Affiliation:
1. Diabetes and Obesity Research Institute Cedars‐Sinai Medical Center Los Angeles California USA
2. University of Pennsylvania School of Veterinary Medicine Philadelphia Pennsylvania USA
3. Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden
4. Department of Endocrinology David Geffen School of Medicine at the University of California Los Angeles California USA
Abstract
AbstractObjectiveSodium‐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.MethodsA 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.ResultsDAPA 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.ConclusionsFor 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.
Funder
AstraZeneca
National Institutes of Health
Subject
Nutrition and Dietetics,Endocrinology,Endocrinology, Diabetes and Metabolism,Medicine (miscellaneous)
Cited by
1 articles.
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