Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a western-style high-fat diet

Brian A. Grice, Kelly J. Barton, Jacob D. Covert, Alec M. Kreilach, Lixuan Tackett, Joseph T. Brozinick, Jeffrey Elmendorf

Research output: Contribution to journalArticle

Abstract

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.

Original languageEnglish (US)
Pages (from-to)E362-E373
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume317
Issue number2
DOIs
StatePublished - Aug 1 2019

Fingerprint

High Fat Diet
Inbred C57BL Mouse
Insulin Resistance
Actins
Skeletal Muscle
Cholesterol
Membranes
Fats
Diet
Glucose Intolerance
Facilitative Glucose Transport Proteins
Liver
Hyperinsulinism
Subcutaneous Injections

Keywords

  • Actin
  • Cholesterol
  • GLUT4
  • Insulin resistance
  • Skeletal muscle

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a western-style high-fat diet. / Grice, Brian A.; Barton, Kelly J.; Covert, Jacob D.; Kreilach, Alec M.; Tackett, Lixuan; Brozinick, Joseph T.; Elmendorf, Jeffrey.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 317, No. 2, 01.08.2019, p. E362-E373.

Research output: Contribution to journalArticle

Grice, Brian A. ; Barton, Kelly J. ; Covert, Jacob D. ; Kreilach, Alec M. ; Tackett, Lixuan ; Brozinick, Joseph T. ; Elmendorf, Jeffrey. / Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a western-style high-fat diet. In: American Journal of Physiology - Endocrinology and Metabolism. 2019 ; Vol. 317, No. 2. pp. E362-E373.
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AB - Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.

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