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Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue

¹Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora; ²School of Health Sciences, Deakin University, Burwood; ³St. Vincent’s Institute and Department of Medicine, University of Melbourne, Fitzroy; and ⁴Commonwealth Scientific and Industrial Research Organisation Molecular and Health Technologies, Parkville, Victoria, Australia

Submitted 4 August 2005 ; accepted in final form 27 September 2005

Hormone-sensitive lipase (HSL) is important for the degradation of triacylglycerol in adipose and muscle tissue, but the tissue-specific regulation of this enzyme is not fully understood. We investigated the effects of adrenergic stimulation and AMPK activation in vitro and in circumstances where AMPK activity and catecholamines are physiologically elevated in humans in vivo (during physical exercise) on HSL activity and phosphorylation at Ser⁵⁶³ and Ser⁶⁶⁰, the PKA regulatory sites, and Ser⁵⁶⁵, the AMPK regulatory site. In human experiments, skeletal muscle, subcutaneous adipose and venous blood samples were obtained before, at 15 and 90 min during, and 120 min after exercise. Skeletal muscle HSL activity was increased by 80% at 15 min compared with rest and returned to resting rates at the cessation of and 120 min after exercise. Consistent with changes in plasma epinephrine, skeletal muscle HSL Ser⁵⁶³ and Ser⁶⁶⁰ phosphorylation were increased by 27% at 15 min (P < 0.05), remained elevated at 90 min, and returned to preexercise values postexercise. Skeletal muscle HSL Ser⁵⁶⁵ phosphorylation and AMPK signaling were increased at 90 min during, and after, exercise. Phosphorylation of adipose tissue HSL paralleled changes in skeletal muscle in vivo, except HSL Ser⁶⁶⁰ was elevated 80% in adipose compared with 35% in skeletal muscle during exercise. Studies in L6 myotubes and 3T3-L1 adipocytes revealed important tissue differences in the regulation of HSL. AMPK inhibited epinephrine-induced HSL activity in L6 myotubes and was associated with reduced HSL Ser⁶⁶⁰ but not Ser⁵⁶³ phosphorylation. HSL activity was reduced in L6 myotubes expressing constitutively active AMPK, confirming the inhibitory effects of AMPK on HSL activity. Conversely, in 3T3-L1 adipocytes, AMPK activation after epinephrine stimulation did not prevent HSL activity or glycerol release, which coincided with maintenance of HSL Ser⁶⁶⁰ phosphorylation. Taken together, these data indicate that HSL activity is maintained in the face of AMPK activation as a result of elevated HSL Ser⁶⁶⁰ phosphorylation in adipose tissue but not skeletal muscle.

hormone-sensitive lipase; exercise; fat metabolism; AMP-activated protein kinase

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