—whether it is present in appropriate amount or in excess.

Emerging clinic evidence has shown that the percentage of VAT is inversely associated with total bone mineral density and osteoporosis [106, 107], as well as with lower levels of HDL-C [108]. In contrast, in postmenopausal women with normal lean mass, VAT does not appear to correlate with bone mineral density or markers of bone formation and resorption. VAT, rather than age, is strongly linked to an increased risk of breast cancer [109], elevated fasting glucose, insulin levels, and cardiovascular risk factors such as triglycerides, apolipoprotein B [108], and blood pressure in postmenopausal women [110, 111, 112]. Notably, peri-coronary epicardial adipose tissue is strongly associated with vascular risk factors and coronary calcification [113]. In contrast, diet-induced weight loss has been shown to significantly improve fasting insulin levels and glucose metabolism [114]. Supplementation with Equol, an ER agonist, can notably alleviate postmenopausal syndromes and reduce VAT mass in postmenopausal women following three months of treatment [115].

Paradoxically, higher adiposity has also been associated with fewer physiological hot flashes among older women experiencing this common postmenopausal symptom, as indicated by age-adjusted models [116]. Furthermore, subcutaneous abdominal fat, but not VAT, appears to be associated with an increased likelihood of hot flashes [117]. These findings suggest that VAT may be a more reliable indicator of metabolic syndrome in menopausal or postmenopausal women, compared to other symptoms such as hot flashes.

VAT, also known as abdominal fat, refers to the fat that surrounds internal organs [7]. Commonly referred to as VAT, it includes a range of fat depots, such as mesenteric, omental, retroperitoneal, intraperitoneal, gonadal, peri-renal, epididymal fat, and others, depending on their anatomical locations [118, 119]. As such, visceral fat is not a homogeneous tissue; it surrounds various intra-abdominal organs and may perform distinct functions depending on the specific abdominal microenvironments. Gene expression studies have also identified validated markers for these fat depots, suggesting a relationship between anatomical location, both adipose tissue identity, and function [120].

VAT depots may differentially contribute to various physiological processes. Regression analyses examining body weight changes in relation to the weights of three visceral fat depots—peri-renal fat, gonadal fat, and mesenteric fat—in C57 mice and nerve-specific receptor-activity modifying protein 1 (RAMP1) overexpressing lean mouse models [121] reveal that mesenteric fat exhibits the largest coefficients compared to the other two fat pads in both strains (unpublished data). Moreover, mesenteric adipocyte size has been associated with a 79% higher likelihood of developing metabolic syndrome compared to other fat depots [18]. Visceral fat, particularly due to its distinct anatomical characteristics and its circulation draining into the portal vein and liver, has been implicated in the development of insulin resistance. Consistent with this, mesenteric fat has been shown to exert more than a two-fold greater influence on improvements in insulin sensitivity in young rats [122].

Other VAT depots also exhibit distinct characteristics, with some being more responsive to dietary changes. For instance, very low energy diets significantly reduce VAT mass, particularly mesorectal fat, while having a lesser impact on total pelvic fat [123]. Among the visceral depots, mesenteric and omental depots contain the fewest macrophages and adipokines [18]. On the other hand, pancreatic fat mass, has been negatively associated with cognition and brain volumes in middle-aged individuals [124]. In contrast, periaortic adipose tissue is characterized by the smallest adipocytes, the highest capillary density, and an elevated secretion of adipokines [18]. There may also be heterogeneity within individual fat depot. For example, in mice, epididymal fat, a component of visceral fat, is divided into distal and proximal regions, each with distinct histochemical and gene expression profiles [125]. This variability may serve an adaptive function, allowing each depot to fulfill more specialized roles in response to subtle nutrient differences within the microenvironment.

The observations outlined above are primarily based on studies in humans and commonly used animal models. To our knowledge, however, no comparative analysis of depot-specific characteristics has been conducted specifically in the context of peri- or post-menopause. Such research could identify the specific fat depots responsible for central adiposity, enhance our understanding of body shape changes during this life stage, and guide the development of targeted therapeutic strategies for related metabolic syndromes.

Fat redistribution due to estrogen deficiency is supported by comparisons of plasma estrogen levels, which range from 100–250 pg/mL in premenopausal women to approximately 10 pg/mL in postmenopausal women [126]. Total estradiol levels are inversely associated with body shape, with the lowest levels observed in postmenopausal women exhibiting an “apple” phenotype and the highest levels found in women with a “pear” phenotype, including both premenopausal women and postmenopausal women using hormone replacement therapy (HRT) [127].

The role of estrogen in regulating fat distribution is further supported by observations in individuals undergoing cross-sex hormonal therapy. Trans women undergoing estrogen therapy exhibit a gynoid pattern of body fat distribution and a lower waist-to-hip ratio, while trans men receiving testosterone display an android pattern of body fat distribution with a reduced hip circumference [128]. These findings suggest that, in the context of estrogen deficiency, fat deposition shifts toward the visceral depot, contributing to the development of an android body shape [12].

The impact of estrogen on energy metabolism is further demonstrated by studies using ER genetic mouse models, in which activation of ER$\alpha$ leads to a decreased body weight, while activation of ER$\beta$ results in an increased body weight [129]. During estrogen deficiency, there is a relative increase in ER$\beta$ expression, accompanied by a corresponding decrease in the ER$\alpha$/ER$\beta$ ratio. Estrogen plays a key role in coordinating central and peripheral metabolism, influencing appetite, satiety, and energy expenditure through central nuclei, such as the arcuate nucleus (ARC), ventromedial nucleus (VMN), and nucleus tractus solitarius (NTS), as well as peripheral organs and mitochondrial function in various cell types [130].

7.5 Estrogens Integrate Nuclear and Mitochondrial Signals to Downregulate Biosynthesis and Enhance $\beta$-Oxidation

At the cellular level, estrogens regulate a variety of functions by binding to cytosolic ER$\alpha$ and ER$\beta$ or the membrane-bound G-protein coupled estrogen receptor (GPER1). In the presence of estrogens, ER$\alpha$ and ER$\beta$ can directly bind to mitochondrial DNA (mtDNA) through mitochondrial estrogen receptor elements (EREs) [144]. This binding modulates the expression of nuclear and mitochondrial factors involved in energy expenditure, including nuclear respiratory factor-1 (NRF-1), estrogen receptor-related receptors (ERR1), peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$) and $\delta$ (PPAR$\delta$), as well as PPAR gamma coactivator 1 alpha (PGC1$\alpha$) and PGC1$\beta$, which regulate nuclear-encoded mitochondrial genes in various cell types, such as adipocytes, muscle cells, and hepatocytes [69].

Estrogens also downregulate enzymes involved in fatty acid and triglyceride synthesis in adipocytes, such as acetyl-CoA carboxylase (ACC1), fatty acid synthase (FAS), and diacylglycerol acyltransferase (DGAT1 and DGAT2) [145]. Simultaneously, they upregulate enzymes that promote fatty acid $\beta$-oxidation, such as medium-chain acyl-coenzyme A dehydrogenase (MCAD) and acetyl-CoA oxidase (ACO) [145]. Additionally, estrogens influence the expression of certain mtDNA-encoded genes involved in mitochondrial respiratory chain complexes [144]. In brain mitochondria, this regulation is primarily initiated by ER$\beta$ binding to EREs [146], although ER$\alpha$ may also play a role in other tissues [144].

Estrogens further modulate cholesterol metabolism by regulating the expression of 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) reductase, which is anchored in the endoplasmic reticulum membrane [147]. Moreover, estrogens interact indirectly with peripheral mediators, such as glucagon-like peptide-1 (GLP-1), in the hypothalamus to cooperatively regulate energy homeostasis [148]. In this way, estrogens coordinate brain and body metabolism, orchestrating both endocrine and paracrine effects. Consistently, during menopause, the decline in plasma estrogen levels coincides with a reduction in bioenergetic function across various tissues and organs [149], contributing to postmenopausal phenotypes. The underlying mechanism and its consequences in the context of postmenopause are summarized as Fig. 1.

Fig. 1.

Impact of estrogen deficiency on central energy regulation, appetite, and adipose tissue remodeling. Estrogen deficiency reduces the expression of ER$\alpha$ and the ER$\alpha$/ER$\beta$ ratio, leading to decreased SF1 expression and impaired PI3K signaling in the VMN, resulting in a reduction in energy expenditure. In the ARC, estrogen deficiency decreases POMC expression and increases NPY expression, promoting increased appetite. Additionally, estrogen deficiency downregulates CCK signaling, which diminishes CCK-induced satiety by inhibiting ER$\alpha$-mediated signaling in the nucleus of the NTS. These disruptions in energy homeostasis create a state of energy surplus, contributing to the remodeling of SAT and VAT. This remodeling is influenced by regional and cellular characteristics, leading to increased VAT expansion and a shift toward an android body shape. ARC, arcuate nucleus; CCK, cholecystokinin; ER, estrogen receptor; HSD1, Hydroxysteroid Dehydrogenase 1; GH, growth hormone; TG, triglyceride; GC, glucocorticoids; NPY, neuropeptide Y; NTS, nucleus tractus solitaries; POMC, pro-opiomelanocortin; SAT, subcutaneous adipose tissue; SF1, steroidogenic factor-1; VAT, visceral adipose tissue; VMN, ventromedial nucleus; FFA, free fatty acid.

Emerging evidence highlights the heterogeneity of adipose tissue in terms of its composition, distribution, and function. These characteristics are prenatally determined by sex chromosomes and SNPs in autosomes and are further influenced by epigenetic factors such as estrogen and energy intake. SAT and VAT are two key representatives that define sex dimorphism in adipose tissue distribution and function.

In the context of menopause, estrogen deficiency leads to a positive energy balance by increasing appetite and food intake through the inhibition of POMC neurons in the ARC, decreasing energy expenditure by inhibiting SF1 neurons in the VMN of the hypothalamus, and reducing satiety while promoting food intake through the NTS in the brainstem. These regulatory processes are primarily mediated by ER$\alpha$ activity. Additionally, the hyperactivation of the HPO axis contributes to the accumulation of VAT.

The distinct characteristics of VAT, including high expandability, elevated FFA mobility, and increased high 11$\beta$-HSD1 activity, make it more susceptible to hypertrophy. VAT accumulation, in turn, compensates for declining estrogen levels by releasing more estradiol and adipocytokines, which exert both inflammatory and anti-inflammatory effects, helping the body adapt to energy stress. However, this “obesity paradox” ultimately contributes to the development of postmenopausal phenotypes.

Although VAT is often termed the “sick fat” associated with postmenopausal syndromes, it is heterogeneous, comprising various anatomically distinct depots such as mesenteric, peri-renal, omental, retroperitoneal, intraperitoneal, and gonadal fat. Recent studies suggest that these depots differ morphologically and functionally [18, 48, 123]. For instance, mesenteric fat within VAT may play a significant role in regulating body weight, insulin resistance, and inflammation.

Further investigation into the specific characteristics of VAT depots in the context of menopause is crucial for a deeper understanding of postmenopausal syndromes. For instance, examining SNPs in autosomes, glucocorticoid receptors (GRs), HSD enzymes, and adipocyte-specific expression of glucose transporter type 4 (GLUT4), along with associated phenotypes in animal models, could shed light on the mechanisms driving VAT accumulation after menopause. Additionally, personalized treatments such as hormone replacement therapies (including phytoestrogens and estrogen-progesterone combinations), non-hormonal medications, and lifestyle interventions (such as regular exercise, healthy diets, and caffeine to boost plasma brain-derived neurotrophic factor (BDNF) levels) could offer tailored therapeutic approaches for patients [150]. In contrast, behaviors such as high-fat diets, smoking, and alcohol consumption, which may exacerbate postmenopausal symptoms, should be avoided.

To conduct this study, a systematic search of electronic databases, including PubMed and ResearchGate, was performed in June 2024 and updated in November 2024. Studies in English published before these dates were considered. Screening was performed using predefined search terms such as obesity and X chromosome (225 results), postmenopausal and SAT (91), postmenopausal and VAT (109), postmenopausal, VAT, and SAT (41), postmenopausal, VAT, SAT, and metabolism (35), and VAT, SAT, and metabolism (845). After removing duplicates, 912 publications were identified. Of these, 150 were included in the references based on their relevance to the manuscript and its sections, as well as their status as classic works or recent impactful studies. Publications not meeting these criteria were excluded.

The research study was designed by all authors, with ZZ responsible for manuscript writing, and ZH, HY, DL, PD, XW contributing to editorial revision. All authors contributed to the manuscript’s editorial changes, read and approved the final version, and are accountable for all aspects of the work.

Not applicable.

This work was supported by grants from Henan Natural Science Foundation (242300421302).

The authors declare no conflict of interest.