Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance.
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.
Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Endocrinology and Nutrition, Hospital Clínic. School of Medicine, University of Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Marc
M
Schneeberger
Marcelo O
MO
Dietrich
David
D
Sebastián
Mónica
M
Imbernón
Carlos
C
Castaño
Ainhoa
A
Garcia
Yaiza
Y
Esteban
Alba
A
Gonzalez-Franquesa
Ignacio Castrillón
IC
Rodríguez
Analía
A
Bortolozzi
Pablo M
PM
Garcia-Roves
Ramon
R
Gomis
Ruben
R
Nogueiras
Tamas L
TL
Horvath
Antonio
A
Zorzano
Marc
M
Claret
D000818:Animals; D059865:Endoplasmic Reticulum Stress; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism
D020738:Leptin; D011333:Pro-Opiomelanocortin; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse