Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

Abstract

Upper-and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m 2 ). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depotspecific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper-and lower-body obesity.Lower-body fat accumulation, as opposed to central obesity, is inversely associated with metabolic risk factors, including hyperinsulinemia, dyslipidemia, and hypertension (1), and is also associated with a reduced incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) (2,3). Conversely, loss of lower-body fat during weight reduction relates to adverse changes in blood lipid and glucose profiles as well as blood pressure (4).

Effects of a multi-component camp-based intervention on inflammatory markers and adipokines in children: A randomized controlled trial

“…A recent study demonstrated that gluteal subcutaneous adipose tissue (GSAT) had less inflammatory profiles than abdominal subcutaneous adipose tissue (ASAT). The release of IL-6 was higher from ASAT than from GSAT (Pinnick et al, 2014). The authors also observed that the android fat mass was positively associated with insulin resistance and CRP, whereas the opposite was seen for gynoid fat mass after adjusting for total fat mass.…”

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects

“…The gene was identified as a regulator of preadipocyte proliferation and adipogenic differentiation in abdominal adipose tissue under epigenetic control. 36 The zinc finger protein 714 (ZNF714) exhibited the highest DNA methylation difference and was mapped by 5 DMCpGs located in island/shore and promoter regions. The gene was found to present lower methylation levels in IR than in IS patients in association with increased transcription levels.…”

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

“…As part of the 1 H-MRS spectra of liver metabolites, hepatic glycogen was measured (one peak, chemical shift 3.984), and content as a percentage of the liver water determined. Whole-body composition and fat distribution were measured using DEXA (21).…”