Myostatin Induces Insulin Resistance via Casitas B-Lineage Lymphoma b (Cblb)-mediated Degradation of Insulin Receptor Substrate 1 (IRS1) Protein in Response to High Calorie Diet Intake

Bonala, Sabeera; Lokireddy, Sudarsanareddy; McFarlane, Craig; Sreekanth, Patnam; Sharma, Mridula; Kambadur, Ravi

doi:10.1074/jbc.m113.529925

Cited by 41 publications

(14 citation statements)

References 68 publications

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“…Myostatin deficiency enhances BAT differentiation and function and protects from HFD-and high glucose-induced insulin resistance in myocytes (Braga et al, 2013; Kim et al, 2012; Zhang et al, 2011), and myostatin acutely blunts insulin signaling in cultured myocytes and hepatocytes (Bonala et al, 2014). To assess whether myostatin can also induce insulin resistance in brown adipocytes, we investigated the effect of incubating cultured immortalized brown adipocytes with increasing doses of myostatin on insulin-evoked AKT phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

Steculorum

Ruud

Karakasilioti

et al. 2016

Cell

229

234

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SUMMARY Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

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Section: Resultsmentioning

confidence: 99%

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

Steculorum

Ruud

Karakasilioti

et al. 2016

Cell

229

234

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“…Mstn has been reported to induce degradation of IRS1 (Bonala et al. ) and to inhibit PI3K/AKT/GSK3ß signaling (Morissette et al. ; Yang et al.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings are consistent with prior reports. Mstn has been reported to induce degradation of IRS1 (Bonala et al 2014) and to inhibit PI3K/AKT/GSK3ß signaling (Morissette et al 2006;Yang et al 2007). Inhibition of Mstn augmented Glut4 expression and glucose uptake in vivo (Cleasby et al 2014), and Mstn knockouts increase expression and phosphorylation of AMPK in skeletal muscle (Shan et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts

2018

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The glucose transporter 4 (Glut4) mediates insulin‐dependent glucose uptake. Glut4 expression levels are correlated with whole‐body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue‐specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type‐2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary‐induced obesity and insulin resistance. The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells. Mstn significantly reduced basal and insulin‐induced IRS‐1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3β phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin‐induced Glut4 membrane translocation and glucose uptake. Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP‐activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator. These data suggest that Mstn inhibits Glut4 expression and insulin‐induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin‐desensitizing effect and indirect suppression of AMPK activation.

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“…Myostatin expression is increased in dyslipidaemia by inhibiting brown adipocyte differentiation 24 . The increased myostatin also is likely to be a potent inducer of insulin resistance 25 . In turn, IL-6 promotes myogenic differentiation of skeletal muscle cells 26 .…”

Section: Discussionmentioning

confidence: 99%

Relationship between grip strength and newly diagnosed nonalcoholic fatty liver disease in a large-scale adult population

Meng

Wang

Fang

et al. 2016

Sci Rep

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Enhanced muscle strength is often related to improved insulin sensitivity and secretion, control of lipid metabolism, and increased secretion of myokines. These factors have emerged as important mechanisms involved in the development and progression of nonalcoholic fatty liver disease (NAFLD), implying that muscle strength may be a useful predictor for NAFLD. We aimed to assess the relationship between grip strength (GS) and NAFLD in a large-scale adult population. GS was assessed using an electronic hand-grip dynamometer, and NAFLD was diagnosed by the liver ultrasonography. Multiple logistic regression analysis was used to assess the relationship between the quartiles of GS per body weight and the prevalence of NAFLD. After adjusting for potentially confounding factors, the odds ratios (95% confidence interval) for overall NAFLD, NAFLD with normal alanine aminotransferase levels, and NAFLD with elevated alanine aminotransferase levels across the quartiles of GS were 1.00 (reference), 0.89 (0.78, 1.01), 0.77 (0.67, 0.89), and 0.67 (0.57, 0.79); 1.00 (reference), 0.91 (0.80, 1.04), 0.79 (0.68, 0.92), and 0.72 (0.61, 0.85); 1.00 (reference), 0.77 (0.61, 0.98), 0.67 (0.51, 0.86), and 0.53 (0.40, 0.71) (all P for trend < 0.01), respectively. This is the first study shows that increased GS is independently associated with lower prevalence of NAFLD.

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Myostatin Induces Insulin Resistance via Casitas B-Lineage Lymphoma b (Cblb)-mediated Degradation of Insulin Receptor Substrate 1 (IRS1) Protein in Response to High Calorie Diet Intake

Cited by 41 publications

References 68 publications

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts

Relationship between grip strength and newly diagnosed nonalcoholic fatty liver disease in a large-scale adult population

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