Inhibition of insulin signalling as a treatment for obesity

Abstract

Introduction: Current treatments for obesity are only able to promote mild weight loss and are often unsuccessful long-term. Insulin is an anabolic hormone that promotes nutrient storage as lipids in adipose tissue and insulin signalling is often dysregulated in obesity. Previous research has suggested that reducing insulin’s ability to promote lipid storage may reduce body weight. However, these models mostly involve genetic manipulation and have not been translated to the clinic. Furthermore, most pre-clinical weight loss research is only performed in male subjects despite sexual differences in insulin sensitivity and adiposity. We wished to assess whether pharmacologically reducing insulin signalling in the context of energy surplus (obesity) could promote weight and fat loss in both male and female mice. Methods: Obesity was induced in male and female mice by the provision of a high-fat diet. Insulin signalling was then inhibited by the administration of either a small-molecule PI3K inhibitor (BYL-719; BYL) or an anti-insulin receptor monoclonal antibody (IRAB). A subset of mice was also exposed to a ketogenic diet (KD) to mimic carbohydrate restriction induced by insulin inhibition. Body weight was measured for 10 weeks of treatment as well as measures of body composition, substrate oxidation, and energy intake and expenditure. Results: Female mice required greater drug concentrations to inhibit insulin signalling than male mice. Body weight and adiposity were substantially reduced by BYL and KD treatment but not by IRAB treatment. BYL-treated mice sustained lower body weight for the duration of treatment, whereas after 4 weeks of treatment, KD mice showed an increase in body weight. Both BYL and KD increased lipid oxidation, but only BYL increased body weight-adjusted energy expenditure and reduced food intake. IRAB-treated mice were able to restore insulin sensitivity despite ongoing antibody treatment. Conclusions: Inhibition of insulin signalling through PI3K reduces insulin signalling, fat mass, and body mass in obese mice more effectively than inhibition of the insulin receptor and may promote changes in energy balance that prevent weight regain following weight loss. Additionally, sex is a critical variable influencing the response to pharmacological inhibition of insulin signalling.