Modulation of nutrient sensing nuclear hormone receptors promotes weight loss through appetite suppression in mice

Aim: Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiolog...

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Published in:	Diabetes, obesity & metabolism Vol. 12; no. 3; pp. 234 - 245
Main Authors:	Perreault, M, Will, S, Panza, D, Gareski, T, Harding, K, Kubasiak, D, Jalenak, M, Gartrell, K, Wang, S, Bollag, G, Artis, D.R, Ibrahim, P.N, Womack, P, Lin, J.J, Saiah, E, Mansour, T.S, Vlasuk, G.P, Erbe, D.V, Tobin, J.F
Format:	Journal Article
Language:	English
Published:	Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-03-2010 Blackwell Publishing Ltd Wiley Subscription Services, Inc
Subjects:	Agonists Animals Appetite Appetite Depressants - pharmacology Appetite Regulation - physiology appetite suppression Body composition Body weight loss Energy expenditure Energy Metabolism - physiology Food composition Food intake Glucose metabolism Insulin Resistance - physiology Isoforms Ketones Lipid metabolism Lipid peroxidation Lipid Peroxidation - physiology Male Mice Mice, Inbred C57BL Mice, Knockout Nuclear receptors obesity Obesity - drug therapy Obesity - physiopathology Peroxisome proliferator-activated receptors Pharmacology Physiology PPAR alpha - agonists PPAR alpha - genetics PPAR delta - agonists PPAR gamma - agonists PPAR gamma - genetics PPAR pan agonism Skeletal muscle Thiazoles - pharmacology Thiazolidinediones - pharmacology Triglycerides Weight Loss - physiology
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Summary:	Aim: Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiological effect of simultaneous activation of PPARα, γ and δ is only starting to emerge. We sought to determine the biological effects of a novel PPAR pan activator and elucidate the physiological mechanisms involved. Methods:Ob/ob, diet-induced obese (DIO) or PPARα knockout mice were administered a novel agonist that activates all PPARs to various degrees to determine the effect on body weight, body composition, food intake and energy expenditure. In addition, serum parameters including glucose, insulin, triglycerides and ketone bodies as well as tissue acylcarnitine were evaluated. The effect of the novel agonist on liver and skeletal muscle histopathology was also studied. Results: We report that simultaneous activation of all PPARs resulted in substantial weight loss in ob/ob and DIO mice. Consistent with known PPAR pharmacology, we observed that agonist treatment increased lipid oxidation, although appetite suppression was mainly responsible for the weight loss. Agonist-induced weight loss was completely absent in PPARα knockout mice suggesting that PPARα pharmacology was the major contributor to weight regulation in mice. Conclusions: Our work provides evidence that simultaneous activation of PPARα, γ and δ decreases body weight by regulating appetite. These effects of the pan agonist were completely absent in PPARα knockout mice, suggesting that PPARα pharmacology was the major contributor to weight loss.
Bibliography:	http://dx.doi.org/10.1111/j.1463-1326.2009.01157.x ArticleID:DOM1157 ark:/67375/WNG-21KDXBPG-8 istex:169413C96AFED48AF029609FFFFE6CE45C507FD3 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1462-8902 1463-1326
DOI:	10.1111/j.1463-1326.2009.01157.x