Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin‐resistant canine model

Abstract

Objective Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin‐resistant canine model. Methods A total of 12 dogs were fed a high‐fat diet (HFD) for 6 weeks and then were given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. Results DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and β‐hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP‐activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. Conclusions For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin‐resistant canine model.

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

“…By lowering calories and improving hypothalamic insulin response, SGLT2i treatment might cause adipocytes in perivascular adipose tissues to become smaller and promote them to spend more energy. Significant weight loss would follow, along with reductions in visceral fat, subcutaneous fat, and overall adiposity (98)(99)(100). But SGLT2i treatment-induced weight loss was limited.…”

Comparative efficacy and safety of SGLT2is and ns-MRAs in patients with diabetic kidney disease: a systematic review and network meta-analysis

“…Obesity is considered to be closely related to insulin resistance. The weight-reducing effect of SGLT2is could improve insulin resistance, regulate energy homeostasis, and thereby exert renal protective effects that go beyond glucose-lowering ( 50 ). It has been proposed that SGLT2is maintain the balance of sodium-potassium ion exchange (natriuretic and diuretic effects) and energy metabolism, as well as reduce oxidative stress in cells to provide favorable effects on the risk of renal protection ( 51 , 52 ).…”

Narrative Review of Immunomodulatory and Anti-inflammatory Effects of Sodium-Glucose Cotransporter 2 Inhibitors: Unveiling Novel Therapeutic Frontiers

“… 75 Several studies have also explored the influence of SGLT2 inhibitors on adipokines such as leptin and adiponectin and its impact on antiinflammatory effect. 76 , 77 These multifaceted effects contribute to improvement in obesity, alleviation of inflammation, and enhanced insulin sensitivity.…”