title: Nervous System Expression of PPARγ and Mutant PPARγ Has Profound Effects on Metabolic Regulation and Brain Development.
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 NestinCre) 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, NesCre/PPARγ-WT mice exhibited severe microcephaly and brain malformation, suggesting that PPARγ can modulate brain development. On the contrary, NesCre/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. NesCre/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.
authors: 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.
authors: Madeliene
authors: M
authors: Stump
authors: 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.
authors: Deng-Fu
authors: DF
authors: Guo
authors: 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.
authors: Ko-Ting
authors: KT
authors: Lu
authors: 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.
authors: Masashi
authors: M
authors: Mukohda
authors: 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.
authors: Martin D
authors: MD
authors: Cassell
authors: 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.
authors: Andrew W
authors: AW
authors: Norris
authors: 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.
authors: Kamal
authors: K
authors: Rahmouni
authors: 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.
authors: Curt D
authors: CD
authors: Sigmund
mesh_terms: D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005215:Fasting / Q000097:blood; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D047495:PPAR gamma; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; D005947:Glucose