Dysregulation of lipolysis and lipid metabolism in visceral and subcutaneous adipocytes by high-fat diet: role of ATGL, HSL, and AMPK

Abstract

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.

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

“…Socs3 AKO mice have similar adiposity, adipose-tissue cell size SOCS3 has been proposed to be a negative regulator of leptin signalling in adipocytes [8]; consistent with this idea, recent studies have shown that AMPK activity is reduced in adipose tissue with obesity [23,24]. We hypothesised that AMPK activity might be elevated in adipose tissue of Socs3 AKO mice and that this might be associated with reductions in adipose-tissue cell size.…”

“…This activation of AMPK is associated with the rapid depletion of lipid from adipocytes and results in increases in glycerol but not NEFA, suggesting that leptin reduces adipose tissue mass by increasing the rate of adipose tissue fatty-acid oxidation [21,22]. Consistent with the potential for SOCS3 to inhibit adipose tissue leptin signalling, recent reports in both rodents [23] and humans [24] have found that AMPK phosphorylation is reduced with obesity.…”

The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

“…We isolated primary adipocytes to determine the in vitro lipolysis as previously reported [20] . Briefly, epididymal, omental, and retroperitoneal fat pads (approximately 2 g) from sham and chronic renal failure rats were extracted, weighed, and then finely minced using microscissors at room temperature.…”

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

“…In addition, we and others have reported that AMPK activation is associated with reduced insulinstimulated glucose transport in adipocytes [14][15][16], although a conflicting study has reported no effect of AMPK stimulation when assessing translocation of the insulinsensitive glucose transporter, GLUT4 [17]. Several physiological and pharmacological stimuli have been reported to stimulate rodent adipose tissue AMPK, including exercise, starvation, troglitazone and adrenaline (epinephrine) [10,[18][19][20], whereas AMPK is inhibited in response to ghrelin, corticosterone and a high-fat diet [21][22][23] in vivo. However, only one study has investigated AMPK activity in human adipose in vivo; in this study, insulin-resistant patients with Cushing's syndrome exhibited reduced AMPK activity compared with controls [24].…”