Regulation of Visceral and Subcutaneous Adipocyte Lipolysis by Acute AICAR‐induced AMPK Activation

Abstract

This study investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in the regulation of lipolysis in visceral (VC) and subcutaneous (SC) rat adipocytes and the molecular mechanisms involved in this process. VC (epididymal and retroperitoneal) and SC (inguinal) adipocytes were isolated from male Wistar rats (160-180 g). Adipocytes were incubated either in the absence or in the presence of the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, 0-500 µmol/l). AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, basal and epinephrine-stimulated (100 nmol/l) glycerol release, and hormone-sensitive lipase (HSL) phosphorylation and activity were determined. AICAR-induced (500 µmol/l) AMPK activation inhibited basal glycerol release by ~42, 41, and 44% in epididymal, retroperitoneal, and inguinal adipocytes, respectively. Epinephrine-stimulated glycerol release was almost completely prevented by AICAR treatment in adipocytes from all fat depots. The AMPK inhibitor compound C (20 µmol/l) prevented AICAR-induced phosphorylation of AMPK and significantly increased basal (~1.3-, 1.4-, and 1.7-fold) and epinephrine-stimulated (~1.3-, 1.2-, 1.4-fold) glycerol release in epididymal, retroperitoneal, and inguinal adipocytes, respectively. AICAR increased phosphorylation of HSL Ser565 and inhibited epinephrine-induced phosphorylation of HSL Ser563 and HSL Ser660 . This was also accompanied by a 73% reduction in epinephrine-stimulated HSL activity. Compound C prevented the phosphorylation of HSL Ser565 induced by AICAR and partially prevented the inhibitory effect of this drug on basal and epinephrinestimulated lipolysis in adipocytes in VC and SC fat depots. In summary, despite different fat depots eliciting distinct rates of lipolysis, acute AICAR-induced AMPK activation suppressed HSL phosphorylation/activation and exerted similar antilipolytic effects on both VC and SC adipocytes.

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

“…We have demonstrated [8] by manipulating AMPK activity using dominant positive and negative forms of the kinase that AMPK is inhibitory in mature adipocytes. More recent studies have confirmed that AMPK activation inhibits the lipolytic pathway in rodent adipocytes [11,14].…”

“…Concerning the mechanism by which AMPK could restrain lipolysis, an effect of AMPK on HSL activation has been described in rodent adipocytes [8,12,14]. AMPK phosphorylates Serine 565 of HSL, potentially precluding phosphorylation of other serine residues crucial for activation of the enzyme [46].…”

“…We and others have shown in rodents that AMP-activated protein kinase is activated during the lipolytic process in adipocytes [7][8][9][10][11] and could contribute to restrain lipolysis [8,[11][12][13][14]. Interestingly, administration of the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) reduces whole-body lipolysis in rodents and in humans [14,15].…”

Decreased expression of adipose CD36 and FATP1 are associated with increased plasma non-esterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris)

“…LPL, hepatic lipase, pancreatic lipase) and reduced activity of adipose lipases, the calculations show that the majority of lipolysis still occurs in adipose tissue. There is a lack of a change in plasma glycerol and twofold increase in the NEFA:glycerol ratio in late-fasted seals during the glucose challenge that seems to disagree with the maintenance of adipose lipolysis (Naito and Okada, 1975;Gruen et al, 1980;Anthony et al, 2009;Gaidhu and Ceddia, 2011). However, chronic AMPK activation in adipose tissue (Viscarra et al, 2011b) may have inhibited the complete hydrolysis of triglycerides, leading to a disconnect in the relationship between plasma NEFA and glycerol.…”

Cardiotrophin-1 stimulates lipolysis through the regulation of main adipose tissue lipases

“…Nevertheless, the effects of AMPK activation on lipolysis are complex because both antilipolytic (37)(38)(39) and lipolytic ( 40,41 ) actions have been reported. In fact, AMPK effects on lipolysis seem to be time-dependent, involving antagonistic modulation of HSL and ATGL ( 42 ).…”