PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis

The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone-sensitive lipase (HSL). TAG resynthesis is associated with high-energy consumption, which when inordinate, leads to increased AMPK activity that acts to restrain hydrolysis of TAGs by inhibiting PKA-mediated activation of HSL. Here, we report that in primary mouse adipocytes, PKA associates with and phosphorylates AMPK alpha 1 at Ser-173 to impede threonine (Thr-172) phosphorylation and thus activation of AMPK alpha 1 by LKB1 in response to lipolytic signals. Activation of AMPK alpha 1 by LKB1 is also blocked by PKA-mediated phosphorylation of AMPK alpha 1 in vitro. Functional analysis of an AMPK alpha 1 species carrying a non-phosphorylatable mutation at Ser-173 revealed a critical function of this phosphorylation for efficient release of free fatty acids and glycerol in response to PKA-activating signals. These results suggest a new mechanism of negative regulation of AMPK activity by PKA that is important for converting a lipolytic signal into an effective lipolytic response. The EMBO Journal (2010) 29, 469-481. doi: 10.1038/emboj.2009.339; Published online 26 November 2009