Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance

被引：429

作者：

Schneeberger, Marc ^{[1
,2
,3
]}

Dietrich, Marcelo O. ^{[4
,5
]}

Sebastian, David ^{[3
,6
,7
]}

Imbernon, Monica ^{[8
,9
]}

Castano, Carlos ^{[1
,3
]}

Garcia, Ainhoa ^{[1
,3
]}

Esteban, Yaiza ^{[1
,3
]}

Gonzalez-Franquesa, Alba ^{[1
]}

Castrillon Rodriguez, Ignacio ^{[3
,6
,7
]}

Bortolozzi, Analia ^{[10
,11
]}

Garcia-Roves, Pablo M. ^{[1
,3
]}

Gomis, Ramon ^{[1
,2
,3
]}

Nogueiras, Ruben ^{[8
,9
]}

Horvath, Tamas L. ^{[4
]}

Zorzano, Antonio ^{[3
,6
,7
]}

Claret, Marc ^{[1
,3
]}

机构：

[1] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Diabet & Obes Res Lab, Barcelona 08036, Spain

[2] Univ Barcelona, Sch Med, Hosp Clin, Dept Endocrinol & Nutr, E-08036 Barcelona, Spain

[3] Ctr Invest Biomed Red Diabet & Enfermedades Metab, Barcelona 08036, Spain

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

[5] Univ Fed Rio Grande do Sul, Dept Biochem, BR-90035 Porto Alegre, RS, Brazil

[6] Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain

[7] Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain

[8] Univ Santiago de Compostela, Inst Invest Sanitaria, Sch Med, Dept Physiol, Santiago De Compostela 15782, Spain

[9] Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Santiago De Compostela 15782, Spain

[10] IIBB CSIC IDIBAPS, Dept Neurochem & Neuropharmacol, Barcelona 08036, Spain

[11] Ctr Invest Biomed Red Salud Mental CIBERSAM, Barcelona 08036, Spain

来源：

CELL | 2013年 / 155卷 / 01期

关键词：

ENDOPLASMIC-RETICULUM STRESS; DIET-INDUCED OBESITY; MITOCHONDRIAL FUSION; HOMEOSTASIS REGULATION; SKELETAL-MUSCLE; AGRP NEURONS; FOOD-INTAKE; MFN2; METABOLISM; INSULIN;

D O I：

10.1016/j.cell.2013.09.003

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：

Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria- endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.

引用

页码：172 / 187

页数：16

共 42 条

[31] Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit [J].