Effect of selective expression of dominant-negative PPAR gamma in pro-opiomelanocortin neurons on the control of energy balance

摘要

Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPAR gamma in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPAR gamma in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPAR gamma and the tdTomato reporter. Inducible expression of both forms of PPAR gamma was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre- recombinase either in all neurons (NESCre/PPAR gamma-P467L) or selectively in POMC neurons (POMCCre/PPAR gamma-P467L). Whereas POMCCre/PPAR gamma-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPAR gamma-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPAR gamma-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPAR gamma-WT, but not POMCCre/PPAR gamma-P467L, mice increased body weight in response to rosiglitazone, a PPAR gamma agonist. These observations support the concept that alterations in PPAR gamma-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.