Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight

Mancini, Giacomo; Pirruccio, Kevin; Yang, Xiaoyong; Blüher, Matthias; Rodeheffer, Matthew S.; Horváth, Tamás L.

doi:10.1016/j.celrep.2019.03.065

Cited by 16 publications

(19 citation statements)

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“…Several transcriptional factors including PPARα, PPARδ and PPARγ in the skeletal muscle involved in enhancing insulin sensitivity, glucose tolerance, energy expenditure, and lipid metabolism . Activation of these transcriptional factors enhanced mitochondrial biogenesis leads to dramatically increased endurance, ameliorated insulin resistance in obesity, and type 2 diabetes . It has been known that mitochondrial dysfunction and cellular oxidative stress induced by excess energy states and elevations in circulating free fatty acid (FFA) are associated with insulin resistance in skeletal muscle .…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6][7][8] Activation of these transcriptional factors enhanced mitochondrial biogenesis leads to dramatically increased endurance, ameliorated insulin resistance in obesity, and type 2 diabetes. [9][10][11][12][13] It has been known that mitochondrial dysfunction and cellular oxidative stress induced by excess energy states and elevations in circulating free fatty acid (FFA) are associated with insulin resistance in skeletal muscle. [14][15][16][17][18][19][20] Therefore, in order to improve skeletal muscle insulin resistance and energy expenditure, it is important to stimulate mitochondrial biogenesis to preserve mitochondrial pool and to increase mitochondrial oxidative phosphorylation and FFA metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

103

125

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Background Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance. Methods We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis. Results AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic–euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. Conclusions We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

103

125

View full text Add to dashboard Cite

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“…We could not detect any meaningful changes in the total myocellular abundance of Opa1 or Drp1 in L6 myotubes in response to PA overloading (data not shown) but did observe a significant reduction in MFN2. MFN2 expression has been shown to be rapidly downregulated in vivo in response to high fat feeding and its expression is also reduced by proinflammatory cytokines, lipid availability, and glucocorticoids [50,51]. In skeletal muscle, PGC1α has been shown to stimulate expression of the Mfn2 gene promoter [52] and given that PA represses PGC1α in our myotubes this may help account for the observed reduction in MFN2.…”

Section: Discussionmentioning

confidence: 84%

Mono- and Polyunsaturated Fatty Acids Counter Palmitate-Induced Mitochondrial Dysfunction in Rat Skeletal Muscle Cells

Nisr

Shah

Hundal

2020

Cell Physiol Biochem

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“…Moreover, in adipose tissue the association between mitochondria and lipid droplets is important for both lipid storage and consumption (80,81), while adipocyte specific knockout of MFN2 leads to obesity in mice (34,82,83). Finally, the R707W MFN2 variant, which causes CMT2A when present heterozygously, also causes lipomatosis when present homozygously (50,51).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel variant in the HR1 domain ofMFN2in a patient with ataxia, optic atrophy and sensorineural hearing loss

Sharma

Saubouny

Joel

et al. 2021

Preprint

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Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

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Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight

Cited by 16 publications

References 0 publications

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Mono- and Polyunsaturated Fatty Acids Counter Palmitate-Induced Mitochondrial Dysfunction in Rat Skeletal Muscle Cells

Characterization of a novel variant in the HR1 domain ofMFN2in a patient with ataxia, optic atrophy and sensorineural hearing loss

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