Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

Agrawal, Saaket; Wang, Minxian; Klarqvist, Marcus D. R.; Smith, K. E.; Shin, Joseph; Dashti, Hesam; Diamant, Nathaniel; Choi, Seung Hoan; Jurgens, Sean J.; Ellinor, Patrick T.; Philippakis, Anthony; Claussnitzer, Melina; Ng, Kenney; Udler, Miriam S.; Batra, Puneet; Khera, Amit V.

doi:10.1038/s41467-022-30931-2

Cited by 77 publications

(71 citation statements)

References 122 publications

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“…In rare Mendelian lipodystrophies – as occurs in individuals who harbor pathogenic LMNA mutations – an extreme example of this paradigm leads to marked reduction of ASAT and GFAT but increased VAT and increased rates of severe insulin resistance 41 . Whether individuals in the extreme tails of low GFATadjBMI and ASATadjBMI or high VATadjBMI might be enriched for genetic perturbations in lipodystrophy genes or the inherited component to these metrics is largely ‘polygenic’ – due to the aggregate effects of many common DNA variants, each of modest effect size – warrants further study 42 – 44 . Sex differences will also be important to consider in future studies on local adiposity – for example, here we demonstrate that ASATadjBMI and GFATadjBMI are more correlated in male participants than in female participants, which may point to sex-dependent fat depot specificity.…”

Section: Discussionmentioning

confidence: 99%

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases

et al. 2023

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For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results – describing three metabolically distinct fat depots at scale – clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.

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Section: Discussionmentioning

confidence: 99%

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases

et al. 2023

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“…A recent study demonstrated that distinct sets of genetic variants associated with a higher WHR but either with lower gfSAT or with higher VAT are both associated with higher risks of T2D and CVD [ 60 ]. Inversely, the stratification of individuals based on the polygenic scores relevant for the volumes of gfSAT, abdominal SAT (aSAT) or VAT showed that the individuals with higher gfSAT scores exhibited better cardio-metabolic profile with higher HDL-cholesterol, lower plasma triglycerides and lower risks of T2D and CVD [ 61 ]. Therefore, the inability of gfSAT to expand may be a determinant in unhealthy fat distribution promoting central fat depots.…”

Section: Sex Differences In Fat Depots and Cardiometabolic Healthmentioning

confidence: 99%

“…Expression quantitative trait loci (eQTLs) analysis in relevant tissues together with exome sequencing further highlighted enrichment in the brain- or peripheral-tissue-related pathways as a determinant for BMI or WHRadjBMI, respectively. For example, the predictive loss of function (pLoF) of adipocyte-expressed PLIN1 , INSR , ACVR1C and PDE3B and liver-expressed INHBE variants are associated with increased gfSAT and healthy metabolic phenotypes [ 61 , 70 , 71 ]. Importantly, WHRadjBMI-associated loci exhibit heritability and effect size stronger in women than men with one-third of all signals sexually dimorphic [ 72 ].…”

Section: Determinants Of the Fat Depot Repartition According To The Sexmentioning

confidence: 99%

“…The GWAS highlight several peripheral tissue- and cell-enriched pathways as determinants for WHRadjBMI suggesting that WAT intrinsic cell composition, function and remodeling are key contributors in fat depot repartition [ 61 , 70 , 71 ]. Recent single-cell atlas of human and mouse WAT provides a transcriptional basis of the heterogeneity in subsets of resident progenitors and adipocytes with fat depot-specific prevalence and functions [ 82 ].…”

Section: Determinants Of the Fat Depot Repartition According To The Sexmentioning

confidence: 99%

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The Sexual Dimorphism of Human Adipose Depots

et al. 2022

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The amount and the distribution of body fat exhibit trajectories that are sex- and human species-specific and both are determinants for health. The enhanced accumulation of fat in the truncal part of the body as a risk factor for cardiovascular and metabolic diseases is well supported by epidemiological studies. In addition, a possible independent protective role of the gluteofemoral fat compartment and of the brown adipose tissue is emerging. The present narrative review summarizes the current knowledge on sexual dimorphism in fat depot amount and repartition and consequences on cardiometabolic and reproductive health. The drivers of the sex differences and fat depot repartition, considered to be the results of complex interactions between sex determination pathways determined by the sex chromosome composition, genetic variability, sex hormones and the environment, are discussed. Finally, the inter- and intra-depot heterogeneity in adipocytes and progenitors, emphasized recently by unbiased large-scale approaches, is highlighted.

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“…All participants from this study who donated samples gave informed consent, and the National Bioethics Committee of Iceland approved the study, which was conducted in agreement with conditions issued by the Data Protection Authority of Iceland (VSN_14-015). Genome-wide effect estimates on measures of fat distribution were obtained from a recent study on 38,965 UK Biobank participants who analysed MRI-derived measures of visceral, abdominal subcutaneous and gluteofemoral fat tissue volumes [17].…”

Section: Adulthood Estimates Of Circulating Leptin Levels and Fat Dis...mentioning

confidence: 99%

Time-varying and tissue-dependent effects of adiposity on leptin levels: a Mendelian randomization study

Richardson

Leyden

Smith

2022

Preprint

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BackgroundFindings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.MethodGenetic instruments for childhood and adult adiposity were used to estimate lifestage specific effects on leptin levels measured during early life (mean age:10 years) in the Avon Longitudinal Study of Parents and Children (ALSPAC) and in adulthood (mean age:55 years) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MR to simultaneously estimate their separate effects on childhood and adult leptin levels.ResultsThere was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 years in the lifecourse (Beta=1.10, 95% CI=0.90 to 1.30, P=6×10−28), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (Beta=0.74, 95% CI=0.62 to 0.86, P=1×10−33). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain-tissue mediated pathways (Beta=0.79, 95% CI=0.22 to 1.36, P=6×10−3& Beta=0.51, 95% CI=0.32 to 0.69, P=1×10−7respectively).ConclusionsOur findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the aetiological importance of appetite regulation in the effect of adiposity on leptin levels, as well as raising implications for the gene-environment equivalence assumption in MR.FundingThis work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).

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Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

Cited by 77 publications

References 122 publications

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases

The Sexual Dimorphism of Human Adipose Depots

Time-varying and tissue-dependent effects of adiposity on leptin levels: a Mendelian randomization study

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