Obesity-Associated Chronic Inflammation: A Protective Mechanism against Type 2 Diabetes

Chronic inflammation is widely considered a risk factor for T2DM by inducing insulin resistance, but all attempts to translate the concept into clinical therapies have failed in the past 30 years. Anti-inflammatory medicines, including anti-TNF-α antibody (Etanercept), anti-IL1 antibody (Anakinra), anti-IL6 (Ziltivekimab), and NLRP3 inflammasome inhibitor (Colchicine) have excellent activities in the control of inflammation in arthritis. They reduced inflammation in T2DM patients in the clinical trials, but none improved insulin sensitivity. Some of them exhibited a mild and transient activity in the control of blood glucose, but the activities were related to the improvement of insulin secretion by β-cells. The failure may be related to followings: over-interpretation of TNF-α activity; ignoring the role of anti-inflammatory cytokines; differences between mice and humans. However, the species difference cannot fully explain the failure as these therapies did not work in the animal models as well. Moreover, genome-wide association studies (GWAS) show that T2DM is not associated with proinflammatory cytokine genes, including TNF-α, IL-1β, IL-6, and CCL2(MCP1). More studies suggest that inflammation has beneficial activities in the mobilization of energy stores and promotion of energy expenditure to prevent energy surplus, a risk factor of obesity-associated T2DM. Inflammatory cytokines induce lipolysis, thermogenesis, and satiety. In this regard, the inflammatory response is a compensatory event to obesity-associated stress with beneficial effects on energy metabolism. It is time to reconsider inflammation activity in obesity for protective activities.