Adipocyte development and insulin resistance

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Our hypothesis is that cell-size dependent cell death is an important component of adipose tissue remodeling under changing diet conditions. In mammals, fat must be either utilized or stored. Thus, we hypothesize that a dysfunction in adipose tissue growth may be a key factor in peripheral insulin resistance. Adipose tissue growth requires the recruitment and then the development of adipose precursor cells, but little is known about these processes in vivo. In this study, adipose cell-size probability distributions were measured in two Zucker fa/fa rats over a period of 151 and 163 days, from four weeks of age, using micro-biopsies to obtain subcutaneous (inguinal) fat tissue from the animals. These longitudinal probability distributions were analyzed to assess the probability of periodic phenomena. Adipose tissue growth in this strain of rat exhibits a striking temporal periodicity of approximately 55 days. We proposed a simple model for the periodicity, with PPAR signaling driven by a deficit in lipid uptake capacity leading to the periodic recruitment of new adipocytes. This model predicts that the observed period will be diet-dependent. We are collaborating with the Cushman laboratory to obtain data that tests this hypothesis. Thiazolidinediones (TZDs) are insulin-sensitizing drugs. They have multiple mechanisms of action as ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ ). A particularly interesting action is on adipose tissue. The hypothesis that a TZD regimen involving repeated treatments of limited duration may suffice for improvements in insulin sensitivity merits investigation. The Zucker fatty rat is a well-studied model of obesity. We treated three Zucker fatty rats with daily doses of rosiglitazone and kept three as controls. We developed a micro-biopsy technique to measure adipose cell-size distributions without killing the animal so we could follow the development of adipose tissue in the same animal over time, thus avoiding inter-animal variation evident in our preliminary experiments. We found that TZD treatment leads to adipose cell-size increase and adipose cell number increase. The adipose cell number increase appears to take place mostly over the first eight days of treatment. The availability of additional lipid storage due to treatment may alleviate lipotoxicity and thereby promote insulin sensitivity. Adipose tissue dynamically adapts to an excess or a scarcity of energy availability. The capacity of energy storage can be regulated by changes in adipose cell number or in cell size. We extended this model to take into account new data from the Hall group on changes in cell-size distributions under weight loss due to diet change. We find that apoptosis at small cell sizes and lipolysis can account for the weight loss data, but that cell death for large cells occurs for extended periods of high-fat feeding. In this study, we take advantage of precise measurements of adipose cell-size probability distributions to mathe- matically model changes in these distributions of C57BL/6 mice under continuous high-fat diet and under diet change from high-fat to regular diet. We examined intra-abdominal epididymal, mesenteric, and retroperitoneal fat as well as subcutaneous inguinal fat to see the fat-depot specific responses to diets. Although high-fat diet enlarges adipose cells and increases cell number initially, in the longer-term there is a failure to store excess energy. Large adipose cells are more susceptible to cell death, however the number of newly re- cruited adipose cells decreases as well because the high demand of differentiation shrinks the self-renewal pool of adipose precursor cells. Under diet change from high-fat to regular diet, adipose cells shrink and cell number decreases. Compared with the passive decrease of cell number under continuous weight gain, cell death mainly occurs at small cells under weight loss, suggesting an active mechanism to decrease the potential capacity of energy storage. These changes of adipose tissue under weight gain and loss were common in the four fat depots. Based on the quantitative modeling of adipose cell-size distributions, we conclude that adipose tissue can regulate cell growth and death depending on cell size to adjust to the demands of energy storage.