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

Peroxisome proliferator-activated receptor- (PPAR), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPAR 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 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 and the tdTomato reporter. Inducible expression of both forms of PPAR 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-P467L) or selectively in POMC neurons (POMCCre/PPAR-P467L). Whereas POMCCre/PPAR-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-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-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPAR-WT, but not POMCCre/PPAR-P467L, mice increased body weight in response to rosiglitazone, a PPAR agonist. These observations support the concept that alte...
Source: Physiological Genomics - Category: Genetics & Stem Cells Authors: Tags: Physiological and Genetic Control of Neural Function Source Type: research