Mechanisms regulating functional heterogeneity of subcutaneous adipose tissues in women

Summary Accumulating evidence indicates that lower body (LB) fat distribution, independent of visceral and total adiposity, decreases risk for metabolic diseases such as type 2 diabetes that afflict ~7-15% of Americans. Premenopausal women who have a LB fat distribution, i.e. `pear' as compared to `apple' shape, are protected from metabolic disease. LB (gluteal-femoral) and upper body (UB) subcutaneous adipose tissues (SAT) are developmentally distinct and vary in metabolic and endocrine function. The ability of adipose depots to expand or remodel via hyperplasia, i.e. recruitment of adipose progenitors, is critical for maintaining adipose function. In vivo studies indicate that the rates of appearance of new preadipocytes and adipocytes are higher in femoral (FSAT) than abdominal SAT (ASAT). In addition, there are also depot differences in adipocyte size and metabolic function. The microenvironment within SATs may result from cell autonomous differences in adipose progenitors from different depots that influence their secretome and persist after culture ex vivo. We will test the hypothesis that adipose progenitors from LB fat depots of women with `apple' shape and low FSAT mass have a more limited ability to remodel due to 1) an inability to recruit adipose progenitors, 2) decreased capacity to increase fat storage. We further hypothesize that depot differences in the growth and metabolism of UB and LB SATs are related to differences in cell composition and their secreted products that determine the microenvironment within each depot. Toward the long-term goal of understanding the mechanisms underlying the association of fat distribution and metabolic health in humans, we will use single cell RNAseq to interrogate the cell composition of ASAT and FSAT in two groups of non-obese, healthy premenopausal women – one with a `pear shape' and the other `apple shape' and sample adipose tissue from each SAT. We will focus Aim 1 on defining populations of cells in fibroblastic/adipose stem cells and test their adipogenic potential. We will assess how the adipogenic capacity of adipose progenitors differs as a function of body fat distribution, metabolic status, and the size and number of mature adipocytes in each SAT of the donor. Aim 2 will use LC MS/MS to compare the secretome of ASAT and FSAT to assess if depot differences and will test the effects of differentially expressed secreted factors on the proliferation and differentiation of LB and UB APs in culture with loss and gain of function studies. We expect that these analyses will allow us to discover markers for the ability of human SAT depots to remodel and maintain healthy function to decrease risk for metabolic disease in women. These tools will be invaluable for future studies of sex differences in adipose tissue function, testing how different SAT respond to dietary challenges, and developing interventions to improve metabolic status and prevent the onset of metabolic disease.