Journal article
Nervous System Expression of PPARγ and Mutant PPARγ Has Profound Effects on Metabolic Regulation and Brain Development
Endocrinology (Philadelphia), Vol.157(11), pp.4266-4275
11/2016
DOI: 10.1210/en.2016-1524
PMCID: PMC5086539
PMID: 27575030
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
) 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
/PPARγ-WT mice exhibited severe microcephaly and brain malformation, suggesting that PPARγ can modulate brain development. On the contrary, Nes
/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
/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.
Details
- Title: Subtitle
- Nervous System Expression of PPARγ and Mutant PPARγ Has Profound Effects on Metabolic Regulation and Brain Development
- Creators
- Madeliene Stump - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Deng-Fu Guo - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Ko-Ting Lu - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Masashi Mukohda - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Martin D Cassell - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Andrew W Norris - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Kamal Rahmouni - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Curt D Sigmund - Medical Scientist Training Program (M.S., K.R., C.D.S.); Neuroscience Graduate Program (M.S.); Departments of Pharmacology (D.-F.G., K.-T.L., M.M., K.R., C.D.S.), Anatomy and Cell Biology (M.D.C.), and Pediatrics (A.W.N.); and University of Iowa Healthcare Center for Hypertension Research (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Endocrinology (Philadelphia), Vol.157(11), pp.4266-4275
- Publisher
- United States
- DOI
- 10.1210/en.2016-1524
- PMID
- 27575030
- PMCID
- PMC5086539
- ISSN
- 0013-7227
- eISSN
- 1945-7170
- Grant note
- R01 HL125603 / NHLBI NIH HHS R24 DK096518 / NIDDK NIH HHS T32 GM007337 / NIGMS NIH HHS R01 HL131689 / NHLBI NIH HHS R01 DK097820 / NIDDK NIH HHS P01 HL062984 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS
- Language
- English
- Date published
- 11/2016
- Academic Unit
- Molecular Physiology and Biophysics; Endocrinology and Diabetes; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984024540502771