PPAR gamma 2 Prevents Lipotoxicity by Controlling Adipose Tissue Expandability and Peripheral Lipid Metabolism

Abstract

Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2^−/− Lep^ob/Lep^ob (POKO mouse), resulted in decreased fat mass, severe insulin resistance, β-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the β-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of β-cells to insulin resistance. It is known that obesity is linked to type 2 diabetes, however how obesity causes insulin resistance and diabetes is not well understood. Some extremely obese people are not diabetic, while other less obese people develop severe insulin resistance and diabetes. We believe diabetes occurs when adipose tissue becomes “full,” and fat overflows into other organs such as liver, pancreas, and muscle, causing insulin resistance and diabetes. Peroxisome proliferator activated receptor gamma (PPARg) is essential for the development of adipose tissue and control of insulin sensitivity. PPARg2 is the isoform of PPARg regulated by nutrition. Here we investigate the role of PPARg2 under conditions of excess nutrients by removing the PPARg2 isoform in genetically obese mice, the POKO mouse. We report that removing PPARg2 decreases adipose tissue's capacity to expand and prevents the mouse from making as much fat as a normal obese mouse, despite eating similarly. Our studies suggest that PPARg plays an important antitoxic role when it is induced in liver, muscle, and beta cells by facilitating deposition of fat as relatively harmless lipids and thus prevents accumulation of toxic lipid species. We also show that PPARg2 may be involved in the adaptive response of beta cells to insulin resistance.