We continue our collaboration with the Cushman lab (NIDDK) and several extramural 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. In contrast, we have found that in a group of leaner, younger subjects who were first degree relatives of type 2 diabetics that the size of the large cells is positively correlated with insulin resistance (paper in preparation). We suggest that this is because the leaner subjects are still able to expand their adipose cells whereas the more obese subjects have reached the limit of cell expansion (hypertrophy) and must recruit new cells (hyperplasia). Furthermore, administration of insulin-sensitizing drugs, such as pioglitazone or rosiglitazone, leads to both recruitment of new cells, which increases the proportion of small cells, and expansion of existing large cells (paper in preparation). Thus, in all these cases the distribution of adipose cell sizes is related to metabolic status, but the particular response is dependent on the metabolic status and history of the subject. We suggest that the ability of subjects to properly store lipids in adipose tissue, and avoid spillover to other tissues not equipped to handle large quantities of lipids, is central to insulin sensitivity. We have also extended our studies to obese adolescents in collaboration with the Caprio lab at Yale. Previous studies had shown that insulin resistance was associated with a high proportion of visceral adipose tissue (VAT) in relation to total adipose tissue (VAT plus SAT, subcutaneous adipose tissue), or VAT/(VAT + SAT). In addition, those subjects were more likely to exhibit ectopic deposit of fat in the liver (hepatic steatosis). We obtained subcutaneous abdominal adipose tissue and carried out a cell size analysis and found that subjects with high VAT/(VAT + SAT) had larger large adipose cells but a smaller proportion of large cells. Microarray analysis of genes involved in lipid metabolism also showed deficiencies in the high VAT/(VAT + SAT) group. Although causation cannot be determined in this type of study, we suggest that impairments in lipid storage in subcutaneous tissue are involved in insulin resistance. The results have been published in Ref. # 1.
