Adipogenesis and Insulin Resistance

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We continue our collaboration with the Cushman (NIDDK) and Reaven (Stanford) labs to analyze cell-size distributions in adipose tissue in order to elucidate relationships between fat cell size and insulin resistance. We previously reported that such distributions are roughly bi-model, with a Gaussian peak of large, mature cells and an exponential tail of small cells. In contrast to prior hypotheses, we found that the size of the large fat cells per se is not associated with insulin resistance (IR) when moderately obese subjects are matched for obesity. Rather, we found a correlation between the proportion of large cells and IR, with resistant subjects having a deficit of large cells. We proposed that this reflects an impairment of adipocyte differentiation and leads to insufficient fat storage capacity and ectopic fat deposition in other organs, such as liver, pancreas, and muscle, that are not well equipped to handle large volumes of fat. Further cross-sectional study of insulin-sensitive and resistant subjects has examined the relationship between IR and expression of inflammation genes. We studied 14 IR and 19 IS moderately obese women (Ref. #2). Several genes associated with inflammation (CD68, EMR1, IL8, IL6, and MCP/CCL2)were significantly increased in the IR group. We also investigated the relationship between inflammation gene expression and cell size characteristics. We found that inflammation and IR are independently associated with a reduced proportion of large cells (Ref. # 3). In contrast to other studies, we did not find a relationship between the size of the large cell sub-population and inflammation. Thus, our study does not support the hypothesis that inflammation is associated with larger adipose cells, at least in moderately obese individuals. In sum three properties, IR, inflammation, and diminished large-cell proportion, thus seem to form a triangular complex. Further work is needed to determine whether inflammation impairs adipose cell differentiation or impaired differentiation predisposes to inflammation. The above studies were conducted using subcutaneous adipose tissue (SAT), but we were able to obtain samples of visceral adipose tissue (VAT) as well from bariatric surgery patients (11 females; Ref. # 1). We found that the SAT cells were larger than the VAT cells. Interestingly, in SAT, the size of the large cells increased with the percentage of small cells, which may reflect a form of conservation of fat mass: a given amount of fat can be stored in many small cells or few large cells. This relationship did not hold in VAT, which may indicate that VAT is not primarily a global storage organ but serves a different set of functions, such as signaling or local storage. We also found that several inflammation markers were increased in VAT relative to SAT. We have also extended these studies to intervention with the insulin sensitizer, pioglitazone (Ref. # 4). We found that the drug led to an increase of the proportion of small cells, perhaps reflecting increased recruitment of new adipocytes from precursor cells. In support of this, CT scans of subcutaneous tissue combined with the distribution of cell size allowed us to estimate the average volume per cell and the numbers of small and large cells. The drug increased the number of small cells but did not reduce the number of large cells. Although this seems superficially at odds with the previously reported higher proportion of large cells in insulin sensitive subjects, we note that amelioration of insulin resistance by drug treatment does not necessarily restore the metabolic state of an insulin resistant subject to that of a normal subject. The finding is also consistent with the observation that the subjects experienced a decrease of visceral adipose tissue volume and an increase in abdominal subcutaneous adipose tissue volume, suggesting a transfer of fat from one compartment to the other permitted by the recruitment of new small subcutaneous cells. Finally, it is possible that the newly recruited small cells would eventually accumulate more fat and become large. Further study is needed to determine whether the biological activity of the small cells is different from that of the large cells.