Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPARγ hypomorphic mice

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPARγ2-specific exon B, resulting in a white adipose tissue knockdown of PPARγ. Although homozygous (PPARγ ^hyp/hyp) mice are born with similar weight as the WT mice, the PPARγ^hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPARγ ^hyp/hyp mice die before adulthood, whereas the surviving PPARγ^hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPARγ^hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPARγ^hyp/hyp mice unequivocally demonstrate that PPARγ is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.