Recent evidence from human studies suggests that adipocytes turnover throughout adult life. While it has long been thought that adult adipocytes are generated from a stem cell population, recent lineage mapping experiments in mice provide strong evidence for an adipocyte precursor residing within adipose tissue. Many questions regarding the role of adipocyte turnover during normal homeostasis and in obesity remain incompletely elucidated, in large part because there have not been definitive methods to quantitate adipogenesis in vivo. The central hypothesis of this project is that caloric excess results in dynamic changes in precursor-dependent white adipose turnover. Deconstructing the role of adipogenesis in obesity and diabetes will not only yield important mechanistic insight into these disease processes, but may provide the rationale to directly target adipogenesis with pharmacotherapies. To address the central hypothesis, novel approaches to quantitate adipogenesis in vivo using stable isotope labeling and two mass spectrometry based platforms will be utilized. Rare stable isotopes differ in mass from more common isotopic forms of elements, but they are not radioactive, and thus are entirely safe and biologically inert. Preliminary data suggests that stable isotope-enriched thymidine is an effective tracer to detect DNA synthesis and cellular division. Using pulse-chase strategies and mass spectrometry, including multi-isotope mass spectrometry (MIMS) an exciting new microscopy methodology that can detect areas of stable isotope incorporation within tissues with sub-cellular resolution, adipogenesis can be quantified after biologically relevant interventions, in vivo.
Aim 1 : To test the hypothesis that high fat feeding will result in a dynamic increase in white adipose adipogenesis. Adult mice will be randomized to a normal diet or an adipogenic (high-fat) diet, and two stable isotope based approaches will be used to determine whether adipose expansion as occurs in obesity is associated with increased generation of new adipocytes.
Aim 2 : To test the hypothesis that prolonged high fat feeding with resultant obesity-related insulin resistance results in a relative deficiency in subcutaneous adipogenesis in favor of increased visceral adipogenesis. The rates of adipogenesis will be compared between obese and lean mice in response to a high fat diet, with the aim to answer the question of whether obesity results in depot specific defects in adipogenesis, which may contribute to coexistent insulin resistance.
Aim 3 : To test the hypothesis that PPAR-gamma activation will stimulate white adipose adipogenesis, in vivo. Stable isotope methods will be used to quantitate adipogenesis after pharmacologic stimulation of PPAR-gamma with a thiazolidinedione in obese and lean mice.
Obesity and Type 2 Diabetes Mellitus represent major causes of morbidity and mortality in the developed world. Defining the capacity to generate new fat cells in states of Obesity and Diabetes may yield a critical mechanistic link between these related diseases. This project will study the role of new fat cell formation in obesity and diabetes, an understanding of which may provide the therapeutic rationale to pharmacologically control fat cell formation.
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