title: Deficiency of clusterin exacerbates high-fat diet-induced insulin resistance in male mice.
abstract: The present study examined the role of clusterin in insulin resistance in high fat-fed wild-type and clusterin knockout (KO) mice. The plasma levels of glucose and C-peptide and islet size were increased in clusterin KO mice after an 8-week high-fat diet. In an ip glucose tolerance test, the area under the curve for glucose was not different, whereas the area under the curve for insulin was higher in clusterin KO mice. In a hyperinsulinemic-euglycemic clamp, the clamp insulin levels were higher in clusterin KO mice after the high-fat diet. After adjusting for the clamp insulin levels, the glucose infusion rate, suppression of hepatic glucose production, and glucose uptake were lower in clusterin KO mice in the high fat-fed group. The plasma levels of clusterin and clusterin mRNA levels in the skeletal muscle and liver were increased by the high-fat diet. The mRNA levels of the antioxidant enzymes were lower, and the mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 1 and cytokines and protein carbonylation were higher in the skeletal muscle and liver in clusterin KO mice after the high-fat diet. Palmitate-induced gene expressions of NOX1 and cytokines were higher in the primary cultured hepatocytes of clusterin KO mice compared with the wild-type mice. Clusterin inhibited the gene expression and reactive oxygen species generation by palmitate in the hepatocytes and C2C12. AKT phosphorylation by insulin was reduced in the hepatocytes of clusterin KO mice. These results suggest that clusterin plays a protective role against high-fat diet-induced insulin resistance through the suppression of oxidative stress and inflammation.
authors.affiliation: Departments of Physiology (M.J.K., T.-j.J., J.-Y.H., Y.-W.K., J.-Y.K., S.-Y.P.), Internal Medicine (K.-C.W.), Biochemistry and Molecular Biology (J.-R.K.), and Pathology (Y.K.B.) and Aging-Associated Vascular Disease Research Center (T.-j.J., J.-Y.H., J.-R.K., S.-Y.P.), College of Medicine, Yeungnam University, Daegu 705-703, South Korea; Department of Anatomy (I.-S.P.), College of Medicine, Inha University, Incheon 400-712, South Korea; Department of Pharmacology (B.-H.M.), College of Medicine, Korea University, Seoul 136-705, South Korea; and Department of Internal Medicine (I.-K.L.), School of Medicine, Kyungpook National University, Daegu 700-712, South Korea.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kwon
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Ju
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Heo
authors.forename: Yong-Woon
authors.initials: YW
authors.lastname: Kim
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Won
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
authors.forename: Young Kyung
authors.initials: YK
authors.lastname: Bae
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.forename: Bon-Hong
authors.initials: BH
authors.lastname: Min
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D051152:Clusterin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005434:Flow Cytometry; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050050:Protein Carbonylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051152:Clusterin