Obesity is associated with adipose dysfunction, which contributes to insulin resistance, diabetes, and heart disease. It has been proposed that adipose dysfunction is caused by an inappropriate response to hypoxia that results in increased ECM expression and reduced angiogenesis. Our data indicate that adipocytemacrophage crosstalk results in increased expression of thrombospondin-1 (TSP-1), a multifunctional protein that promotes fibrosis by activating TGF-beta signaling. TGF-beta has multiple effects on adipose in addition to inducing fibrosis including inhibiting adipogenesis and complicated effects on angiogenesis. Recently, a whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with improved metabolic function and browning of their white adipose;this was due in part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha. Our overall hypothesis is that increased TSP-1 expression and TGF-beta signaling in white adipose with obesity cause increased fibrosis, reduced capillary density, reduced PGC-1 alpha and reduced UCP-1 expression hence less "browning", and impaired WAT function. Thus, inhibiting the TGF-beta pathway in humans may improve adipose function and reverse the effects of obesity on insulin resistance.
The first aim will characterize the white adipose ECM and capillary density of TSP-1 knockout mice and their littermate controls challenged with a high fat diet.
The second aim will knockout TGF-beta in adipose using cre/lox technology to elucidate the role of TGF-beta signaling on adipose function is response to high fat feeding.
The third aim will determine whether the dramatic reduction in adipocyte PGC-1 alpha by macrophage coculture is TGF-beta dependent.
The fourth aim will determine whether toll-like receptor (TLR) signaling is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta signaling in macrophages. Thus, the two mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose dysfunction with obesity. The coculture studies will begin to define the mechanisms by which adipocytes and macrophages communicate with each other to induce TSP-1 expression by both cells types and to decrease PGC-1 alpha expression in adipocytes.
Adipose tissue becomes dysfunctional with obesity by a complex process. We hypothesize that TGF-beta signaling contributes to this by promoting adiopose fibrosis and by inhibiting the ability of adipose to metabolize fat;inhibiting TGF-beta signaling may be an effective method to combat obesity.
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