Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway.
After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.
Choi
Sarah M
SM
Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Tucker
David F
DF
Gross
Danielle N
DN
Easton
Rachael M
RM
DiPilato
Lisa M
LM
Dean
Abigail S
AS
Monks
Bob R
BR
Birnbaum
Morris J
MJ
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
D007328:Insulin; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases