Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

Madeliene Stump; Deng-Fu Guo; Ko-Ting Lu; Masashi Mukohda; Xuebo Liu; Kamal Rahmouni; Curt D Sigmund

doi:10.1152/physiolgenomics.00032.2016

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Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

Journal article

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Peer reviewed

Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

Madeliene Stump, Deng-Fu Guo, Ko-Ting Lu, Masashi Mukohda, Xuebo Liu, Kamal Rahmouni and Curt D Sigmund

Physiological genomics, Vol.48(7), pp.491-501

07/01/2016

DOI: 10.1152/physiolgenomics.00032.2016

PMCID: PMC4967222

PMID: 27199455

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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.

Adipogenesis - drug effects

Humans

Leptin - metabolism

Body Weight - drug effects

Male

Weight Gain - physiology

PPAR gamma - metabolism

Brain - physiology

Adipogenesis - physiology

Brain - metabolism

HEK293 Cells

Female

Weight Gain - drug effects

Neurons - metabolism

Homeostasis - drug effects

Energy Metabolism - physiology

Neurons - drug effects

Thiazolidinediones - pharmacology

Diet, High-Fat - methods

Cell Line

Obesity - physiopathology

Obesity - metabolism

Brain - drug effects

Pro-Opiomelanocortin - metabolism

Animals

Homeostasis - physiology

PPAR gamma - agonists

Mice

Body Weight - physiology

3T3 Cells

Energy Metabolism - drug effects

Details

Title: Subtitle: Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance
Creators: Madeliene Stump - Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and
Deng-Fu Guo - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and
Ko-Ting Lu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and
Masashi Mukohda - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and
Xuebo Liu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and
Kamal Rahmouni - Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Curt D Sigmund - Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa curt-sigmund@uiowa.edu
Resource Type: Journal article
Publication Details: Physiological genomics, Vol.48(7), pp.491-501
Publisher: United States
DOI: 10.1152/physiolgenomics.00032.2016
PMID: 27199455
PMCID: PMC4967222
ISSN: 1094-8341
eISSN: 1531-2267
Grant note: R01 HL125603 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS R01 HL131689 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 07/01/2016
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040012802771

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