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Cited by 107Metabolism, Diabetes, and CancerDiet, Metabolism, and DiseaseAdipose Tissue and Metabolism

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

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Fujii, Nobuharu, Ho, Richard C., Manabe, Yasuko, Jessen, Niels, Toyoda, Taro, Holland, William L., Summers, Scott A., Hirshman, Michael F. +1 more·2008·Diabetes
DOI 10.2337/db07-1187PMC PMC2570392
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Abstract

OBJECTIVE—We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance. RESEARCH DESIGN AND METHODS—Muscle-specific transgenic mice expressing an inactive form of the AMPK α2 catalytic subunit (α2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks. RESULTS—Compared with wild-type mice, glucose tolerance in α2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 μU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by ∼50% in α2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the α2i TG mice. High-fat feeding in α2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle. CONCLUSIONS—The lack of skeletal muscle AMPK α2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK α2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.

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  • The exacerbated insulin resistance in high-fat fed α2iTg mice occurs independently of an increase in muscle lipids.

    “However, an alternative muscle-specific mouse model on a model FVB background, rather than a C57Bl6 background, overexpressing a muscle-specific KD AMPKα2 B157A mutation (α2iTg), are glucose intolerant and develop exacerbated skeletal muscle insulin resistance when fed a high-fat diet for 30 weeks, which occurs independently of an increase in muscle lipids [37].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [37]

  • Muscle-specific KD AMPKα2 B157A mutation (α2iTg) mice on FVB background are glucose intolerant and develop exacerbated skeletal muscle insulin resistance when fed a high-fat diet for 30 weeks.

    “However, an alternative muscle-specific mouse model on a model FVB background, rather than a C57Bl6 background, overexpressing a muscle-specific KD AMPKα2 B157A mutation (α2iTg), are glucose intolerant and develop exacerbated skeletal muscle insulin resistance when fed a high-fat diet for 30 weeks, which occurs independently of an increase in muscle lipids [37].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [37]

  • High-fat fed α2iTg mice had reduced IRS1 and Akt protein expression in skeletal muscle compared to WT.

    “In this study, high-fat fed α2iTg mice had reduced IRS1 and Akt protein expression in skeletal muscle compared to WT counterparts, which may have contributed to the reduced skeletal muscle glucose uptake in response to insulin [37].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [37]

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Authors
Fujii, N., Ho, R. C., Manabe, Y., Jessen, N., Toyoda, T., Holland, W. L., Summers, S. A., Hirshman, M. F., & Goodyear, L. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Research Division, Joslin Diabetes Center, and the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  • University of Utah (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2008-11-01
Volume
57
Issue
11
Pages
2958-2966
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db07-1187
PMC
PMC2570392
OpenAlex
W2103856172
Cited by
107
References
54
Citations by year
2025: 1 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 10 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 8 · 2013: 10 · 2012: 12
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • Joslin Diabetes Center
  • National Institutes of Health (DK 36836)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK36836, R01DK068626, P30DK036836)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045670, F32AR049662)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
AMPK, AMPKα2, skeletal muscle insulin resistance, high-fat diet, impaired glucose tolerance, insulin-stimulated glucose transport, insulin signaling, metformin, physical activity
MeSH terms
Animals, Blood Glucose, Body Weight, Dietary Fats, Fatty Acids, Nonesterified, Glucose, Glucose Tolerance Test, Glycogen, Insulin, Insulin Resistance, Mice, Transgenic, Muscles, Triglycerides, Immunoblotting, Mice, AMP-Activated Protein Kinases

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