Lipolysis response to endoplasmic reticulum stress in adipose cells.
In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center and Key Laboratory of Molecular Cardiovascular Sciences, the Ministry of Education, Beijing 100191, China.
Jingna
J
Deng
Shangxin
S
Liu
Liangqiang
L
Zou
Chong
C
Xu
Bin
B
Geng
Guoheng
G
Xu
D050153:Abdominal Fat / Q000166:cytology / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008066:Lipolysis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009765:Obesity / Q000378:metabolism; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000070778:Perilipin-1; D010750:Phosphoproteins; D014415:Tunicamycin; D019284:Thapsigargin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008049:Lipase