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Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

ABSTRACT: OBJECTIVE:Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. RESEARCH DESIGN AND METHODS:We validated increased clusterin expression in adipocytes from a separate group of 18 lean and 54 obese individuals. The relationship of clusterin gene expression and plasma clusterin with IR, cardiovascular biomarkers, and risk of cardiovascular disease (CVD) was then determined. Further investigations in human cultured cells and in aged LDLR-/- mice prone to development of obesity-associated complications were performed. RESULTS:SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating human clusterin exhibited similar associations. In human adipocytes, palmitate enhanced clusterin secretion, and in human hepatocytes, clusterin attenuated insulin signaling and APOA1 expression and stimulated hepatic gluconeogenesis. LRP2 (megalin), a clusterin receptor, highly expressed in liver, mediated these effects, which were inhibited by LRP2 siRNA. In response to Western diet feeding, an increase in adipocyte clusterin expression was associated with a progressive increase in liver fat, steatohepatitis, and fibrosis in aged LDLR-/- mice. CONCLUSIONS:Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.

SUBMITTER: Bradley D

PROVIDER: S-EPMC6385696 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

Bradley David D Blaszczak Alecia A Yin Zheng Z Liu Joey J Joseph Joshua J JJ Wright Valerie V Anandani Kajol K Needleman Bradley B Noria Sabrena S Renton David D Yearsley Martha M Wong Stephen T C STC Hsueh Willa A WA

Diabetes care 20190118 3

<h4>Objective</h4>Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine <i>1</i>) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and <i>2 ...[more]

PMID: 30659075

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Project description:ObjectiveCarbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in the liver, the effect of hepatic ChREBP on insulin sensitivity remains unknown. To clarify the importance of hepatic ChREBP on glucose homeostasis, we have generated a knockout mouse model that lacks this protein specifically in the liver (Liver-ChREBP KO).MethodsUsing Liver-ChREBP KO mice, we investigated whether hepatic ChREBP deletion influences insulin sensitivity, glucose homeostasis and the development of hepatic steatosis utilizing various dietary stressors. Furthermore, we determined gene expression changes in response to fasted and fed states in liver, white, and brown adipose tissues.ResultsLiver-ChREBP KO mice had impaired insulin sensitivity as indicated by reduced glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamps on both chow (25% lower) and high-fat diet (33% lower) (p < 0.05). This corresponded with attenuated suppression of hepatic glucose production. Although Liver-ChREBP KO mice were protected against carbohydrate-induced hepatic steatosis, they displayed worsened glucose tolerance. Liver-ChREBP KO mice did not show the expected gene expression changes in liver in response to fasted and fed states. Interestingly, hepatic ChREBP deletion also resulted in gene expression changes in white and brown adipose tissues, suggesting inter-tissue communication. This included an almost complete abolition of BAT ChREBPβ induction in the fed state (0.15-fold) (p = 0.015) along with reduced lipogenic genes. In contrast, WAT showed inappropriate increases in lipogenic genes in the fasted state along with increased PEPCK1 in both fasted (3.4-fold) and fed (5.1-fold) states (p < 0.0001).ConclusionsOverall, hepatic ChREBP is protective in regards to hepatic insulin sensitivity and whole body glucose homeostasis. Hepatic ChREBP action can influence other peripheral tissues and is likely essential in coordinating the body's response to different feeding states.

Project description:PURPOSE:Bariatric surgery is considered as an effective therapeutic strategy for weight loss in severe obesity. Remission of type 2 diabetes is often achieved after the surgery. We investigated whether increase in self-reported habitual physical activity associates with improved skeletal muscle insulin sensitivity and reduction of fat depots after bariatric surgery. METHODS:We assessed self-reported habitual physical activity using Baecke questionnaire in 18 diabetic and 28 nondiabetic patients with morbid obesity (median age, 46 yr; body mass index, 42.0 kg·m) before and 6 months after bariatric surgery operation. Insulin-stimulated femoral muscle glucose uptake was measured using fluorodeoxyglucose positron emission tomography method during hyperinsulinemia. In addition, abdominal subcutaneous and visceral fat masses were quantified using magnetic resonance imaging and liver fat content using magnetic resonance spectroscopy. Also, serum proinflammatory cytokines were measured. RESULTS:Patients lost on average 22.9% of weight during the follow-up period of 6 months (P < 0.001). Self-reported habitual physical activity level increased (P = 0.017). Improvement in skeletal muscle insulin sensitivity was observed only in those patients who reported increase in their physical activity postoperatively (P = 0.018). The increase in self-reported physical activity associated with the loss of visceral fat mass (P = 0.029). Postoperative self-reported physical activity correlated also positively with postoperative hepatic insulin clearance (P = 0.02) and tended to correlate negatively with liver fat content (P = 0.076). Postoperative self-reported physical activity also correlated negatively with serum TNF?, methyl-accepting chemotaxis protein and interleukin 6 levels. CONCLUSIONS:Self-reported physical activity is associated with reversal of skeletal muscle insulin resistance after bariatric surgery as well as with the loss of visceral fat content and improved postoperative metabolism in bariatric surgery patients. TRIAL REGISTRATION:Clinicaltrials.gov, NCT00793143 (SLEEVEPASS), NCT01373892 (SLEEVEPET2).

Dataset Information

Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

Publications

Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

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