title: CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice.
abstract: C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD- or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGFβ1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity.
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Risa M
authors.initials: RM
authors.lastname: Wolf
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China; and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Zhi-Chun
authors.initials: ZC
authors.lastname: Yang
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Maeva
authors.initials: M
authors.lastname: Nyandjo
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stefanie Y
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland gwwong@jhmi.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D054392:Adipokines / Q000235:genetics*; D000273:Adipose Tissue; D000818:Animals; D002153:Calorimetry, Indirect; D018932:Chemokine CCL2 / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D005260:Female; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015430:Weight Gain / Q000235:genetics
chemical_list: D054392:Adipokines; C428135:CORS26 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D005992:Glycerol-3-Phosphate O-Acyltransferase; D051048:Diacylglycerol O-Acyltransferase; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse; D005947:Glucose
keywords: C1q/tumor necrosis factor; C1q/tumor necrosis factor-related protein; adipokine; diabetes; fatty liver; obesity