title: PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding.
abstract: Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
authors.forename: Lihong
authors.initials: L
authors.lastname: Long
authors.forename: Chitoku
authors.initials: C
authors.lastname: Toda
authors.forename: Jing Kwon
authors.initials: JK
authors.lastname: Jeong
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006963:Hyperphagia / Q000517:prevention & control; D007333:Insulin Resistance; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D020738:Leptin; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011333:Pro-Opiomelanocortin; D005947:Glucose
references.citation: Free Radic Biol Med. 1992 Nov;13(5):557-80
references.pmid: 1334030
references.citation: Diabetes. 2006 Feb;55(2):390-7
references.pmid: 16443772
references.citation: Cell Metab. 2009 Jan 7;9(1):35-51
references.pmid: 19117545
references.citation: Nat Med. 2011 May;17(5):618-22
references.pmid: 21532596
references.citation: Diabetes. 2003 Sep;52(9):2249-59
references.pmid: 12941763
references.citation: Cell. 2008 Oct 3;135(1):61-73
references.pmid: 18854155
references.citation: Nat Neurosci. 2005 Oct;8(10):1289-91
references.pmid: 16158063
references.citation: Nat Med. 2010 Apr;16(4):403-5
references.pmid: 20348924
references.citation: Endocrinology. 2012 Feb;153(2):683-9
references.pmid: 22202165
references.citation: Nat Med. 2011 Aug 28;17(9):1121-7
references.pmid: 21873987
references.citation: Cell. 1992 Mar 6;68(5):879-87
references.pmid: 1312391
references.citation: Nature. 2008 Aug 14;454(7206):846-51
references.pmid: 18668043
references.citation: Trends Endocrinol Metab. 2010 Nov;21(11):643-51
references.pmid: 20846876
references.citation: Endocrinology. 2004 Nov;145(11):4880-9
references.pmid: 15271881
references.citation: Cell. 2005 Dec 16;123(6):993-9
references.pmid: 16360030
references.citation: Diabetes. 2013 Jul;62(7):2295-307
references.pmid: 23530005
references.citation: Nat Med. 2004 Jul;10(7):739-43
references.pmid: 15208705
references.citation: Science. 2004 Apr 2;304(5667):110-5
references.pmid: 15064421
references.citation: Diabetes Care. 1998 Sep;21(9):1470-4
references.pmid: 9727893
references.citation: Cell. 2013 Sep 26;155(1):172-87
references.pmid: 24074867
references.citation: Endocrinology. 2009 Feb;150(2):707-12
references.pmid: 18845632
references.citation: Nature. 1990 Oct 18;347(6294):645-50
references.pmid: 2129546
references.citation: Cell. 2013 Sep 26;155(1):188-99
references.pmid: 24074868
references.citation: Mol Metab. 2013 Jan 11;2(1):23-30
references.pmid: 24024131
references.citation: Nat Med. 2011 May;17(5):623-6
references.pmid: 21532595