1711-P: Dapagliflozin Promotes Adipose Beiging and Lipolysis and Reduces Adipocyte Size in the Obese Prediabetic Dog

Abstract

Selective sodium glucose cotransporter-2 inhibition promotes urinary glucose excretion, thus reducing blood glucose. Previously we showed that 6 weeks of Dapagliflozin (Dapa) treatment improved insulin sensitivity and prevented weight gain in a canine model of mild type 2 diabetes. Little is known about the effects of Dapa on adipose tissue (AT) function. Eleven dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were then exposed to Dapa (n=5, 1.25mg/kg) or placebo (n=6) once per day for 6 weeks, while remaining on the high fat diet. At the end of the study, subcutaneous (SC) and visceral (VIS) fat depots were obtained for adipocytes isolation and molecular studies and fasting plasma parameters were measured. Fasting plasma glucose and insulin levels were unaffected by Dapa treatment. Finite mixture modeling linear regression was used for adipocyte distributions. Dapa decreased adipocyte size and bimodal distributions in both SC and VIS by 10% (P<0.001). Dapa increased UCP1, PGC1α and Prdm16 gene expression by 2.68, 2.34 and 2.16 folds (<0.05) in SC and 2.5, 3.6 and 1.6 folds (<0.05) in VIS depots respectively. Immunostaining of UCP1 in SC and VIS tissues confirmed beiging process. Primary adipocytes were cultured for 4 and 24h. Lipolysis, indicated by glycerol release into the media increased by 40% in SC and 43% in vis after 24h (P<0.05). Adiponectin levels increased only in the SC adipocytes by 80% (P<0.05) after 4 and 24h cultures. Leptin levels increased in SC (by 3 folds P<0.05) and VIS by 2.6 P<0.05) after 24h adipocyte cultures. In conclusion, Dapa promotes AT beiging, lipolysis, adiponectin and leptin release by adipocytes and decreased adipocyte size and distributions. These changes were independent of glucose and insulin. Thus, for the first time we are beginning to identify mechanisms by which Dapa enhances AT function and improves energy homeostasis in mild type 2 diabetes canine model. Disclosure M. Kabir: None. R.N. Bergman: None. F. Piccinini: Employee; Self; Medtronic. D. Stefanovski: None. V. Gopaul: None. H. Yang: Employee; Self; AstraZeneca. C.M. Kolka: Research Support; Self; AstraZeneca. Funding AstraZeneca (D1690L00045-CSR212966)