Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

Chung, Hyo Kyun; Ryu, Dongryeol; Kim, Koon Soon; Chang, Jong San; Kim, Yong Kyung; Yi, Hyon‐Seung; Kang, Sun Hyung; Choi, Min Jeong; Lee, Seong Eun; Jung, Saet Byel; Ryu, Min Jeong; Kim, Soung Jung; Kweon, Gi Ryang; Kim, Hail; Hwang, Jung Hwan; Lee, Chul‐Ho; Lee, Se Jin; Wall, Christopher E.; Downes, Michael; Evans, Ronald M.; Auwerx, Johan; Shong, Minho

doi:10.1083/jcb.201607110

Cited by 259 publications

(317 citation statements)

References 80 publications

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“…Whole body KO mice of Acadvl and a skeletal muscle-specific KO of Cpt1b are similarly resistant to HFD-induced sequelae (Vandanmagsar et al, 2016; Wicks et al, 2015; Zhang et al, 2010). Other models of impaired mitochondrial oxidative metabolism are also resistant to HFD-induced obesity and glucose intolerance, presumably via a hormetic response as well (Chung et al, 2017; Pospisilik et al, 2007). Similarly, part of the mechanism of action of the anti-diabetic drug metformin may be a mild inhibition of mitochondrial electron transport chain (Owen et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

et al. 2017

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SUMMARY The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long chain fatty acid β-oxidation (Cpt2L−/− mice). Paradoxically, Cpt2L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress and systemic carnitine deficiency. Feeding a HFD induced hepatokines in mice with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

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Section: Discussionmentioning

confidence: 99%

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

et al. 2017

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“…Growth differentiation factor 15 (GDF15) expression is a second retrograde‐responsive secreted ligand that systemically regulates metabolism. GDF15 transcription and secretion are increased in mice with a muscle specific mutation in a mitochondrial ribosomal protein . The increased release of FGF21 and GDF15, as a result of mitochondrial dysfunction in muscle, protects mice from diet induced obesity and insulin resistance.…”

Section: Mitochondrial Retrograde Signaling In Metazoansmentioning

confidence: 99%

Mitochondrial retrograde signaling in the nervous system

Hunt

Bateman

2017

FEBS Letters

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Edited by Wilhelm JustMitochondria generate the majority of cellular ATP and are essential for neuronal function. Loss of mitochondrial activity leads to primary mitochondrial diseases and may contribute to neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Mitochondria communicate with the cell through mitochondrial retrograde signaling pathways. These signaling pathways are triggered by mitochondrial dysfunction and allow the organelle to control nuclear gene transcription. Neuronal mitochondrial retrograde signaling pathways have been identified in disease model systems and targeted to restore neuronal function and prevent neurodegeneration. In this review, we describe yeast and mammalian cellular models that have paved the way in the investigation of mitochondrial retrograde mechanisms. We then discuss the evidence for retrograde signaling in neurons and our current knowledge of retrograde signaling mechanisms in neuronal model systems. We argue that targeting mitochondrial retrograde pathways has the potential to lead to novel treatments for neurological diseases.

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“…As an endocrine organ, muscle can shape metabolic changes in distant tissues such as the liver, adipose, and pancreas through the secretion of muscle-derived proteins (myokines), as well as metabolic substrates and intermediates. Various myokines can either independently or cooperatively direct energy homeostasis by regulating multiple aspects of glucose metabolism, lipid metabolism, and insulin sensitivity in other tissues [1, 2, 12–14]). Thus, muscle acts as a key endocrine and metabolic mediator of systemic lipid metabolism that is required to govern energy homeostasis, and understanding how muscle communicates with fat storage tissues to coordinate energy expenditure remains an integral question.…”

Section: Introductionmentioning

confidence: 99%

Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila

Zhao

Karpac

2017

Current Biology

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Summary Inter-tissue communication is critical to control organismal energy homeostasis in response to temporal changes in feeding and activity or external challenges. Muscle is emerging as a key mediator of this homeostatic control through consumption of lipids, carbohydrates, and amino acids, as well as governing systemic signaling networks. However, it remains less clear how energy substrate usage tissues, such as muscle, communicate with energy substrate storage tissues in order to adapt with diurnal changes in energy supply and demand. Using Drosophila, we show here that muscle plays a crucial physiological role in promoting systemic synthesis and accumulation of lipids in fat storage tissues, which subsequently impacts diurnal changes in circulating lipid levels. Our data reveal that the metabolic transcription factor Foxo governs expression of the cytokine Unpaired 2 (Upd2) in skeletal muscle, which acts as a myokine to control glucagon-like adipokinetic hormone (AKH) secretion from specialized neuroendocrine cells. Circulating AKH levels, in turn, regulate lipid homeostasis in fat body/adipose and the intestine. Our data also reveal that this novel myokine-dependent hormone module is critical to maintain diurnal rhythms in circulating lipids. This tissue cross-talk provides a putative mechanism that allows muscle to integrate autonomous energy demand with systemic energy storage and turnover. Together, these findings reveal a diurnal inter-tissue signaling network between muscle and fat-storage tissues that constitutes an ancestral mechanism governing systemic energy homeostasis.

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Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

Cited by 259 publications

References 80 publications

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

Mitochondrial retrograde signaling in the nervous system

Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila

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