Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity

被引：215

作者：

Diano, Sabrina ^{[1
,2
,3
,4
]}

Liu, Zhong-Wu ^{[1
,3
]}

Jeong, Jin Kwon ^{[1
,2
]}

Dietrich, Marcelo O. ^{[1
,3
,5
]}

Ruan, Hai-Bin ^{[1
,3
]}

Kim, Esther ^{[6
,7
]}

Suyama, Shigetomo ^{[1
,3
]}

Kelly, Kaitlin ^{[1
,2
]}

Gyengesi, Erika ^{[1
,2
]}

Arbiser, Jack L. ^{[8
]}

Belsham, Denise D. ^{[9
,10
]}

Sarruf, David A. ^{[11
,12
]}

Schwartz, Michael W. ^{[11
,12
]}

Bennett, Anton M. ^{[1
,3
,13
]}

Shanabrough, Marya ^{[1
,3
]}

Mobbs, Charles V. ^{[5
]}

Yang, Xiaoyong ^{[1
,3
]}

Gao, Xiao-Bing ^{[1
,2
,3
]}

Horvath, Tamas L. ^{[1
,2
,3
,4
]}

机构：

[1] Yale Univ, Sch Med, Program Integrat Cell Signaling & Neurobiol Metab, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA

[4] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA

[5] Univ Fed Rio Grande do Sul, Dept Biochem, Porto Alegre, RS, Brazil

[6] Mt Sinai Sch Med, Dept Neurosci, Friedman Brain Inst, New York, NY USA

[7] Mt Sinai Sch Med, Dept Geriatr, Friedman Brain Inst, New York, NY USA

[8] Emory Univ, Sch Med, Dept Dermatol, Winship Canc Inst,Atlanta VA Med Ctr, Atlanta, GA 30322 USA

[9] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[10] Toronto Gen Hosp, Div Cellular & Mol Biol, Res Inst, Univ Hlth Network, Toronto, ON, Canada

[11] Univ Washington, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA

[12] Univ Washington, Dept Med, Seattle, WA USA

[13] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

来源：

NATURE MEDICINE | 2011年 / 17卷 / 09期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED-RECEPTOR-GAMMA; CENTRAL LEPTIN INFUSION; CENTRAL-NERVOUS-SYSTEM; OXIDATIVE STRESS; PPAR-GAMMA; ENDOPLASMIC-RETICULUM; NPY/AGRP NEURONS; ENERGY-BALANCE; HYPOTHALAMUS; INFLAMMATION;

D O I：

10.1038/nm.2421

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system(1,2). Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor gamma (PPAR-gamma) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-gamma agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.

引用

页码：1121 / U130

页数：8

共 37 条

[1] UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals [J].