Body Fat Distribution In Humans Research Articles

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes

BackgroundObesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.MethodsWe searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.ResultsHere, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.ConclusionsOur study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue.

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient’s hormonal status.

Single-cell analysis of human adipose tissue identifies depot and disease specific cell types.

The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depot-specific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status and those include a population of potential dysfunctional CD8+ T cells expressing metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, which shares common features with beige preadipocytes. Our human single-cell transcriptome atlas across fat depots provides a resource to dissect functional genomics of metabolic disease.

Determinants of body fat distribution in humans may provide insight about obesity-related health risks

Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. As such, understanding the determinants of the location and health of adipose tissue can provide insight about the pathological consequences of obesity and can begin to outline targets for novel therapeutic approaches to combat the obesity epidemic. Although age and sex hormones clearly play roles in fat distribution and location, much remains unknown about gene regulation at the level of adipose tissue or how genetic variants regulate fat distribution. In this review, we discuss what is known about the determinants of body fat distribution, and we highlight the important roles of sex hormones, aging, and genetic variation in the determination of body fat distribution and its contribution to obesity-related comorbidities.

MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition

BackgroundAbdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored. MethodsAn initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue. FindingsWe found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways. InterpretationThese data identify a role for miR-196a in regulating human body fat distribution. FundThis work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.

Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans.

The sexual dimorphism in human body fat distribution suggests a causal role for sex hormones. This is of particular importance when considering the role of excess visceral adipose tissue accumulation as a critical determinant of obesity-related cardiometabolic alterations. Scientific literature on the modulation of body fat distribution by androgens in humans is abundant, remarkably inconsistent and difficult to summarize. We reviewed relevant literature on this topic, with a particular emphasis on androgen replacement, androgen effects on selected parameters of adipose tissue function and adipose tissue steroid-converting enzymes. In men, low androgenic status mostly reflected by reduced total testosterone is a frequent feature of visceral obesity and the metabolic syndrome. Regarding testosterone therapy, however, studies must be appreciated in the context of current controversies on their cardiovascular effects. Analyses of available studies suggest that decreases in waist circumference in response to testosterone are more likely observed in men with low levels of testosterone and high BMI at study onset. In women with androgen excess, higher testosterone and free testosterone levels are fairly consistent predictors of increased abdominal and/or visceral adipose tissue accumulation, which is not the case in nonhyperandrogenic women. Regarding mechanisms, androgens decrease adipogenesis and markers of lipid storage in vitro in men and women. Evidence also suggest that local steroid transformations by adipose tissue steroid-converting enzymes expressed in a depot-specific fashion may play a role in androgen-mediated modulation of body fat distribution. Accumulating evidence shows that androgens are critical modulators of body fat distribution in both men and women. © 2018 American Physiological Society. Compr Physiol 8:1253-1290, 2018.

Archaic Adaptive Introgression in TBX15/WARS2.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.

LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion

SummaryCommon variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Androgens, body fat Distribution and Adipogenesis.

Androgens are regulators of important adipocyte functions such as adipogenesis, lipid storage, and lipolysis. Through depot-specific impact on the cells of each fat compartment, androgens could modulate body fat distribution patterns in humans. Testosterone and dihydrotestosterone have been shown to inhibit the differentiation of preadipocytes to lipid-storing adipocytes in several models including primary cultures of human adipocytes from both men and women. Androgen effects have also been observed on some markers of lipid metabolism such as LPL activity, fatty acid uptake, and lipolysis. Possible depot-specific and sex-specific effects have been observed in some but not all models. Transformation of androgen precursors to active androgens or their inactivation by enzymes that are expressed and functional in adipose tissue may contribute to modulate the local availability of active hormones. These phenomena, along with putative depot-specific interactions with glucocorticoids may contribute to human body fat distribution patterns.

