A novel IKKbeta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance.
Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKAy mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion.
Kamon
Junji
J
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Yamauchi
Toshimasa
T
Muto
Susumu
S
Takekawa
Sato
S
Ito
Yusuke
Y
Hada
Yusuke
Y
Ogawa
Wataru
W
Itai
Akiko
A
Kasuga
Masato
M
Tobe
Kazuyuki
K
Kadowaki
Takashi
T
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002867:Chromones / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism; D051550:I-kappa B Kinase; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D013997:Time Factors; D015854:Up-Regulation
D052242:Adiponectin; D001549:Benzamides; D001786:Blood Glucose; D002867:Chromones; D004791:Enzyme Inhibitors; D005947:Glucose; D051550:I-kappa B Kinase; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse