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  • Under conditions of energy scarcity or nutritional restricti

    2020-06-30

    Under conditions of energy scarcity or nutritional restriction, AMPK, a critical energy sensor, is activated in response to the increased ratio of AMP to ATP. Various kinases may phosphorylate AMPK, leading to its activation. For example, AMPK phosphorylation by liver kinase B 1 (LKB1) at Thr172 results in activation. However, phosphorylation of AMPK at Ser173 by cyclic adenosine monophosphate (cAMP)–dependent protein kinase A (PKA) results in AMPK inactivation. AMPK can regulate and maintain the energy balance in cells in response to intracellular energy alteration (Shackelford and Shaw, 2009). Under conditions of shock, hypoxia, or sustained exercise, AMPK is activated to inhibit the events corresponding to energy consumption (e.g., fatty Torin 1 and steroid synthesis) and to activate the energy metabolism pathway (e.g., fatty acid oxidation). We and other researchers have shown that activated AMPK increases the expression of adipose triglyceride lipase (ATGL) in triacylglycerol (TG) hydrolysis, resulting in an increase in the release of glycerol and fatty acids (Cheng et al., 2015). PKA signaling is a crucial pathway for fat decomposition in response to β-adrenergic stimuli. Increased cAMP levels lead to PKA activation through β-adrenergic receptor–mediated adenylate cyclase activation. After adipocyte lipolytic stimulation, perilipin becomes the most abundant phosphoprotein. Perilipin phosphorylation by PKA increases translocation of perilipin from the surface of lipid droplets (LDs) to the cytosol (Londos et al., 1999, Souza et al., 1998). Perilipin also serves as a docking protein for the binding of hormone-sensitive lipase (HSL) to the LD surface (Blanchette-Mackie et al., 1995). In addition, PKA can activate HSL by phosphorylating it at Ser563, thereby increasing HSL translocation from the cytosol to the LD surface for diacylglyceride hydrolysis. By contrast, PKA-induced phosphorylation of HSL at Ser660 increases intrinsic enzyme activity. The coordination of perilipin and HSL activation through PKA phosphorylation in β-adrenergic agonist–mediated lipolysis has been intensively examined (Martinez-Botas et al., 2000, Sztalryd et al., 2003, Tansey et al., 2001). Counteractive effects of PKA and AMPK in lipolysis have been reported. PKA phosphorylates AMPK at Ser173, resulting in the reduction of pAMPK-Thr172 levels and AMPK activity in adipocytes. Conversely, when activated through phosphorylation at Thr172, AMPK induces ATGL expression and increases the hydrolysis of TG to diacylglycerol (DG). On the other hand, AMPK can phosphorylate HSL at Ser565, resulting in HSL inactivation, and a consequent decrease in DG hydrolysis. Thus, AMPK inhibits PKA-mediated HSL activation; this inhibition can alleviate toxicity due to excessive production of fatty acids (FAs) (Djouder et al., 2010). Therefore, coordination between PKA and AMPK is crucial for efficient lipolysis in adipocytes. By contrast, prolonged 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-induced AMPK activation can increase ATGL expression and TG lipase activity in white adipocytes, resulting in an increase in the adipocytes’ release of FAs (Gaidhu et al., 2009). However, these effects were not observed in adipose-specific ATGL knockout mice (Ahmadian et al., 2011). These findings indicate that the AMPK–ATGL axis is critical in TG hydrolysis. In a previous study, we showed that kinsenoside induced adipocyte lipolysis by inducing ATGL and carnitine palmitoyltransferase I (CPT1) expression through AMPK-mediated lipolysis and FA oxidation. In this study, we further explored the synergistic effect of PKA in modulating AMPK function in lipolysis in vitro and in vivo.
    Materials and methods
    Results
    Discussion We previously reported that kinsenoside-mediated lipolysis in adipocytes was the result of ATGL and CPT1 upregulation through the AMPK–PPARα–PGC1α axis (Cheng et al., 2015). In the present study, we extended our previous findings and showed that PKA can activate HSL and perilipin by phosphorylating them. The in vivo effect of kinsenoside on obesity suggests that kinsenoside may reduce the risks related to the overweight or obese conditions that occur in more than one-third of the global population.