UCLA

Obesity and metabolic dysfunction are prevalent in the United States and often lead to severe secondary health complications including type 2 diabetes, cardiovascular disease, and certain forms of cancer. Peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis, is the target of antidiabetic thiazolidinedione (TZD) drugs. Although TZDs have shown strong insulin sensitizing and glucose lowering effects in human subjects, they promote adiposity and deleterious off-target effects in the heart. For these reasons, we need to determine more elegant ways to harness the power of this transcription factor to improve therapeutic efficacy. Moreover, the sex- and tissue-specific molecular actions of PPARγ remain incompletely understood. To address these gaps in our understanding, we have generated PPARγ muscle-specific knockout (MKO) mice. We propose to investigate the muscle-specific actions of PPARγ in male and female mice. Our findings suggest that PPARγ acts in an antagonistic manner to dampen the insulin sensitizing effects of estrogen in skeletal muscle of female animals and estrogenized males.