Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1.
Insulin resistance in skeletal muscle is found in obesity and type 2 diabetes. A mechanism for impaired insulin signaling in peripheral tissues is the inhibition of insulin action through serine phosphorylation of insulin receptor substrate (Irs) proteins that abolish the coupling of Irs proteins to the activated insulin receptor. Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. In analogy, in lymphocytes of obese hyperleptinemic human subjects basal Ser-318 phosphorylation levels were increased compared to lean individuals. During a hyperinsulinemic euglycemic clamp, the increment in Ser-318 phosphorylation observed in lean individuals was absent in obese. In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects.
Hennige
Anita M
AM
University of Tuebingen, Department of Internal Medicine IV, Tuebingen D-72076, Germany.
Stefan
Norbert
N
Kapp
Katja
K
Lehmann
Rainer
R
Weigert
Cora
C
Beck
Alexander
A
Moeschel
Klaus
K
Mushack
Joanne
J
Schleicher
Erwin
E
Häring
Hans-Ulrich
HU
D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003847:Deoxyglucose / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes / Q000378:metabolism; D053614:Janus Kinase 2; D020738:Leptin / Q000494:pharmacology*; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology; D009765:Obesity / Q000201:enzymology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism*
C526292:IRS1 protein, human; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007527:Isoenzymes; D020738:Leptin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012694:Serine; D003847:Deoxyglucose; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051745:Protein Kinase C-delta