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Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity.

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.

SUBMITTER: Dietrich MO

PROVIDER: S-EPMC4142434 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity.

Dietrich Marcelo O MO Liu Zhong-Wu ZW Horvath Tamas L TL

Cell 20130901 1

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 b ...[more]

PMID: 24074868

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Project description:Diet-induced obesity impairs mitochondrial respiratory responses in tissues that are highly metabolically active, such as the heart. However, less is known about the impact of obesity on the respiratory activity of specific cell types, such as splenic B cells. B cells are of relevance, as they play functional roles in obesity-induced insulin resistance, inflammation, and responses to infection. Here, we tested the hypothesis that high-fat-diet (HFD)-induced obesity could impair the mitochondrial respiration of intact and permeabilized splenic CD19+ B cells isolated from C57BL/6J mice and activated ex vivo with lipopolysaccharide (LPS). High-resolution respirometry was used with intact and permeabilized cells. To reveal potential mechanistic targets by which HFD-induced obesity dysregulates B cell mitochondria, we conducted proteomic analyses and 3D serial block face scanning electron microscopy (SBFEM). High-resolution respirometry revealed that intact LPS-stimulated B cells of obese mice, relative to controls, displayed lower ATP-linked, as well as maximal uncoupled, respiration. To directly investigate mitochondrial function, we used permeabilized LPS-stimulated B cells, which displayed increased H2O2 emission and production with obesity. We also examined oxidative phosphorylation efficiency simultaneously, which revealed that oxygen consumption and ATP production were decreased in LPS-stimulated B cells with obesity relative to controls. Despite minimal changes in total respiratory complex abundance, in LPS-stimulated B cells of obese mice, three of the top ten most downregulated proteins were all accessory subunits of respiratory complex I. SBFEM showed that B cells of obese mice, compared to controls, underwent no change in mitochondrial cristae integrity but displayed increased mitochondrial volume that was linked to bioenergetic function. Collectively, these results establish a proof of concept that HFD-induced obesity dysregulates the mitochondrial bioenergetic metabolism of activated splenic B cells.

Dataset Information

Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity.

Publications

Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity.

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