Jinhan He1, Chong Xu2, Jiangying Kuang3, Qinhui Liu3, Hongfeng Jiang4, Li Mo5, Bin Geng4, Guoheng Xu6. 1. Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China. Electronic address: Jinhanhe@scu.edu.cn. 2. Astronaut Research and Training Center of China, Beijing 100094, China. 3. Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China. 4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China. 5. Department of Geriatrics, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China. 6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address: xug@bjmu.edu.cn.
Abstract
BACKGROUND: Elevated levels of circulating free fatty acids induce insulin resistance and often occur in obese and diabetic conditions. One pharmacological basis for the antidiabetic effects of thiazolidinediones (TZDs) is that TZDs reduce levels of circulating FFAs by accelerating their uptake and reesterification from plasma into adipocytes. Here, we investigated whether TZDs affect adipose lipolysis, a process controlling triglyceride hydrolysis and FFA efflux to the bloodstream. METHODS: The effects of TZDs on lipolysis were investigated in primary rat adipocytes in vitro and in rats in vivo. RESULTS: In rat primary adipocytes, the TZDs pioglitazone, rosiglitazone and troglitazone inhibited the lipolytic reaction dose- and time-dependently and in a post-receptor pathway by decreasing cAMP level and total lipase activity. TZDs increased the phosphorylation of Akt/protein kinase B, an action required for activating cyclic-nucleotide phosphodiesterase 3B, a major enzyme responsible for cAMP hydrolysis in adipocytes. Furthermore, rosiglitazone inhibited the lipolytic action in dexamethasone-stimulated adipocytes, thereby preventing the increased level of circulating FFAs, and ameliorated insulin resistance in vivo in dexamethasone-treated rats. CONCLUSIONS: TZDs may attenuate lipolysis and FFA efflux by activating Akt signaling to decrease cAMP level and hence reduce lipase activity in adipocytes. Inhibiting lipolysis and FFA efflux with TZDs could be a pharmacological basis by which TZDs antagonize diabetes, particularly in patients with hypercortisolemia or glucocorticoid challenge.
BACKGROUND: Elevated levels of circulating free fatty acids induce insulin resistance and often occur in obese and diabetic conditions. One pharmacological basis for the antidiabetic effects of thiazolidinediones (TZDs) is that TZDs reduce levels of circulating FFAs by accelerating their uptake and reesterification from plasma into adipocytes. Here, we investigated whether TZDs affect adipose lipolysis, a process controlling triglyceride hydrolysis and FFA efflux to the bloodstream. METHODS: The effects of TZDs on lipolysis were investigated in primary rat adipocytes in vitro and in rats in vivo. RESULTS: In rat primary adipocytes, the TZDspioglitazone, rosiglitazone and troglitazone inhibited the lipolytic reaction dose- and time-dependently and in a post-receptor pathway by decreasing cAMP level and total lipase activity. TZDs increased the phosphorylation of Akt/protein kinase B, an action required for activating cyclic-nucleotide phosphodiesterase 3B, a major enzyme responsible for cAMP hydrolysis in adipocytes. Furthermore, rosiglitazone inhibited the lipolytic action in dexamethasone-stimulated adipocytes, thereby preventing the increased level of circulating FFAs, and ameliorated insulin resistance in vivo in dexamethasone-treated rats. CONCLUSIONS:TZDs may attenuate lipolysis and FFA efflux by activating Akt signaling to decrease cAMP level and hence reduce lipase activity in adipocytes. Inhibiting lipolysis and FFA efflux with TZDs could be a pharmacological basis by which TZDs antagonize diabetes, particularly in patients with hypercortisolemia or glucocorticoid challenge.
Authors: Diana Alemán-González-Duhart; Samuel Álvarez-Almazán; Miguel Valdes; Feliciano Tamay-Cach; Jessica Elena Mendieta-Wejebe Journal: PPAR Res Date: 2021-12-31 Impact factor: 4.964