Editors' ChoiceDiabetes

Understanding PPAR-γ Action—Just Use Your Brain!

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Science Translational Medicine  25 May 2011:
Vol. 3, Issue 84, pp. 84ec77
DOI: 10.1126/scitranslmed.3002658

Although obesity contributes to the development of type 2 diabetes, a key side effect of one class of antidiabetic drugs—the thiazolidinediones (TZDs)—is weight gain. TZDs are agonists of the nuclear receptor peroxisome proliferator–activated receptor–γ (PPAR-γ); they improve peripheral insulin sensitivity and preserve pancreatic β cell function in diabetic patients. PPAR-γ is a master regulator of adipogenesis, and TZD-associated weight gain has been mostly attributed to the formation of new fat cells. Now, independent groups led by Olefsky and Seeley have uncovered a previously unrecognized role for central nervous system PPAR-γ in the regulation of food intake, energy expenditure, and total body metabolic homeostasis, which may contribute to weight gain with TZD use.

The group led by Seeley used direct intracerebral injections to administer the TZD drug rosiglitazone into the hypothalamus of rats. Acute rosiglitazone administration led within 24 hours to significantly increased food intake and weight gain. Indeed, after just one injection, food intake was increased for as long as 3 days. Oral delivery of rosiglitazone resulted in similar effects; these effects could be blocked by inhibiting PPAR-γ, as could food intake in high-fat-diet–fed animals.

The group led by Olefsky used a complementary but distinct toolkit to study this problem. Lu et al. used Cre-LoxP technology to generate a neuronal knockout model of PPAR-γ. Mice lacking brain PPAR-γ gained less weight and had decreased food intake when placed on a high-fat diet. Interestingly, these knockout mice were also more active and thus had both increased energy expenditure and decreased energy intake as compared with control mice. Moreover, mice lacking brain PPAR-γ gained less weight than did control mice when fed a high-fat diet supplemented with rosiglitazone. However, these mice also demonstrated worse glucose tolerance; deletion of brain PPAR-γ led to a nearly complete abrogration of the beneficial effects of rosiglitazone in inhibiting hepatic glucose production.

The findings of these two groups provide new and unexpected insights into the tissue-specific actions of PPAR-γ. They suggest that TZD treatment affects the central nervous system, resulting in increased food consumption and limited energy expenditure. Surprisingly, activation of brain PPAR-γ was also an obligatory component of TZD-induced improvements in liver insulin sensitivity. Mechanistically, exactly how all this occurs is still unknown. However, as the research and pharmaceutical communities look toward the development of new and improved PPAR-γ agonists, these new results must be entered into a “metabolic homeostatic equation” that has now grown to include intersecting circuits between the brain, liver, muscle, fat, gut, and pancreas. That’s a lot to wrap your head around.

K. K. Ryan et al., A role for central nervous system PPAR-γ in the regulation of energy balance. Nat. Med. 17, 623–626 (2011). [Abstract]

M. Lu et al., Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effects of thiazolidinediones. Nat. Med. 17, 618–622 (2011). [Abstract]

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