SGLT2 inhibition and adipose tissue metabolism: current outlook and perspectives

Abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as important agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT2 inhibitors have been associated with improved cardiovascular outcomes, not only through their immediate hemodynamic effects-such as glycosuria and (at least temporary) increased natriuresis-but also due to their multifaceted impact on metabolism. Recently, studies have also focused on the effects of SGLT2 inhibitors on adipose tissue. Aside from the well-documented effects on human adiposity, SGLT2i have shown, both in vitro and in murine models, the ability to reduce fat mass, upregulate genes related to browning of white adipose tissue, influence adipocyte size and fatty acid oxidation, and improve oxidative stress and overall metabolic health. In humans, even though data are still limited, recent evidence seems to confirm that the SGLT2i effects observed in cardiovascular outcome trials could be partially explained by their impact on adipose tissue. This review aims to clarify the impact of SGLT2i on adipose tissue, highlighting their role in metabolic health and their potential to transform treatment strategies for T2DM beyond glucose metabolism.

Keywords: Adipose organ; Diabetes; Epicardial adipose tissue; Metabolism; Precision medicine; SGLT-2i.

Fig. 1

SGLT2i, by inducing glycosuria, lead to the hepatic production of the ketone β-OH-B, which stimulates FFA production in adipose tissue. This process also modifies histone H3K9, leading to increased adiponectin levels and promoting the browning of white adipose tissue (WAT). Consequently, the activation of BAT increases the secretion of FGF21, promoting brown adipose tissue (BAT) activity and browning of WAT (confirmed by the increase of UCP1, PGC1α, and PRDM16 expression). When BAT activity increases, insulin sensitivity and metabolism are enhanced. All these effects are reflected in the cardiovascular system at epicardial adipose tissue (EAT) level, where SGLT2i induce a reduction in EAT thickness which leads to a reduction of EAT inflammation, improving coronary flow reserve (CFR)