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Updated: Aug 9, 2025
Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
A role for β-catenin in diet-induced skeletal muscle insulin resistance
Stewart W C Masson1, Waruni C Dissanayake2,3, Sophie C Broome1
1Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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.
Insights
Dysfunctional beta-catenin signaling contributes to skeletal muscle insulin resistance. This study shows high-fat diets and palmitate reduce beta-catenin, impairing glucose uptake and linking it to type 2 diabetes.
Area of Science:
- Metabolic Physiology
- Molecular Biology
- Endocrinology
Background:
- Insulin resistance impairs skeletal muscle glucose uptake, a key factor in metabolic disease.
- While the insulin receptor-PI3k-Akt pathway is studied, distal signaling defects remain unclear.
- Beta-catenin is implicated as a regulator of insulin-stimulated GLUT4 trafficking in muscle and fat cells.
Purpose of the Study:
- To investigate the role of beta-catenin in skeletal muscle insulin resistance.
- To determine if high-fat diet (HFD) or palmitate affects beta-catenin expression and phosphorylation.
- To examine the association between beta-catenin function and insulin resistance in humans with type 2 diabetes.
Main Methods:
- Utilized a 5-week high-fat diet (HFD) mouse model to assess skeletal muscle beta-catenin.
- Generated muscle-specific beta-catenin knockout mice to study its role in insulin responsiveness.
- Treated L6-GLUT4-myc myocytes with palmitate to investigate effects on beta-catenin and actin remodeling.
- Analyzed muscle biopsies from individuals with type 2 diabetes for beta-catenin S552 phosphorylation and total expression.
Main Results:
- HFD significantly decreased skeletal muscle beta-catenin expression and insulin-stimulated S552 phosphorylation.
- Muscle-specific beta-catenin deletion impaired insulin responsiveness, with HFD exacerbating insulin resistance.
- Palmitate treatment reduced beta-catenin expression and attenuated insulin-stimulated S552 phosphorylation and actin remodeling in myocytes.
- Individuals with type 2 diabetes exhibited reduced beta-catenin S552 phosphorylation in muscle tissue.
Conclusions:
- Beta-catenin dysfunction, specifically reduced S552 phosphorylation, is linked to skeletal muscle insulin resistance.
- Impaired beta-catenin signaling may be a contributing factor to the development of insulin resistance.
- These findings highlight beta-catenin as a potential therapeutic target for metabolic disorders.
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