Faculty Collaboration Database

Nervous System Expression of PPARγ and Mutant PPARγ Has Profound Effects on Metabolic Regulation and Brain Development. Endocrinology 2016 Nov;157(11):4266-4275

Date

11/02/2016

Pubmed ID

27575030

Pubmed Central ID

PMC5086539

DOI

10.1210/en.2016-1524

Scopus ID

2-s2.0-84994285912 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

Peroxisome proliferator activated receptor (PPARγ) is a nuclear receptor transcription factor that regulates adipogenesis and energy homeostasis. Recent studies suggest PPARγ may mediate some of its metabolic effects through actions in the brain. We used a Cre-recombinase-dependent (using Nestin^Cre) conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ to examine mechanisms by which PPARγ in the nervous system controls energy balance. Inducible expression of PPARγ was evident throughout the brain. Expression of 2 PPARγ target genes, aP2 and CD36, was induced by WT but not P467L PPARγ in the brain. Surprisingly, Nes^Cre/PPARγ-WT mice exhibited severe microcephaly and brain malformation, suggesting that PPARγ can modulate brain development. On the contrary, Nes^Cre/PPARγ-P467L mice exhibited blunted weight gain to high-fat diet, which correlated with a decrease in lean mass and tissue masses, accompanied by elevated plasma GH, and depressed plasma IGF-1, indicative of GH resistance. There was no expression of the transgene in the pancreas but both fasting plasma glucose, and fed and fasted plasma insulin levels were markedly decreased. Nes^Cre/PPARγ-P467L mice fed either control diet or high-fat diet displayed impaired glucose tolerance yet exhibited increased sensitivity to exogenous insulin and increased insulin receptor signaling in white adipose tissue, liver, and skeletal muscle. These observations support the concept that alterations in PPARγ-driven mechanisms in the nervous system play a role in the regulation of growth and glucose metabolic homeostasis.

Author List

Stump M, Guo DF, Lu KT, Mukohda M, Cassell MD, Norris AW, 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

Adipogenesis
Animals
Body Composition
Brain
Diet, High-Fat
Energy Metabolism
Fasting
Glucose
Glucose Tolerance Test
Humans
Insulin
Insulin Resistance
Insulin-Like Growth Factor I
Male
Mice
Mice, Transgenic
Mutation
PPAR gamma
Receptor, Insulin