Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity
Open accessAbstract
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 alpha2AMPK 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 alpha2AMPK 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 alpha2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.
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AMPK α1 KO and α2KD mice have normal insulin sensitivity on a chow and high-fat diet.
“AMPK α1 KO and α2KD mice have normal insulin sensitivity on a chow and high-fat diet [33,36].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [36]
AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle.
“In support of this, insulin also does not increase AMPK T172 or ACC S79/212 phosphorylation [74] and AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle [26,28,30,36,100] despite blunted TBC1D1 PAS and T590 phosphorylation in response to insulin [30,74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [36]
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- Authors
- Beck Jørgensen, S., O’Neill, H. M., Hewitt, K., Kemp, B. E., & Steinberg, G. R.
- Affiliations
- The University of Melbourne (AU)
- Venue
- Diabetologia
- Published
- 2009-08-18
- Volume
- 52
- Issue
- 11
- Pages
- 2395-2404
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2062045473
- Cited by
- 42
- References
- 51
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 7 · 2012: 7
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- AMPK, skeletal muscle, insulin resistance, obesity, high-fat diet, acetyl-CoA carboxylase 2, lipid accumulation, triglycerides, diacylglycerol, ceramide, muscle glucose uptake, Akt phosphorylation, mitochondrial biogenesis, lipid oxidation, glucose tolerance
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Aminoimidazole Carboxamide, Animals, Body Weight, Deoxyglucose, Dietary Fats, Insulin Resistance, Kinetics, Lipids, Male, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Protein Kinases, Reference Values, Ribonucleotides, Lipid Peroxidation, Muscle, Skeletal, Mice
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