Dapagliflozin Attenuates Pericardial Adipose Tissue-Derived Leptin-Mediated Myocardial Remodeling in Obese Rats

The favorable cardiovascular effects of sodium-glucose co-transporter 2 inhibitors in diabetes are well established, but their potential to ameliorate obesity-related cardiac dysfunction remains unclear. Pericardial adipose tissue (PAT)-derived adipocytokines, particularly leptin, contribute to obesity-associated cardiac remodeling. We investigated the detrimental effects of PAT-derived leptin on cardiac remodeling and whether dapagliflozin confers cardioprotection by reducing and counteracting PAT-derived leptin in obese rodents.

Male Wistar rats, C57BL/6J mice, and ob/ob mice were fed a normal or high-fat diet for 20 weeks, with or without dapagliflozin (1 mg/kg per day) for the final 8 weeks. PAT adipocytes from 8-week-old rats were isolated and induced to insulin resistance. Primary cardiac fibroblasts and cardiomyocytes were exposed to PAT-conditioned medium, leptin antagonist, dapagliflozin (10 μM), reactive oxygen species scavenger N-acetylcysteine (50 mM), pNaKtide (10 μM), Src inhibitor PP2 (10 μM). Na⁺-K⁺-ATPase expression and activity, mitochondrial membrane potential, and mitochondrial permeability transition pore opening were assessed.

The intervention of dapagliflozin to high-fat diet-fed Wistar rats could reduce body weight and improve metabolic disorders. Furthermore, dapagliflozin significantly alleviated the adipocyte hypertrophy of PAT, cardiac fibrosis and apoptosis, as well as the leptin production and secretion from PAT. In vitro, dapagliflozin inhibits the leptin production and secretion in insulin-resistant adipocytes of PAT by regulating the phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathway. Meanwhile, dapagliflozin could counteract the profibrotic effect of PAT-derived leptin via inhibiting the signal transducer and activator of transcription 3-reactive oxygen species/Na⁺-K⁺-ATPase/Src oxidative stress loop signaling pathway. Meanwhile, dapagliflozin could also attenuate cardiomyocytes apoptosis induced by PAT-derived leptin via suppressing Janus kinase 2/signal transducer and activator of transcription 3-Bax and inhibiting reactive oxygen species/Na⁺-K⁺-ATPase/Src oxidative stress loop.

Dapagliflozin reduced PAT-derived leptin via phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2 signaling and mitigated PAT-derived leptin-induced myocardial fibrosis and apoptosis by inhibiting signal transducer and activator of transcription 3-mediated reactive oxygen species/Na⁺-K⁺-ATPase/Src oxidative stress signaling.