Region‐specific alterations in adipose tissue function: cardiometabolic risk goes belly‐up

Human body fat distribution patterns are heterogeneous and result from extrinsic influences (e.g. hormonal effects) and regional differences in intrinsic properties of adipose cells. The capacity of preadipocytes to differentiate and then store or mobilize lipids in each fat compartment is a major determinant of body fat distribution patterns. It also reflects the metabolic role of the cells of each region and directly relates to the high cardiometabolic risk closely associated with abdominal, visceral obesity. Visceral adipocytes (e.g. omental cells) are efficient for hypertrophy through lipid storage and show high lipolytic responsiveness, whereas subcutaneous cells have a high capacity for hyperplasia. We examined the potential of omental and subcutaneous adipose tissues as stem cell sources using the ceiling culture approach of adipocyte dedifferentiation. This cellular process generates multipotent mesenchymal stem cells through rapid downregulation of lipogenic/adipogenic transcripts and activation of matrix remodelling programs. Dedifferentiation is slightly more effective in subcutaneous than omental cells. Thus, adipose cell characteristics and origin closely relate to metabolic status and stem cell properties.

Racial differences in abdominal depot–specific adiposity in white and African American adults

There is increasing interest in understanding racial differences in adiposity in specific body depots as a way to explain differential health risks associated with obesity. Our aim was to examine the differences in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) between white and African American adults. The sample included 1967 adults aged 18-84 y, including 790 white women, 435 African American women, 606 white men, and 136 African American men. Total body fat was measured by using dual-energy X-ray absorptiometry, whereas abdominal VAT and SAT cross-sectional areas (L4-L5 level) were measured by using computed tomography. Sex-specific differences in SAT and VAT between racial groups were analyzed by the use of general linear models, which controlled for age and total body fat. Additional models tested for racial differences in VAT and SAT and controlled for age, total body fat, smoking, and menopausal status. Statistical significance was accepted at P < 0.05. Abdominal VAT was significantly higher in white than in African American men and women, even after adjustment for covariates. White women had significantly lower SAT than did African American women, both before and after adjustment for covariates. White men had significantly higher SAT than did African American men, but after adjustment for covariates, their SAT was lower than that of African American men. Abdominal visceral adiposity is significantly greater in white men and women. After adjustment for covariates, white men and women had significantly lower SAT than did African American men and women. The results of this study highlight the heterogeneity of human body fat distribution across racial groups.This trial was registered at clinicaltrials.gov as NCT00959270.

Mechanisms of androgenic action in adipose tissue

Androgens are involved in the modulation of adipose tissue function and body fat distribution in humans. The mechanisms involved include signaling through the androgen receptor and its coregulators as well as the crosstalk of several intracellular signaling pathways. Local modulation of androgen concentrations by steroid-converting enzymes, such as aldo–keto reductases 1C is associated with visceral fat accumulation and omental adipocyte enlargement. A recent study suggested that local androgen metabolism may be regulated by glucocorticoids in preadipocytes. Together, the available literature suggests that androgens possibly affect human body fat distribution through several potential mechanisms. This review article summarizes in vitro and in vivo findings on androgenic effects in adipose tissue, with a specific emphasis on signaling and pre-receptor regulation of androgen availability.

RARRES2, encoding the novel adipokine chemerin, is a genetic determinant of disproportionate regional body fat distribution: a comparative magnetic resonance imaging study

