Department of Diabetes and Endocrinology, Graduate School of Interdisciplinary Research, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 4093898, Japan.
Department of Diabetes and Endocrinology, Graduate School of Interdisciplinary Research, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 4093898, Japan.
Pharmacol Ther. 2024 Oct;262:108699. doi: 10.1016/j.pharmthera.2024.108699. Epub 2024 Aug 5.
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.
肥胖的发病率在全球范围内迅速增加。肥胖相关的胰岛素抵抗一直被认为是肥胖相关疾病（如 2 型糖尿病和动脉粥样硬化）的重要危险因素。胰岛素在全身葡萄糖代谢中起着关键作用，肝脏、骨骼肌和脂肪组织是主要的作用组织。胰岛素受体和下游胰岛素信号相关分子在包括血管内皮细胞、血管平滑肌细胞和单核细胞/巨噬细胞在内的各种组织中表达。在肥胖中，胰岛素作用的降低被认为是相关疾病的驱动因素。然而，胰岛素作用对肥胖相关疾病是有益还是有害，取决于其作用的组织。虽然肝脏中胰岛素信号的增强会增加肝脂肪堆积并加重血脂异常，但脂肪组织中胰岛素信号的增强通过增加脂肪在脂肪组织中的堆积能力并抑制异位脂肪堆积，从而保护各种器官免受肥胖相关功能障碍。因此，通过增强脂肪组织而不是肝脏中的胰岛素敏感性来实现这种“健康的脂肪组织扩张”，可能是治疗肥胖相关疾病的有效策略。为了有效解决肥胖相关的代谢紊乱，必须了解肥胖患者各组织中胰岛素抵抗的机制，并开发增强胰岛素作用的药物。在本文中，我们综述了增强胰岛素信号作为治疗肥胖相关疾病的策略的潜力，重点介绍了每个组织中胰岛素作用的分子机制。
