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1 Cellular & Molecular Metabolism Laboratory, RMIT University, Bundoora, Victoria, Australia
2 School of Health Sciences, Deakin University, Burwood, Victoria, Australia
3 St. Vincents Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
4 St. Vincents Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia; Molecular & Health Technologies, CSIRO, Parkville, Victoria, Australia
* To whom correspondence should be addressed. E-mail: matthew.watt{at}rmit.edu.au.
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 both AMPK activity and catecholamines are physiologically elevated in humans in vivo (during physical exercise) on HSL activity and phosphorylation at Ser 563 and Ser 660, the protein kinase A (PKA) regulatory sites, and Ser 565, the AMPK regulatory site. In human experiments, skeletal muscle, subcutaneous adipose and venous blood samples were obtained prior to, 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 post, exercise. Consistent with changes in plasma epinephrine, skeletal muscle HSL Ser 563 and Ser 660 phosphorylation were both increased by 27% at 15 min (P<0.05), remained elevated at 90 min and returned to pre-exercise values post-exercise. Skeletal muscle HSL Ser 565 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 Ser 660 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 Ser 660, but not Ser 563, phosphorylation. HSL activity was reduced in L6 myotubes expressing a 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 Ser 660 phosphorylation. Taken together, these data indicate that HSL activity is maintained in the face of AMPK activation, as a result of elevated HSL Ser 660 phosphorylation in adipose tissue, but not skeletal muscle.
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