Faculty Collaboration Database

Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance. Physiol Genomics 2016 Jul 01;48(7):491-501

Date

05/21/2016

Pubmed ID

27199455

Pubmed Central ID

PMC4967222

DOI

10.1152/physiolgenomics.00032.2016

Scopus ID

2-s2.0-85047288791 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ 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 (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-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. POMC(Cre)/PPARγ-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 POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

Author List

Stump M, Guo DF, Lu KT, Mukohda M, Liu X, Rahmouni K, Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Adipogenesis
Animals
Body Weight
Brain
Cell Line
Diet, High-Fat
Energy Metabolism
Female
HEK293 Cells
Homeostasis
Humans
Leptin
Male
Mice
Neurons
Obesity
PPAR gamma
Pro-Opiomelanocortin
Thiazolidinediones
Weight Gain