Treatment of obesity-related diabetes: significance of thermogenic adipose tissue and targetable receptors

Abstract

Diabetes mellitus is mainly classified into four types according to its pathogenesis, of which type 2 diabetes mellitus (T2DM) has the highest incidence rate and is most relevant to obesity. It is characterized by high blood glucose, which is primarily due to insulin resistance in tissues that are responsible for glucose homeostasis (such as the liver, skeletal muscle, and white adipose tissue (WAT)) combined with insufficiency of insulin secretion from pancreatic β-cells. Treatment of diabetes, especially treatment of diabetic complications (such as diabetic nephropathy), remains problematic. Obesity is one of the main causes of insulin resistance, which, however, could potentially be treated by activating thermogenic adipose tissues, like brown and beige adipose tissues, because they convert energy into heat through non-shivering thermogenesis and contribute to metabolic homeostasis. In this review, we summarize the function of certain anti-diabetic medications with known thermogenic mechanisms and focus on various receptor signaling pathways, such as previously well-known and recently discovered ones that are involved in adipose tissue-mediated thermogenesis and could be potentially targeted to combat obesity and its associated diabetes, for a better understanding of the molecular mechanisms of non-shivering thermogenesis and the development of novel therapeutic interventions for obesity-related diabetes and potentially diabetic complications.

Keywords: beige adipose tissue; brown adipose tissue; diabetes; obesity; receptor.

FIGURE 1

Crosstalk between brown/beige adipose tissue and distant organs and regulation of perirenal BAT (black dots in perirenal adipocytes represent UCP1). The figure was created using BioRender (https://biorender.com/).

FIGURE 2

Classical non-shivering thermogenesis and the mechanisms of certain anti-diabetic medications. AMPK, AMP-activated protein kinase; AR, adrenergic receptor; GLP-1, glucagon-like peptide-1; NE, norepinephrine; PKA, protein kinase A; PPARγ, peroxisome proliferator-activated receptor gamma; PGC-1α, PPARγ coactivator-1α; PRDM16, protein PR domain-containing 16; SGLT2, sodium-glucose co-transporter 2; SIRT1, sirtuin 1; TZDs, thiazolidinediones; UCP1, uncoupling protein 1. The figure was created using BioRender (https://biorender.com/).