TY - JOUR

T1 - Ampk activation by a-769662 and 991 does not affect catecholamine-induced lipolysis in human adipocytes

AU - Kopietz, Franziska

AU - Berggreen, Christine

AU - Larsson, Sara

AU - Säll, Johanna

AU - Ekelund, Mikael

AU - Sakamoto, Kei

AU - Degerman, Eva

AU - Holm, Cecilia

AU - Göransson, Olga

PY - 2018/11

Y1 - 2018/11

N2 - Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue, whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR), suggest an antilipolytic role of AMPK in adipocytes. The aim of this work was to reinvestigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991, or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release, and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, were then monitored. Our results show that both A-769662 and 991 activated AMPK to a level that was similar to, or greater than, that induced by AICAR. In contrast to AICAR, which as expected was antilipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment led to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the antilipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK independent.

AB - Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue, whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR), suggest an antilipolytic role of AMPK in adipocytes. The aim of this work was to reinvestigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991, or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release, and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, were then monitored. Our results show that both A-769662 and 991 activated AMPK to a level that was similar to, or greater than, that induced by AICAR. In contrast to AICAR, which as expected was antilipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment led to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the antilipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK independent.

KW - Allosteric small-molecule AMPK activators

KW - AMP-activated protein kinase

KW - Hormone-sensitive lipase

KW - Human adipocytes

KW - Lipolysis

UR - http://www.scopus.com/inward/record.url?scp=85056603779&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00110.2018

DO - 10.1152/ajpendo.00110.2018

M3 - Journal article

C2 - 30253109

AN - SCOPUS:85056603779

VL - 315

SP - E1075-E1085

JO - A J P: Endocrinology and Metabolism (Online)

JF - A J P: Endocrinology and Metabolism (Online)

SN - 1522-1555

IS - 5

ER -