This work has been supported by: RecerCaixa Grant 2010ACUP_00275 (M.C.); EFSD/Lilly Fellowship Award (M.C.); Ministerio de Ciencia e Innovación (MICINN), Instituto de Salud Carlos III (ISCIII) Grant PI10/01074 (M.C.); MICINN Grant SAF2010-19527 (R.G.); Ministerio de Economia y Competitividad (MINECO) Grant BFU2012-35255 (RN); Xunta de Galicia Grant EM2012/039 and 2012-CP069 (R.N.); CIBERobn (R.N.); European Community’s Seventh Framework Programme Grant ERC-2011-StG-OBESITY53-281408 (R.N.); MINECO Grant SAF2008-03803 (A.Z.); Generalitat de Catalunya Grant 2009SGR915 (A.Z.); CIBERDEM (A.Z.); INTERREG IV-B-SUDOE-FEDER (DIOMED, SOE1/P1/E178) (A.Z.); European Commission Seventh Framework Programme (FP7), MITIN Grant HEALTH-F4-2008-223450 (A.Z.); MICINN Grant BFU2011- 24679 (P.M.G.-R.); ISCIII Grant PI10/00290 (A.B.). T.L.H. and M.O.D. are supported by NIH (DP1DK006850, R01AG040236, P01NS062686), American Diabetes Association, Helmholtz society (ICEMED) and by Conselho Nacional de Desenvolvimento Científico e Tecnológico (401476/2012-0, Brazil). M.S. is a recipient of an undergraduate grant from the University of Barcelona. M.C. is a recipient of a Miguel Servet contract (CP09/00233) from MICINN-ISCIII. P.M.G.-R. is a recipient of a Ramon y Cajal contract (RYC-2009-05158) from MICINN. Some of these grants are cofinanced by the European Regional Development Fund “A way to build Europe.” This work was carried out in part at the Esther Koplowitz Centre, Barcelona.

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. © 2013 Elsevier Inc.

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