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- Title
Lipolysis Decreases the Energy State and Activates AMP-Activated Protein Kinase (AMPK) in the Adipocyte.
- Authors
Gauthier, Marie-Soleil; Miyoshi, Hideaki; Souza, Sandra C.; Saha, Asish K.; Greenberg, Andrew S.; Ruderman, Neil B.
- Abstract
Activation of the fuel-sensing enzyme AMPK has been shown to improve various conditions associated with obesity and type 2 diabetes. In adipocytes, beta-adrenergic agonists activate AMPK; however the mechanism(s) by which they do so is not known. In the present study we examined whether the effect of these agents is dependent on their ability to stimulate lipolysis. Incubation of 3T3-L1 adipocytes with isoproterenol, isobutylmethylxanthine or forskolin increased AMPK activity, as reflected by a 3-fold increase in P-ACC Ser79 and a 2-fold increase in P-AMPK T172-within 1 hour. ShRNA-mediated silencing of adipose tissue triglyceride lipase (ATGL), a key regulator of triglyceride hydrolysis, totally inhibited the stimulation of both lipolysis and AMPK activation by forskolin. Likewise, co-incubation of the adipocytes with the general lipase inhibitor orlistat caused a 50% inhibition of both forskolin-stimulated lipolysis and AMPK activation. In contrast, orlistat did not diminish forskolin-induced increases in the abundance of P-CREB Ser 133 or P-LKB1 Ser431, indicating that it did not alter signaling events caused by PKA activation. We then assessed whether a change in cellular energy state (AMP/ATP ratio) mediated the activation of AMPK caused by lipolysis. In support of this notion, incubation with forskolin caused a 4-fold increase in the cellular AMP/ATP ratio. Conversely, when forskolin stimulated-lipolysis was partially inhibited by orlistat, both the activation of AMPK, and the increase in the AMP/ATP ratio were diminished by 50%. Fatty acyl CoA synthase (ACS) uses ATP and generates AMP when it catalyzes the conversion of flee fatty acids to fatty acyl CoA. When We inhibited ACS with triacsin C, activation of AMPK by forskolin was completely abrogated despite the fact that lipolysis was increased to the same extent as in control conditions. In conclusion, the results indicate that the activation of AMPK following beta-adrenergic stimulation of the adipocyte is secondary to lipolysis and is not the direct result of increases in cAMP abundance or PKA activity. They suggest that a decrease in energy state most likely explains how lipolysis activates AMPK and that the energy-consuming enzyme ACS is involved in this mechanism.
- Publication
Diabetes, 2007, Vol 56, pA355
- ISSN
0012-1797
- Publication type
Academic Journal