title: Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance.
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.
authors.affiliation: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China. Electronic address: Jinhanhe@scu.edu.cn.
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
authors.affiliation: Astronaut Research and Training Center of China, Beijing 100094, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jiangying
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Qinhui
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Geriatrics, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Mo
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Geng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address: xug@bjmu.edu.cn.
authors.forename: Guoheng
authors.initials: G
authors.lastname: Xu
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D000077288:Troglitazone
chemical_list: D002839:Chromans; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D003907:Dexamethasone; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D000077288:Troglitazone; D000077205:Pioglitazone
keywords: Dexamethasone; Free fatty acids; Insulin resistance; Lipolysis; Thiazolidinedione