Tissue-specific activation of insulin signaling as a potential target for obesity-related metabolic disorders

The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this “healthy adipose tissue expansion” by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.