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.

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

“…Of 394 Steiner proteins, 121 (~30%) possess some known disease link according to DisGeNET (Data S4). Some examples include: clusterin (CLU), in which polymorphisms are associated with type 2 diabetes (Daimon et al, 2011) and where knockout in C57BL/6J mice exacerbates HFD-induced insulin resistance (Kwon et al, 2014); L-arginine:glycine amidinotransferase (GATM, a.k.a. AGAT), where knockout in C57BL/6J mice depletes creatine, enhances glucose tolerance, and protects from diet-induced obesity (Choe et al, 2013); and nuclear receptor co-activator 1 (NCOA1, a.k.a.…”

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

“…Under this condition, circulating ApoJ would remain high, as it cannot be utilized by muscle. In this regard, several studies show that elevated circulating ApoJ level is associated with insulin resistance in diet-induced obese mice 43 , as well as humans with PCOS, type 2 diabetes, and atherosclerotic diseases 23,26 . However, insulin-sensitizing interventions, including exercise training 44,45 and pioglitazone treatment 46 , lead to a significant decrease in circulating ApoJ in insulin-resistant humans.…”

Methionine sulfoxide reductase B1 deficiency does not increase high-fat diet-induced insulin resistance in mice

“…A hyperinsulinemic-euglycemic clamp study was performed 4 days after vein cannulation in conscious mice as described previously [22]. Briefly, after overnight fasting, a 2-h hyperinsulinemic-euglycemic clamp was performed with a 900 pmol•kg −1 priming dose and a continuous infusion of human regular insulin (Novolin, Denmark) at 15 pmol•kg −1 •min −1 , and 20% glucose was infused at variable rates to maintain glucose at constant concentrations of 5∼6 mM.…”

“…Protein-carbonyl contents were measured using an OxyBlot Protein Oxidation Detection kit (Chemicon, USA) as previously described [22]. Briefly, tissues were homogenized in lysis buffer (Invitrogen) containing 50 mM DTT.…”