Visceral fat mass is a strong and independent predictor of obesity-related disorders. To date, little is known about the genetic determinants of regional body fat distribution in humans. As candidates of regional fat distribution, we investigated the fat mass– and obesity-associated gene, the peroxisome proliferator–activated receptor– δ gene, and the retinoic acid receptor responder 2 ( RARRES2) gene. We studied whether genetic variation within these genes contributes to the development of disproportionate visceral obesity and obesity-related traits, such as insulin resistance and β-cell dysfunction. We genotyped 337 subjects with an increased risk for type 2 diabetes mellitus for tagging single nucleotide polymorphisms (SNPs) in the 3 genes and performed association analyses with anthropometric data and parameters of insulin sensitivity and β-cell function. All subjects underwent an oral glucose tolerance test; a subset was additionally characterized by a hyperinsulinemic-euglycemic clamp. Body fat distribution was assessed by nuclear magnetic resonance imaging. The fat mass– and obesity-associated gene SNP rs8050136 was nominally associated with body mass index ( P = .0130), but not with body fat distribution, after appropriate adjustment. Magnetic resonance imaging–quantified visceral fat mass was significantly associated with RARRES2 SNP rs17173608 and nominally associated with RARRES2 SNP rs10278590 in nonobese subjects ( P = .0002 and P = .0423, respectively), with carriers of the minor alleles displaying lower visceral adipose tissue mass. Besides, the minor allele of SNP rs17173608 was nominally associated with a lower waist-to-hip ratio ( P = .0295). In obese subjects, these associations were not detected. No associations were found between the peroxisome proliferator–activated receptor– δ gene and measures of whole-body adiposity and of body fat distribution. All SNPs were associated neither with insulin sensitivity nor with insulin secretion. Common genetic variation within RARRES2 is associated with increased visceral fat mass in nonobese subjects. In generalized obesity, this genetic effect may be masked by the close association between whole-body obesity and visceral fat mass.

Sex steroids and leptin regulate 11β-hydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: Sex specificities

Adipose tissue is an important site of steroid hormone biosynthesis, as type I 11β-hydroxysteroid dehydrogenase (HSD1), the enzyme responsible for the conversion of cortisone into cortisol and the P450 aromatase, the enzyme catalysing androgens aromatization into estrogens, are both expressed in human adipose tissue. In the present report, we have investigated the possibility that sex steroids and leptin could regulate these two enzymes in cultured preadipocytes from men and women intra-abdominal fat depots. In women preadipocytes, human recombinant leptin down-regulates HSD1 mRNA expression (−58%) and P450 aromatase activity (−26%). Conversely, leptin up-regulates the HSD1 (2.4-fold) and the P450 aromatase (1.6-fold) mRNA expression in men preadipocytes. In women preadipocytes, 17β-estradiol strongly stimulates HSD1 mRNA expression (10-fold) and, in contrast, decreases by half the P450 aromatase expression. In men, 17β-estradiol has no influence on HSD1 expression but up-regulates P450 aromatase mRNA expression (2.4-fold). Finally, androgens increase by a factor of 2.5–5 the mRNA expression of both enzymes in men. These findings suggest that sex steroids and leptin either increase or decrease local cortisol and estrogens productions in men or in women preadipocytes, respectively. They also indicate that steroid metabolism in adipose tissue is controlled by a coordinated regulation of P450 aromatase and HSD1 expressions. Finally, the important sex-specific differences described herein may also contribute to explain the sexual dimorphism of body fat distribution in humans.

Parasympathetic Innervation May Mediate the Effect of Age and Gender on Body Fat Distribution in Humans

Parasympathetic Innervation May Mediate the Effect of Age and Gender on Body Fat Distribution in Humans

Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans.

We investigated whether serum concentrations of adiponectin are determined by body fat distribution and compared the findings with leptin. Serum concentrations of adiponectin and leptin were measured by radioimmunoassay (n = 394) and analyzed for correlation with sex, age, and body fat distribution, i.e., waist-to-hip ratio, waist and hip circumference, and subcutaneous adipose tissue area of the lower leg as assessed by magnetic resonance imaging. After adjusting for sex and percentage of body fat, adiponectin was negatively (r = -0.17, p < 0.001) and leptin was positively (r = 0.22, p < 0.001) correlated with waist-to-hip ratio. Leptin, but not adiponectin, correlated with both waist (r = 0.49, p < 0.001) and hip circumference (r = 0.46, p < 0.001). Furthermore, leptin, but not adiponectin, correlated with the proportion of subcutaneous fat of the lower leg cross-sectional area (r = 0.37, p < 0.001). These data suggest that both adipocytokines are associated with central body fat distribution, and serum adiponectin concentrations are determined predominantly by the visceral fat compartment.

