title: Loss of CTRP1 disrupts glucose and lipid homeostasis.
abstract: C1q/TNF-related protein 1 (CTRP1) is a conserved plasma protein of the C1q family with notable metabolic and cardiovascular functions. We have previously shown that CTRP1 infusion lowers blood glucose and that transgenic mice with elevated circulating CTRP1 are protected from diet-induced obesity and insulin resistance. Here, we used a genetic loss-of-function mouse model to address the requirement of CTRP1 for metabolic homeostasis. Despite similar body weight, food intake, and energy expenditure, Ctrp1 knockout (KO) mice fed a low-fat diet developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1 KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter glucose transporter 4 levels and AMP-activated protein kinase activation. Loss of CTRP1 enhanced the clearance of orally administered lipids but did not affect intestinal lipid absorption, hepatic VLDL-triglyceride export, or lipoprotein lipase activity. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1 KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet to induce obesity, Ctrp1 KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue; these phenotypes were linked to elevated FGF-21 levels. Due in part to increased hepatic AMP-activated protein kinase activation and reduced expression of lipid synthesis genes, Ctrp1 KO mice fed a high-fat diet also had reduced liver and serum triglyceride and cholesterol levels. Taken together, these results provide genetic evidence to establish the significance of CTRP1 to systemic energy metabolism in different metabolic and dietary contexts.
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Susana
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pia S
authors.initials: PS
authors.lastname: Petersen
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stefanie Y
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Little
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland gwwong@jhmi.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054392:Adipokines / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism / Q000235:genetics; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D054392:Adipokines; D001786:Blood Glucose; C570300:CTRP1 protein, mouse; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: C1q/tumor necrosis factor-related protein 1; adipokine; cholesterol; diabetes; fatty liver; lipids; obesity