Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity.
Mitochondria are key organelles in the maintenance of cellular energy metabolism and integrity. Here, we show that mitochondria number decrease but their size increase in orexigenic agouti-related protein (Agrp) neurons during the transition from fasted to fed to overfed state. These fusion-like dynamic changes were cell-type specific, as they occurred in the opposite direction in anorexigenic pro-opiomelanocortin (POMC) neurons. Interfering with mitochondrial fusion mechanisms in Agrp neurons by cell-selectively knocking down mitofusin 1 (Mfn1) or mitofusin 2 (Mfn2) resulted in altered mitochondria size and density in these cells. Deficiency in mitofusins impaired the electric activity of Agrp neurons during high-fat diet (HFD), an event reversed by cell-selective administration of ATP. Agrp-specific Mfn1 or Mfn2 knockout mice gained less weight when fed a HFD due to decreased fat mass. Overall, our data unmask an important role for mitochondrial dynamics governed by Mfn1 and Mfn2 in Agrp neurons in central regulation of whole-body energy metabolism.
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035, Brazil. Electronic address: marcelo.dietrich@yale.edu.
Marcelo O
MO
Dietrich
Zhong-Wu
ZW
Liu
Tamas L
TL
Horvath
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D059305:Diet, High-Fat; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D053140:Organelle Shape; D053141:Organelle Size; D012727:Sex Characteristics
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse