Dysregulation of lipolysis and lipid metabolism in visceral and subcutaneous adipocytes by high-fat diet: role of ATGL, HSL, and AMPK.
This study investigated the molecular mechanisms by which a high-fat diet (HFD) dysregulates lipolysis and lipid metabolism in mouse epididymal (visceral, VC) and inguinal (subcutaneous, SC) adipocytes. Eight-weeks of HFD feeding increased adipose triglyceride lipase (ATGL) content and comparative gene identification-58 (CGI-58) expression, whereas hormone-sensitive lipase (HSL) phosphorylation and perilipin content were severely reduced. Adipocytes from HFD mice elicited increased basal but blunted epinephrine-stimulated lipolysis and increased diacylglycerol content in both fat depots. Consistent with impaired adrenergic receptor signaling, HFD also increased adipose-specific phospholipase A(2) expression in both fat depots. Inhibition of E-prostanoid 3 receptor increased basal lipolysis in control adipocytes but failed to acutely alter the effects of HFD on lipolysis in both fat depots. In HFD visceral adipocytes, activation of adenylyl cyclases by forskolin increased HSL phosphorylation and surpassed the lipolytic response of control cells. However, in HFD subcutaneous adipocytes, forskolin induced lipolysis without detectable HSL phosphorylation, suggesting activation of an alternative lipase in response to HFD-induced suppression of HSL in VC and SC adipocytes. HFD also powerfully inhibited basal, epinephrine-, and forskolin-induced AMP kinase (AMPK) activation as well peroxisome proliferator-activated receptor gamma coactivator-1alpha expression, citrate synthase activity, and palmitate oxidation in both fat depots. In summary, novel evidence is provided that defective adrenergic receptor signaling combined with upregulation of ATGL and suppression of HSL and AMPK signaling mediate HFD-induced alterations in lipolysis and lipid utilization in VC and SC adipocytes, which may play an important role in defective lipid mobilization and metabolism seen in diet-induced obesity.
Gaidhu
Mandeep P
MP
Muscle Health Research Centre, York Univ., 4700 Keele St., Toronto, ON, Canada M3J 1P3.
Anthony
Nicole M
NM
Patel
Prital
P
Hawke
Thomas J
TJ
Ceddia
Rolando B
RB
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D006801:Humans; D008049:Lipase; D050356:Lipid Metabolism / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases
D000103:Acetyl-CoA Carboxylase; D000263:Adenylate Kinase; D002265:Carboxylic Ester Hydrolases; D002950:Citrate (si)-Synthase; D004041:Dietary Fats; D004075:Diglycerides; D008049:Lipase; D010168:Palmitates; D012333:RNA, Messenger; D002787:Sterol Esterase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases