Compounds that activate the nuclear receptor PPARy are effective in the treatment of type 2 diabetes through their potent insulin sensitizing effects. Despite their impressive benefits, the thiazoladinedione (TZD) class of synthetic PPARy agonists also cause weight gain and fat accumulation. Although this weight gain is often attributed to the effect of PPARy activation to promote adipocyte differentiation and lipid storage, studies have confirmed that TZDs induce hyperphagia in rodents and that this increase in food consumption largely accounts for weight gain induced by these drugs. Reports in humans also suggest that TZDs increase hunger. Here, we investigate the hypothesis that weight gain induced by PPAR? agonists is mediated, at least in part, through a central nervous system (CNS) mechanism whereby neuronal PPARy activation stimulates feeding centers in the brain. Extending this hypothesis, we also propose that PPARy plays a physiological role to promote normal feeding and, consequently, that reduced neuronal signaling via this receptor will promote weight loss and protect against pathological weight gain. Our strategy is four fold: 1) to characterize the distribution of PPARy in specific areas of the brain that regulate feeding, 2) to determine if systemic TZD administration causes weight gain via activation of PPARy in the CNS in rodent models, 3) to identify cellular mechanisms that underlie PPARy mediated feeding, and 4) to determine if central administration of PPARy antagonists reduces food intake and body weight. The CNS expression distribution of PPARy will be mapped by immunostaining and in-situ hybridization in rodents. To selectively modulate PPARy activity in the brain, PPARy ligands will be delivered at low doses to rats through a cerebral cannula and the effects on food intake will be monitored. Biochemical analysis will be performed on discrete feeding-relevant brain areas to determine if infusion of PPARy ligands (both centrally and systemically) has measurable effects on PPARy activity and on cellular pathways implicated in the control of food intake. These studies investigate a novel hypothesis of high potential importance to both the treatment of type 2 diabetes and the regulation of body weight. Accordingly, the outcome of these experiments could lead to the development of novel drug therapies for the treatment of obesity and type 2 diabetes.

Public Health Relevance

These studies investigate whether a factor which controls fat growth and blood sugar levels can regulate feeding behavior and body weight through its actions in the brain. This research will further our understanding of the molecular pathways which control weight gain, appetite, and blood sugar levels, and may lead to the development of new treatments for obesity and diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F06-C (20))
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Castle, Arthur
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Lu, Min; Sarruf, David A; Li, Pingping et al. (2013) Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J Biol Chem 288:10722-35
Lu, Min; Sarruf, David A; Talukdar, Saswata et al. (2011) Brain PPAR-? promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 17:618-22
Sarruf, David A; Thaler, Joshua P; Morton, Gregory J et al. (2010) Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 59:1817-24