Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

Fujii, Nobuharu; Ho, Richard C.; Manabe, Yasuko; Jessen, Niels; Toyoda, Tarō; Holland, William L.; Summers, Scott A.; Hirshman, Michael F.; Goodyear, Laurie J.

doi:10.2337/db07-1187

Cited by 105 publications

(100 citation statements)

References 57 publications

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“…Similar studies in long-term AICAR treatment of rats reported reduced metabolic disturbances and lowered blood pressure in rats displaying features of the insulin resistance syndrome [51]. Finally, muscle-specific ablation of AMPKα 2 activity has been shown to exacerbate insulin resistance induced by high-fat feeding of mice [52].…”

Section: Discussionmentioning

confidence: 69%

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

et al. 2010

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Aims/hypothesis AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKγ 3 subunit, PRKAG3 R225W.Methods Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [ 18 F]fluorodeoxyglucose and positron emission tomography. Results Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p<0.05), higher basal glucose uptake (twofold, p<0.01) and higher glycogen synthesis rates (twofold, p<0.05) than control myotubes. They also had higher levels of intracellular glycogen (p<0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. Conclusions/interpretation Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the γ 3 subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.

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Section: Discussionmentioning

confidence: 69%

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

et al. 2010

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“…2-DG, 2-deoxy-glucose While this manuscript was in preparation, Fujii et al [31] demonstrated that mice on a FVB background overexpressing a muscle-specific KD AMPKα2 Asp157Ala mutation develop more severe muscle insulin resistance after 30 weeks on a high-fat diet with 60% of energy from fat (compared with 12 weeks of a high-fat diet with 45% of energy from fat, as used in the current study), an effect which occurred independently of increases in muscle lipids. The difference between our findings and those of Fujii et al [31] may be related to the use of different diet protocols, but probably more importantly, to the use of different mouse strains, as the FVB strain of mice is known to be resistant to the effects of high-fat diet-induced obesity compared with mice on a C57/BL6 background [32] as used in the current study. But the fact that the genotype effect occurred 26 weeks later than the first evidence of glucose intolerance suggests that AMPK did not have a primary role in the development of insulin resistance, as was recognised by Fujii el al.…”

Section: Discussionmentioning

confidence: 99%

“…But the fact that the genotype effect occurred 26 weeks later than the first evidence of glucose intolerance suggests that AMPK did not have a primary role in the development of insulin resistance, as was recognised by Fujii el al. [31].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is currently not clear whether a reduction in AMPK causes accumulation of skeletal muscle lipids and insulin resistance with obesity. A recent study by Fujii et al [31] reported that reduced muscle AMPK activity aggravated muscle insulin resistance following a high-fat diet over 30 weeks in transgenic mice on an FVB background. However, the mechanisms by which reduced muscle AMPK activity contributed to the worsening of insulin resistance with obesity were unknown, as muscle lipids were not elevated and insulin signalling not assessed.…”

Section: Introductionmentioning

confidence: 99%

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Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

et al. 2009

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Aims/hypothesis Obesity-related insulin resistance is associated with accumulation of bioactive lipids in skeletal muscle. The AMP-activated protein kinase (AMPK) regulates lipid oxidation in muscle by inhibiting acetyl-CoA carboxylase-2 (ACC2) and increasing mitochondrial biogenesis. We investigated whether reduced levels of muscle AMPK promote lipid accumulation and insulin resistance during high-fat feeding. Methods Male C57/BL6 wild-type mice and transgenic littermates overexpressing an α2AMPK kinase-dead (KD) in muscle were fed control or high-fat diet. Whole-body glucose homeostasis was assessed by glucose and insulin tolerance tests, and by measuring fasting and fed serum insulin and glucose. Insulin action in muscle was determined by measuring 2-deoxy-[ 3 H]glucose uptake and Akt phosphorylation in incubated soleus and extensor digitorum longus muscles. Muscle triacylglycerol, diacylglycerol and ceramide content was measured by thin-layer chromatography. Mitochondrial proteins were measured by immunoblotting. Results KD mice had reduced skeletal muscle α2AMPK activity (50% in gastrocnemius and >80% in soleus and extensor digitorum longus) and ACC2 Ser228 phosphorylation (90% in gastrocnemius). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance; however, there were no differences between wild-type and KD littermates. High-fat feeding impaired insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol (p=0.07) and ceramide, but these effects were not exacerbated in KD mice. In response to high-fat feeding, mitochondrial proteins were increased to similar levels in wild-type and KD muscles. Conclusions/interpretation Obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle α2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.

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“…Adult male C57BL/6 mice were purchased from Beijing Vital River Laboratory Animal Technology (Beijing, China). As previously reported, seven-week-old mice were randomly divided into two groups [31]: one group received standard rodent chow (10% energy from fat; Beijing HFK Bioscience, Beijing, China) and the other group received a high-fat diet (HFD; 60% energy from fat; rodent diet D12492, Research Diets, New Brunswick, NJ, USA). Animals were fed a HFD or chow diet for 30 weeks.…”

Section: Methodsmentioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

Cited by 105 publications

References 57 publications

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

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