Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle

Franco Capozza, Terry P. Combs, Alex W. Cohen, You Ree Cho, So Young Park, William Schubert, Terence M. Williams, Dawn L. Brasaemle, Linda A. Jelicks, Philipp E. Scherer, Jason K. Kim, Michael P. Lisanti

Research output: Contribution to journalArticle

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Abstract

Caveolin-3 (Cav-3) is expressed predominantly in skeletal muscle fibers, where it drives caveolae formation at the muscle cell's plasma membrane. In vitro studies have suggested that Cav-3 may play a positive role in insulin signaling and energy metabolism. We directly address the in vivo metabolic consequences of genetic ablation of Cav-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. At age 2 mo, Cav-3 null mice are significantly larger than wild-type mice, and display significant postprandial hyperinsulinemia, whole body insulin resistance, and whole body glucose intolerance. Studies using hyperinsulinemiceuglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole body glucose uptake and whole body glycogen synthesis, respectively. Whole body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Insulin-stimulated glucose uptake in white adipose tissue, which does not express Cav-3, was decreased by ∼70% in Cav-3 null mice, suggestive of an insulin-resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 min of acute insulin stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, compared with wild-type mice treated identically. These results suggest that Cav-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor downregulation. Thus our results demonstrate the importance of Cav-3 in regulating whole body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of caveolinopathies.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number6 57-6
DOIs
StatePublished - Jun 2005

Fingerprint

Caveolin 3
Insulin Receptor
Adiposity
Knockout Mice
Muscle
Insulin Resistance
Skeletal Muscle
Insulin
Ligands
Glucose
Cell membranes
Cell Membrane
Homeostasis
Tissue
Caveolae
White Adipose Tissue
Glucose Intolerance
Liver
Skeletal Muscle Fibers
Clamping devices

Keywords

  • Glucose intolerance
  • Hyperinsulinemia
  • Insulin receptor degradation
  • Limb girdle muscular dystrophy

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle. / Capozza, Franco; Combs, Terry P.; Cohen, Alex W.; Cho, You Ree; Park, So Young; Schubert, William; Williams, Terence M.; Brasaemle, Dawn L.; Jelicks, Linda A.; Scherer, Philipp E.; Kim, Jason K.; Lisanti, Michael P.

In: American Journal of Physiology - Cell Physiology, Vol. 288, No. 6 57-6, 06.2005.

Research output: Contribution to journalArticle

Capozza, Franco ; Combs, Terry P. ; Cohen, Alex W. ; Cho, You Ree ; Park, So Young ; Schubert, William ; Williams, Terence M. ; Brasaemle, Dawn L. ; Jelicks, Linda A. ; Scherer, Philipp E. ; Kim, Jason K. ; Lisanti, Michael P. / Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle. In: American Journal of Physiology - Cell Physiology. 2005 ; Vol. 288, No. 6 57-6.
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AU - Cho, You Ree

AU - Park, So Young

AU - Schubert, William

AU - Williams, Terence M.

AU - Brasaemle, Dawn L.

AU - Jelicks, Linda A.

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