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Mitochondrial Dynamics Controlled by Mitofusins Regulate Agrp Neuronal Activity and Diet-Induced Obesity

Author:
Dietrich, Marcelo O., Liu, Zhong-Wu, Horvath, Tamas L.
Source:
Cell 2013 v.155 pp. 188-199
ISSN:
0092-8674
Subject:
adenosine triphosphate, energy metabolism, high fat diet, knockout mutants, mitochondria, neurons, obesity, pro-opiomelanocortin
Abstract:
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.
Agid:
927004