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• W2739475813 abstract "Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. Obesity is associated with chronic low-grade inflammation in fat depots (1.Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J. Clin. Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (5186) Google Scholar, 2.Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7458) Google Scholar). Inflammatory cytokines, such as TNF-α, produced by adipose tissue macrophages promote insulin resistance by antagonizing insulin action (3.Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (6138) Google Scholar4.Uysal K.T. Wiesbrock S.M. Marino M.W. Hotamisligil G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function.Nature. 1997; 389: 610-614Crossref PubMed Scopus (1906) Google Scholar, 5.Moller D.E. Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes.Trends Endocrinol. Metab. 2000; 11: 212-217Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar6.Hotamisligil G.S. Mechanisms of TNF-α-induced insulin resistance.Exp. Clin. Endocrinol. Diabetes. 1999; 107: 119-125Crossref PubMed Scopus (380) Google Scholar). The recruitment and activation of adipose tissue macrophages in obesity, therefore, is an important contributor to the pathogenesis of obesity-linked metabolic dysfunction. To discover novel metabolic regulators, we characterized a conserved family of secretory proteins of the C1q family, the C1q/TNF-related proteins (CTRP1–15) 2The abbreviations used are: CTRP, C1q/TNF-related protein; BMI, body mass index; HFD, high-fat diet; LFD, low-fat diet; SVF, stromal vascular fraction; eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; BMM, bone marrow-derived macrophage(s); RER, respiratory exchange ratio(s); HTV, hydrodynamic tail vein; T2D, type 2 diabetes; EE, energy expenditure; CLS, crownlike structure; mCTRP6, mouse CTRP6; hCTRP6, human CTRP6; GTT, glucose tolerance test(s); ITT, insulin tolerance test(s); ANOVA, analysis of variance; AUC, area under the curve. 2The abbreviations used are: CTRP, C1q/TNF-related protein; BMI, body mass index; HFD, high-fat diet; LFD, low-fat diet; SVF, stromal vascular fraction; eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; BMM, bone marrow-derived macrophage(s); RER, respiratory exchange ratio(s); HTV, hydrodynamic tail vein; T2D, type 2 diabetes; EE, energy expenditure; CLS, crownlike structure; mCTRP6, mouse CTRP6; hCTRP6, human CTRP6; GTT, glucose tolerance test(s); ITT, insulin tolerance test(s); ANOVA, analysis of variance; AUC, area under the curve. (7.Wong G.W. Wang J. Hug C. Tsao T.S. Lodish H.F. A family of Acrp30/adiponectin structural and functional paralogs.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10302-10307Crossref PubMed Scopus (346) Google Scholar8.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Ge G. Spooner E. Hug C. Gimeno R. Lodish H.F. Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin.FASEB J. 2009; 23: 241-258Crossref PubMed Scopus (219) Google Scholar, 9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar, 10.Wei Z. Peterson J.M. Lei X. Cebotaru L. Wolfgang M.J. Baldeviano G.C. Wong G.W. C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes.J. Biol. Chem. 2012; 287: 10301-10315Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 11.Wei Z. Peterson J.M. Wong G.W. Metabolic regulation by C1q/TNF-related protein-13 (CTRP13): activation OF AMP-activated protein kinase and suppression of fatty acid-induced JNK signaling.J. Biol. Chem. 2011; 286: 15652-15665Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 12.Wei Z. Seldin M.M. Natarajan N. Djemal D.C. Peterson J.M. Wong G.W. C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.J. Biol. Chem. 2013; 288: 10214-10229Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 13.Peterson J.M. Wei Z. Wong G.W. CTRP8 and CTRP9B are novel proteins that hetero-oligomerize with C1q/TNF family members.Biochem. Biophys. Res. Commun. 2009; 388: 360-365Crossref PubMed Scopus (46) Google Scholar, 14.Seldin M.M. Peterson J.M. Byerly M.S. Wei Z. Wong G.W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.J. Biol. Chem. 2012; 287: 11968-11980Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar15.Byerly M.S. Petersen P.S. Ramamurthy S. Seldin M.M. Lei X. Provost E. Wei Z. Ronnett G.V. Wong G.W. C1q/TNF-related protein 4 (CTRP4) is a unique secreted protein with two tandem C1q domains that functions in the hypothalamus to modulate food intake and body weight.J. Biol. Chem. 2014; 289: 4055-4069Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). We and others have shown that multiple CTRPs modulate energy metabolism in vivo by directly regulating glucose and fat metabolism in peripheral tissues (10.Wei Z. Peterson J.M. Lei X. Cebotaru L. Wolfgang M.J. Baldeviano G.C. Wong G.W. C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes.J. Biol. Chem. 2012; 287: 10301-10315Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 14.Seldin M.M. Peterson J.M. Byerly M.S. Wei Z. Wong G.W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.J. Biol. Chem. 2012; 287: 11968-11980Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 16.Peterson J.M. Aja S. Wei Z. Wong G.W. C1q/TNF-related protein-1 (CTRP1) enhances fatty acid oxidation via AMPK activation and ACC inhibition.J. Biol. Chem. 2012; 287: 1576-1587Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar17.Peterson J.M. Seldin M.M. Tan S.Y. Wong G.W. CTRP2 overexpression improves insulin and lipid tolerance in diet-induced obese mice.PLoS One. 2014; 9: e88535Crossref PubMed Scopus (33) Google Scholar, 18.Peterson J.M. Seldin M.M. Wei Z. Aja S. Wong G.W. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism.Am. J. Physiol. Gastrointest. Liver Physiol. 2013; 305: G214-G224Crossref PubMed Scopus (102) Google Scholar, 19.Peterson J.M. Wei Z. Seldin M.M. Byerly M.S. Aja S. Wong G.W. CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013; 305: R522-R533Crossref PubMed Scopus (98) Google Scholar, 20.Peterson J.M. Wei Z. Wong G.W. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output.J. Biol. Chem. 2010; 285: 39691-39701Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 21.Seldin M.M. Lei X. Tan S.Y. Stanson K.P. Wei Z. Wong G.W. Skeletal muscle-derived myonectin activates the mTOR pathway to suppress autophagy in liver.J. Biol. Chem. 2013; 288: 36073-36082Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 22.Wei Z. Lei X. Petersen P.S. Aja S. Wong G.W. Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice.Am. J. Physiol. Endocrinol. Metab. 2014; 306: E779-E790Crossref PubMed Scopus (85) Google Scholar, 23.Lei X. Rodriguez S. Petersen P.S. Seldin M.M. Bowman C.E. Wolfgang M.J. Wong G.W. Loss of CTRP5 improves insulin action and hepatic steatosis.Am. J. Physiol. Endocrinol. Metab. 2016; 310: E1036-E1052Crossref PubMed Scopus (29) Google Scholar, 24.Rodriguez S. Lei X. Petersen P.S. Tan S.Y. Little H.C. Wong G.W. Loss of CTRP1 disrupts glucose and lipid homeostasis.Am. J. Physiol. Endocrinol. Metab. 2016; 311: E678-E697Crossref PubMed Scopus (48) Google Scholar25.Petersen P.S. Lei X. Wolf R.M. Rodriguez S. Tan S.Y. Little H.C. Schweitzer M.A. Magnuson T.H. Steele K.E. Wong G.W. CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress.Am. J. Physiol. Endocrinol. Metab. 2017; 312: E309-E325Crossref PubMed Scopus (35) Google Scholar), modulating food intake via a central mechanism (15.Byerly M.S. Petersen P.S. Ramamurthy S. Seldin M.M. Lei X. Provost E. Wei Z. Ronnett G.V. Wong G.W. C1q/TNF-related protein 4 (CTRP4) is a unique secreted protein with two tandem C1q domains that functions in the hypothalamus to modulate food intake and body weight.J. Biol. Chem. 2014; 289: 4055-4069Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 26.Byerly M.S. Swanson R. Wei Z. Seldin M.M. McCulloh P.S. Wong G.W. A central role for C1q/TNF-related protein 13 (CTRP13) in modulating food intake and body weight.PLoS One. 2013; 8: e62862Crossref PubMed Scopus (46) Google Scholar), or by indirectly modulating inflammatory processes in adipose tissue (27.Enomoto T. Ohashi K. Shibata R. Higuchi A. Maruyama S. Izumiya Y. Walsh K. Murohara T. Ouchi N. Adipolin/C1qdc2/CTRP12 functions as an adipokine that improves glucose metabolism.J. Biol. Chem. 2011; 286: 34552-34558Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) or adipocyte differentiation (12.Wei Z. Seldin M.M. Natarajan N. Djemal D.C. Peterson J.M. Wong G.W. C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.J. Biol. Chem. 2013; 288: 10214-10229Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Among the CTRP family, little is known about the function of CTRP6 (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). Recent studies have shown that CTRP6 regulates immune complement activation, and its deficiency exacerbates joint pathology in mouse models of rheumatoid arthritis (28.Murayama M.A. Kakuta S. Inoue A. Umeda N. Yonezawa T. Maruhashi T. Tateishi K. Ishigame H. Yabe R. Ikeda S. Seno A. Chi H.H. Hashiguchi Y. Kurata R. Tada T. et al.CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis.Nat. Commun. 2015; 6: 8483Crossref PubMed Scopus (47) Google Scholar). In vitro studies have highlighted a role for CTRP6 in regulating adipogenesis (29.Wu W.J. Mo D.L. Zhao C.Z. Zhao C. Chen Y.S. Pang W.J. Yang G.S. Knockdown of CTRP6 inhibits adipogenesis via lipogenic marker genes and Erk1/2 signalling pathway.Cell Biol. Int. 2015; 39: 554-562Crossref PubMed Scopus (35) Google Scholar), fat oxidation (30.Lee W. Kim M.J. Park E.J. Choi Y.J. Park S.Y. C1qTNF-related protein-6 mediates fatty acid oxidation via the activation of the AMP-activated protein kinase.FEBS Lett. 2010; 584: 968-972Crossref PubMed Scopus (43) Google Scholar), cytokine expression (31.Kim M.J. Lee W. Park E.J. Park S.Y. C1qTNF-related protein-6 increases the expression of interleukin-10 in macrophages.Mol. Cells. 2010; 30: 59-64Crossref PubMed Scopus (48) Google Scholar), and fibrogenesis (32.Fan R.H. Zhu X.M. Sun Y.W. Peng H.Z. Wu H.L. Gao W.J. CTRP6 inhibits fibrogenesis in TGF-β1-stimulated human dermal fibroblasts.Biochem. Biophys. Res. Commun. 2016; 475: 356-360Crossref PubMed Scopus (21) Google Scholar). In mice, Ctrp6 is expressed in multiple tissues, including adipose tissue (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). Expression of Ctrp6 in the visceral (epididymal) adipose tissue is up-regulated in leptin-deficient ob/ob mice, a genetic model of severe obesity and insulin resistance (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). Conversely, the expression of Ctrp6 in ob/ob mice is down-regulated by the administration of rosiglitazone, an anti-diabetic drug (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). Mice lacking adiponectin, an insulin-sensitizing adipokine, also have higher serum levels of CTRP6 (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). A meta-analysis of genome-wide association studies also implicates human CTRP6/C1QTNF6 as a candidate gene that confers susceptibility to type 1 diabetes (33.Cooper J.D. Smyth D.J. Smiles A.M. Plagnol V. Walker N.M. Allen J.E. Downes K. Barrett J.C. Healy B.C. Mychaleckyj J.C. Warram J.H. Todd J.A. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.Nat. Genet. 2008; 40: 1399-1401Crossref PubMed Scopus (402) Google Scholar). In the present studies, we aimed to uncover the metabolic role of CTRP6 using gain- and loss-of-function mouse models. We provide here the first genetic and physiological evidence that CTRP6 functions as a secreted regulator of glucose metabolism and inflammation in vivo. Similar to the mouse gene (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar), human CTRP6 is relatively broadly expressed in adult tissues, including adipose tissue (Fig. 1A). To address whether adipose expression of CTRP6 is altered in human obesity, we measured its mRNA levels in visceral (omental) and subcutaneous fat depots. Expression of CTRP6 in both omental and subcutaneous fat depots was positively correlated with body mass index (BMI) (Fig. 1, B and C). Compared with lean controls, CTRP6 expression was strikingly up-regulated in both the visceral and subcutaneous fat depots of obese individuals with and without type 2 diabetes (Fig. 1, D and E). We next addressed whether our observations in humans hold true for diet-induced obese mouse models. Parallel to human data, expression of mouse Ctrp6 was significantly up-regulated in both the visceral (epididymal) and subcutaneous (inguinal) white adipose tissue of obese mice fed a high-fat diet (HFD) relative to lean controls fed a matched control low-fat diet (LFD) (Fig. 2A). Although Ctrp6 is also expressed in interscapular brown adipose tissue (BAT), its levels were not different between HFD-fed and LFD-fed mice (Fig. 2A). To identify which cell population within the fat depot contributes to changes in Ctrp6 expression in response to obesity, we examined Ctrp6 mRNA levels in isolated adipocytes and cells of the stromal vascular fraction (SVF). Whereas both adipocytes and SVF cells express Ctrp6 transcript, its expression was significantly higher in SVF cells in both visceral and subcutaneous fat depots of HFD-fed mice relative to LFD-fed controls (Fig. 2B). SVF contains immune cells, such as macrophages, as well as endothelial cells and smooth muscle cells. Given that large numbers of macrophages are known to infiltrate the fat pad in the obese state (1.Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J. Clin. Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (5186) Google Scholar, 2.Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7458) Google Scholar), elevated CTRP6 in obesity could be produced by adipose tissue macrophages. In support of this finding, when cultured macrophages (RAW264.7) were exposed to high glucose, mimicking the diabetic state, expression of Ctrp6 was significantly induced (Fig. 2C). Mannitol is not metabolized by cells and thus serves as an osmotic control. A genetic loss-of-function mouse model was used to interrogate the metabolic role of Ctrp6 (Fig. 3A). Two sets of primers were designed to amplify a sequence within intron 2 of the WT allele and a sequence spanning the downstream deletion site in the lacZ gene to confirm the genotype of WT and KO mice, respectively (Fig. 3B). As expected from targeted disruption of the gene, Ctrp6 mRNA was absent from epididymal white adipose tissue (eWAT), inguinal white adipose tissue (iWAT), liver, skeletal muscle, and primary bone marrow-derived macrophages (BMM) of KO mice (Fig. 3C). The Ctrp6 gene is not required for development, although it is expressed throughout embryogenesis (9.Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (308) Google Scholar). Ctrp6 KO mice were born at the expected Mendelian ratio and appeared normal with no gross developmental abnormalities. To determine the contribution of CTRP6 to systemic energy metabolism in the normal and obese states, Ctrp6 WT and KO male mice were fed an HFD or a control LFD for 20 weeks, beginning at 4 weeks of age. On an LFD, we observed no differences in body weight, body composition (fat and lean mass), food intake, metabolic rate, energy expenditure, or physical activity level between Ctrp6 WT and KO mice (Fig. 4). When challenged with an HFD, Ctrp6 WT and KO mice also did not differ in body weight (Fig. 5A), body composition (Fig. 5B), or food intake (Fig. 5C). However, metabolic rate as measured by the rates of oxygen consumption (V̇O2) and carbon dioxide production (V̇CO2) were much higher in Ctrp6 KO mice compared with WT littermates (Fig. 5, D and E). Respiratory exchange ratios (RER) were not different between the two groups (Fig. 5F), indicating comparable oxidation of fat and carbohydrates as a fuel source. The increased metabolic rate seen in Ctrp6 KO mice also resulted in enhanced energy expenditure relative to WT controls (Fig. 5G). No differences, however, were observed in physical activity or postprandial thermogenesis (Fig. 5, H and I).Figure 5Increased metabolic rate and energy expenditure in Ctrp6 KO male mice fed an HFD. A, body weight of WT and KO mice fed an HFD over time. B, total fat and lean mass in WT and KO mice quantified by NMR (Echo-MRI) at 20 weeks of age. C, food intake in WT and KO mice (22 weeks of age) during the light and dark cycle. D–H, oxygen consumption (VO2), CO2 production (VCO2), RER, EE, and total activity were measured by CLAMS for WT and KO mice. VO2, VCO2, and EE data were normalized to lean body mass. For WT versus KO, *** indicates p < 0.001 (in D, E, and G); two-way ANOVA. I, rectal temperature of WT and KO mice. WT, n = 8; KO, n = 7. Error bars, S.E.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Diet-induced obesity is known to alter circulating adipokines and inflammatory cytokines. Loss of CTRP6 did not alter serum adiponectin and leptin levels in response to HFD (Fig. 6, A and B). In contrast, circulating pro-inflammatory cytokines, TNF-α and MCP-1, were significantly lower in Ctrp6 KO mice relative to WT littermates (Fig. 6, C and F). Serum IL-1β and IL-6 levels were not different between WT and KO mice (Fig. 6, D and E). Interestingly, white blood cell, especially monocyte, numbers were reduced in Ctrp6 KO mice (Fig. 6G). Two phenotypic and functional subsets of mature blood monocytes have been described: Ly6Chi and Ly6Clo (34.Sunderkötter C. Nikolic T. Dillon M.J. Van Rooijen N. Stehling M. Drevets D.A. Leenen P.J. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.J. Immunol. 2004; 172: 4410-4417Crossref PubMed Scopus (873) Google Scholar, 35.Gordon S. Taylor P.R. Monocyte and macrophage heterogeneity.Nat. Rev. Immunol. 2005; 5: 953-964Crossref PubMed Scopus (3826) Google Scholar). The Ly6Chi blood monocytes are thought to be the source of macrophages that get recruited to sites of inflammation in tissues. The circulating levels of monocytes and neutrophils were assessed by flow cytometry (Fig. 6H). Ctrp6 KO mice have reduced Ly6Chi monocytes compared with WT mice (Fig. 6I). No differences were observed in Ly6Clo monocytes and neutrophils between the two groups (Fig. 6, J and K). These results suggest a better systemic inflammatory profile in CTRP6-deficient animals. We next determined whether local inflammatory profiles within adipose tissue differ between Ctrp6 WT and KO mice. Although adipose tissue weight was not different between WT and KO mice (Fig. 7A), histology revealed a striking reduction in adipose tissue macrophages infiltrating the visceral fat pad and their associated crownlike structures (Fig. 7, B and C). Crownlike structures consist of macrophages surrounding dying or dead adipocytes. When we examined the cell size distribution, WT mice had significantly greater numbers of small adipocytes (<500 μm2) corresponding to dead cells compared with Ctrp6 KO mice (Fig. 7D). In support of the histology data, mRNA expression of pro-inflammatory M1 macrophage marker genes Cd11c and TNF-α were markedly reduced in eWAT of Ctrp6 KO mice relative to WT controls (Fig. 7E). The expression of the pan-macrophage marker gene, F4/80, however, was not different between the two groups. These results suggest that CTRP6 deficiency dampens the local inflammatory milieu within adipose tissue in response to high-fat feeding. To determine whether reduced TNF-α expression in eWAT is causally linked to CTRP6, we treated cultured mouse macrophages (RAW264.7) with recombinant CTRP6 protein to test whether CTRP6 could directly induce TNF-α expression. With 6-h treatment, recombinant CTRP6 dose-dependently induced the mRNA expression and secreted protein levels of TNF-α (Fig. 8, A and B). Treatment of RAW264.7 macrophages with recombinant CTRP6 for a longer time course (24 h) had even stronger effects on inducing TNF-α mRNA and protein expression and secretion (Fig. 8, C and D). To further confirm these observations, we repeated the same experiments in cultured primary macrophages obtained from the bone marrow. A significant increase in TNF-α mRNA and protein expression and secretion was also observed in primary macrophages treated with recombinant CTRP6 for 24 h (Fig. 8, E and F). These results indicate that CTRP6 can directly modulate pro-inflammatory cytokine gene expression in macrophages and that its absence in the KO mice reduced TNF-α in eWAT in response to high-fat feeding. We next sought to determine whether reduced adipose tissue inflammation in Ctrp6 KO mice affects systemic insulin sensitivity. When challenged with a bolus of insulin, the rate of insulin-stimulated glucose clearance in peripheral tissues was significantly greater in Ctrp6 KO mice compared with WT littermates (Fig. 9, A and B). Consistent with enhanced insulin sensitivity, the rate of glucose disposal in response to glucose infusion was also significantly greater in Ctrp6 KO mice (Fig. 9, C and D). To determine whether CTRP6 could directly regulate insulin sensitivity independent of its effects on local inflammatory response within fat depots, we established a CTRP6 overexpression mouse model using hydrodynamic tail vein (HTV) injection (36.Zhang G. Budker V. Wolff J.A. High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA.Hum. Gene Ther. 1999; 10: 1735-1737Crossref PubMed Scopus (821) Google Scholar). HTV injection of naked plasmid DNA is a simple, effective, and widely used method of in vivo gene delivery, leading to an overexpression of the encoded cDNA in liver (36.Zhang G. Budker V. Wolff" @default.
• W2739475813 created "2017-07-31" @default.
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• W2739475813 date "2017-09-01" @default.
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• W2739475813 title "C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance" @default.
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