Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: Focus on fat browning and macrophage polarization

Abstract

Obesity-associated low-grade inflammation underlies insulin resistance and associated metabolic comorbidities, such as type 2 diabetes (T2D) and nonalcoholic fatty liver disease. Excessive ectopic fat deposition in obesity causes disorders of energy homeostasis and low-grade chronic inflammation in metabolic tissues. In particular, obesity-induced recruitment and activation of adipose tissue macrophages play a key role in the pathogenesis of insulin resistance and T2D. Therefore, treatment options for energy metabolism and macrophage polarization in obese subjects are needed. Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, thereby having subsequent anti-hyperglycemic effects and reducing body weight. We recently reported that the SGLT2 inhibitor empagliflozin increases fat utilization and browning in white adipose tissue and attenuates obesity-induced inflammation and insulin resistance by activating M2 macrophages. Thus, this review focuses on the beneficial effects of empagliflozin in energy homeostasis and obesity-related inflammation and insulin resistance.

Keywords: adipose tissue macrophage; empagliflozin; fat browning; inflammation; insulin resistance.

Figure 1.

Obesity-related macrophage polarization and insulin resistance. In a lean state, M2 macrophages are the primary resident macrophages and maintain insulin sensitivity. In contrast, excess calories or a sedentary lifestyle cause adipocyte hypertrophy, which initiates secretion of CCL2 and CCL5, leading to the recruitment of circulating monocytes in adipose tissues. Subsequently, CCR2⁺ macrophages accumulate and presumably maintain inflammation as M1 macrophages in obese adipose tissue. Once these ATMs are present and active, they maintain a vicious cycle involving ATM recruitment and the production of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, in conjunction with adipocytes and other infiltrated immune cells. These secreted proinflammatory cytokines subsequently cause inflammation and insulin resistance in adipose tissue, liver, and skeletal muscle.

Figure 2.

Protective effects of empagliflozin in high-fat diet-induced obese mice. Inhibiting SGLT2 with empagliflozin directly decreases blood glucose levels, leading to the following: (1) Empagliflozin promotes fat utilization by enhancing AMPKα and ACC phosphorylation in skeletal muscle and increasing hepatic and plasma levels of FGF21. (2) Empagliflozin enhances browning and thermogenesis in WAT and BAT, which results in increased energy expenditure. (3) Empagliflozin improves insulin sensitivity by polarizing M2 macrophages in fat and liver.