Genetic Analysis of Adipose Lineage and Development



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Adipose tissues protect t against traumatic and thermal insults, and regulate lifespan, reproduction and metabolism. The importance of forming the appropriate number of adipocytes is highlighted by the significant metabolic disturbances that accompany too few (lipodystrophy) or too many (obesity) adipocytes. Most of our current understanding about adipocyte formation come from in vitro culture studies. Little is known about adipose development in vivo because of the lack of genetic tools. To this end, I generated a few knock-in mice that offer both spatial and temporal controls to manipulate gene expression in adipose tissues. Here I demonstrate the application of one of the tools, PPARgamma tTA, in exploring some important aspects of adipose development, such as the adipose depot specification, the identity of adipocyte progenitor cells and their anatomical niche. Adipose tissues form throughout the body in various places in a stereotypical pattern, with each adipose depot displaying distinctive properties. As the first step to understand depot specificity, I used the PPARgamma tTA mice for lineage tracing on adipose tissues, and found that each adipose depot is specified at very distinctive developmental stages, suggesting that different adipose depots are derived from distinct origins. With new genetic tools, I also marked and isolated adipogenic progenitors. I found that the majority of adipocytes descend from a pool of PPARgamma -expressing proliferateing progenitors already commited early in post-natal life, prior to the development of most adipocytes. These progenitors are morphologically and moleculary distinct from adipocytes, have high potential to undergo adipogenesis both in vitro and in vivo after transplantation. Interestingly, some progenitors reside in the mural cell compartment of blood vessels that supply adipose depots and not in vessels of other tissues. The identification of the adipocyte progenitor and localization to the blood vessel wall indicate the presence of a vascular niche in adipose development and provide a basis to examine the interplay between adipogenesis and angiogenesis that could be exploited as a new avenue for obesity and diabetes therapies.

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