The Immune Signaling Molecule 4-1BB Stimulation Reduces Adiposity, Insulin Resistance, and Hepatosteatosis in Obese Mice

Abstract

Immune cells (e.g. macrophages and T cells) in adipose tissue play a crucial role in the development of obesity-induced inflammation and metabolic disorders. Here we report findings suggesting that the immune signaling molecule 4-1BB/CD137 is a novel target for treatment of obesity and metabolic disorders. 4-1BB stimulation with agonistic antibody reduced body weight and adiposity and markedly improved glucose intolerance and hepatosteatosis in diet-induced obese mice and genetically obese/diabetic mice. Increases in lymphoid T cell expansion/activation and adipose/hepatic CD8+ T cell recruitment were evident in the anti-4-1BB antibody-treated obese mice. Glycolysis, β-oxidation, and oxygen consumption rates also increased in the treated mice. These findings suggest that 4-1BB-stimulation accompanied by CD8+ T cell expansion/activation enhances glucose/lipid metabolism, leading to increased energy expenditure. Manipulation of 4-1BB may provide a unique immunological strategy against obesity and metabolic disorders.