A role for β-catenin in diet-induced skeletal muscle insulin resistance.
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Date
2023-02-17
Open Access Location
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society
Rights
(c) 2023 The Author/s
CC BY 4.0
CC BY 4.0
Abstract
A central characteristic of insulin resistance is the impaired ability for insulin to stimulate glucose uptake into skeletal muscle. While insulin resistance can occur distal to the canonical insulin receptor-PI3k-Akt signaling pathway, the signaling intermediates involved in the dysfunction are yet to be fully elucidated. β-catenin is an emerging distal regulator of skeletal muscle and adipocyte insulin-stimulated GLUT4 trafficking. Here, we investigate its role in skeletal muscle insulin resistance. Short-term (5-week) high-fat diet (HFD) decreased skeletal muscle β-catenin protein expression 27% (p = 0.03), and perturbed insulin-stimulated β-cateninS552 phosphorylation 21% (p = 0.009) without affecting insulin-stimulated Akt phosphorylation relative to chow-fed controls. Under chow conditions, mice with muscle-specific β-catenin deletion had impaired insulin responsiveness, whereas under HFD, both mice exhibited similar levels of insulin resistance (interaction effect of genotype × diet p < 0.05). Treatment of L6-GLUT4-myc myocytes with palmitate lower β-catenin protein expression by 75% (p = 0.02), and attenuated insulin-stimulated β-catenin phosphorylationS552 and actin remodeling (interaction effect of insulin × palmitate p < 0.05). Finally, β-cateninS552 phosphorylation was 45% lower in muscle biopsies from men with type 2 diabetes while total β-catenin expression was unchanged. These findings suggest that β-catenin dysfunction is associated with the development of insulin resistance.
Description
Keywords
Wnt-signaling, glucose transport, insulin resistance, obesity, Mice, Animals, Insulin Resistance, Proto-Oncogene Proteins c-akt, Diabetes Mellitus, Type 2, Phosphatidylinositol 3-Kinases, beta Catenin, Glucose, Muscle, Skeletal, Insulin, Diet, High-Fat, Phosphorylation, Glucose Transporter Type 4
Citation
Masson SWC, Dissanayake WC, Broome SC, Hedges CP, Peeters WM, Gram M, Rowlands DS, Shepherd PR, Merry TL. (2023). A role for β-catenin in diet-induced skeletal muscle insulin resistance.. Physiol Rep. 11. 4. (pp. e15536-).