Resistance to high fat diet-induced obesity but exacerbated insulin resistance in mice overexpressing Pref-1: a new model of partial lipodystrophy

Objective. White adipose tissue is a critical regulator of whole body glucose metabolism. Pref-1 is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole body glucose homeostasis and its contribution to the development of insulin resistance. Research Design and Methods. To gain insights into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild type control mice fed a high fat diet. Results. Mice overexpressing Pref-1 were resistant to high fat diet-induced obesity as reflected by a marked reduction in adipose tissue mass. However, Pref-1 overexpressing mice were severely insulin resistant, mainly due to a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle. Conclusions. Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders.

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