Dueling Kinases Finesse the Fat

Science Signaling  02 Feb 2010:
Vol. 3, Issue 107, pp. ec44
DOI: 10.1126/scisignal.3107ec44

Storage of energy in adipocytes as triacylglycerides (TAGs) and release of such stored energy into the circulation in the form of nonesterified free fatty acids (NEFAs) or glycerol is essential to energy homeostasis. Djouder et al. provide insight into the intricate mechanisms by which lipolysis is regulated in response to hormonal signals that signal increased energy demands and more local sensing of energy status, specifically concentrations of AMP (adenosine monophosphate). Lipolytic hormones stimulate β-adrenergic receptors and cause activation of PKA (cyclic AMP-dependent protein kinase), which in turn phosphorylates hormone-sensitive lipase (HSL) and other enzymes that regulate lipid stores. The authors studied the interplay of this mechanism with control of HSL by the energy status–sensing protein kinase AMPK (adenosine monophosphate–activated protein kinase). AMPK, activated when conditions dictate depletion of ATP and accumulation of ADP, also phosphorylates HSL, at a site distinct from that phosphorylated by PKA. These phosphorylation events on HSL appear to be mutually exclusive, and thus activation of AMPK can prevent further activation of HSL by PKA. But the system appears even more tightly controlled, as Djouder et al.’s results indicate that PKA and AMPK are associated in mouse adipocytes and that phosphorylation of AMPKα1 subunit by PKA inhibits activity of that enzyme. The authors provide evidence that phosphorylation of AMPKα1 by PKA at Ser173 prevents phosphorylation of AMPKα1 at the adjacent Ser172 by the AMPK-activating kinase LKB1. The physiological relevance of such regulation is supported by experiments in which the authors expressed a mutant version of AMPKα1 that cannot be phosphorylated by PKA in mouse embryo fibroblasts that lack AMPKα1. When these cells were differentiated into adipocytes, they released less glycerol than did cells expressing the wild-type enzyme and were less responsive to isoproterenol, a stimulus that activates PKA and thus enhances lipolysis. Studies in primary mouse adipocytes also showed that stimuli that activate PKA inhibited activation of AMPK in response to glucose deprivation. Lipid hydrolysis promoted by HSL increases cellular concentrations of AMP, also providing feedback to AMPK. The authors propose that these linked feedback mechanisms help balance effects of PKA and AMPK so that acute effects of PKA to stimulate lipolysis are followed at later times by activation of AMPK to prevent excessive depletion of lipid stores.

N. Djouder, R. D. Tuerk, M. Suter, P. Salvioni, R. F. Thali, R. Scholz, K. Vaahtomeri, Y. Auchli, H. Rechsteiner, R. A. Brunisholz, B. Viollet, T. P. Mäkelä, T. Wallimann, D. Neumann, W. Krek, PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis. EMBO J. 29, 469–481 (2010). [PubMed]