The Role of AEBP1 in Sex-Specific Diet-Induced Obesity
Obesity is an important risk factor for heart disease, diabetes, and certain cancers, but the molecular basis for obesity is poorly understood. The transcriptional repressor AEBP1, which functions as a negative regulator of PTEN through a protein-protein interaction, is highly expressed in the stromal compartment of adipose tissues, including proliferative preadipocytes, and its expression is abolished in terminally differentiated, nonproliferative adipocytes. Here we show that transgenic overexpression of AEBP1 during adipogenesis coupled with a high-fat diet (HFD) resulted in massive obesity in female transgenic (AEBP1TG) mice via adipocyte hyperplasia. AEBP1 levels dynamically changed with aging, and HFD induced AEBP1 expression in females. Thus, HFD-fed AEBP1TG females display hyperinduction of AEBP1 and a marked reduction of PTEN level with concomitant hyperactivation of the survival signal in white adipose tissue. Our results suggest that AEBP1 plays a key functional role in in vivo modulation of adiposity via fat-cell proliferation and is involved in a sex-specific susceptibility to diet-induced obesity by the estrogen signaling pathway.
We are indebted to Bradford Lowell and Joel A. Lawitts for their support in this work, which was initiated during H.-S.R.’s sabbatical leave from the Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School. This work was supported by grants from the Canadian Diabetes Association, the Heart and Stroke Foundation (Nova Scotia) of Canada (HSFC), the Natural Sciences and Engineering Research Council (NSERC) of Canada, and Canadian Institutes of Health Research (CIHR) to H.S.R. We acknowledge the support of the HSFC Visiting Scientist Award to H.S.R. and the Postdoctoral Fellowship Program of Korea Science & Engineering Foundation (KOSEF) to H.-J.L.
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