Hormonal control of regional fat distribution.

Hormones exert powerful influences on body fat distribution in humans. Studies under fully controlled conditions in vitro have indicated that cortisol and insulin facilitate lipid accumulation by expressing lipoprotein lipase (LPL). Growth hormone (GH) abolishes this and turns metabolism towards lipid mobilization. Testosterone and GH inhibit LPL and stimulate lipolysis markedly. Cortisol effects are mediated via a glucocorticoid receptor, and testosterone effects via an androgen receptor, the density of which appears to be higher in visceral than subcutaneous adipose tissue. The receptor-mediated effects are probably expressed via transcription of appropriate genes. The female sex steroids also regulate adipose tissue metabolism, but apparently not directly in the absence of specific cellular receptors. Oestrogens seem to exert net effects similar to those of testosterone. These results of cellular studies agree well with in-vivo studies of triglyceride uptake and turnover in different adipose tissue regions. Furthermore, clinical entities with characteristic disturbances in hormone levels show the expected redistribution patterns.

DNA Polymorphisms in the α2‐ and β2 Adrenoceptor Genes and Regional Fat Distribution in Humans: Association and Linkage Studies

The aim of this study was to investigate the relationships between DNA restriction fragment length polymorphisms (RFLP) in the alpha 2- and beta 2-adrenoceptor genes and body fat distribution in humans. Skinfold thickness measurements and genetic analyses (Southern blot) were performed on 280 individuals (142 parents and 138 offsprings) from the Québec Family Study. Using the association study design in unrelated adults, women but not men carrying the 6.3-kb allele of an alpha 2A-adrenoceptor/DraI RFLP had a significantly higher trunk to extremity skinfold ratio (= sum of subscapular+suprailiac+abdominal skinfolds/sum of biceps+triceps+medial calf skinfolds) compared to women without the allele (1.44 +/- 0.52 vs. 1.12 +/- 0.33; p < 0.005 after adjustment for age, p < 0.002 after adjustment for age and body mass index or for age and subcutaneous fat). Using the sib-pair linkage procedure, a significant inverse relationship was found between the proportion of alleles identical by descent shared by sibs at the alpha 2A RFLP marker locus and the squared differences of the trunk to extremity skinfold ratio (p = 0.02 after adjustment for age or for age and body mass index or for age and subcutaneous fat). For a beta 2-adrenoceptor/BanI RFLP, no significant association or linkage was found between fat distribution indicators and the marker. These results suggest that alpha 2A-adrenoceptor gene variability detected with DraI is associated with a relative subcutaneous fat pattern favoring accumulation of truncal-abdominal fat in women, and that the alpha 2A-adrenoceptor gene, or a locus in close proximity, may be linked to body fat distribution in humans independently of the overall level of fatness.

Cellular mechanisms for the regulation of adipose tissue lipid metabolism in pregnancy and lactation.

Pregnancy and lactation are two physiological situations in which major metabolic adaptations of the mother must occur to sustain the different and varying demands of foetal growth and milk production. The extra energy needs are met by increased food intake and/or by mobilization of stored fuels. The latter are mainly triacylglycerols contained in adipose tissue. In this contribution the changes in adipose tissue lipid metabolism during pregnancy and lactation in the rat and the cellular mechanisms which may control them are discussed. Although alterations in lipid metabolism during reproduction in the rat are more pronounced and therefore easier to measure than in the human, it is likely that the strategies and mechanisms employed are similar. To understand them it is first necessary to outline the regulation of lipid deposition and mobilization in the normal situation. For more wide-ranging reviews of adipose tissue lipid metabolism and its regulation the reader is referred to Saggerson (1985) and Vernon and Clegg (1985) and, for particular information on human adipose tissue, to Galton (1971). Factors regulating the physiological control of body fat distribution in humans are discussed by Leibel and colleagues (1989).

Physiologic basis for the control of body fat distribution in humans.

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