C1q/TNF-related protein 6 (CTRP6) links 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, 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. 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PubMed Scopus Google modulating a Seldin M.M. Lei X. E. Z. Wong G.W. C1q/TNF-related protein is a secreted protein with C1q that in the to modulate and body Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Z. Seldin M.M. Wong G.W. A role for C1q/TNF-related protein in modulating and body PubMed Scopus Google or by modulating inflammatory in adipose tissue T. R. A. T. N. as an adipokine that improves glucose Biol. Chem. 2011; 286: Full Text Full Text PDF PubMed Scopus Google or 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. Full Text Full Text PDF PubMed Scopus Google Scholar). the family, is the of CTRP6 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). have shown that CTRP6 regulates and deficiency in mouse models of A. N. T. T. H. R. A. R. T. is an regulator that PubMed Scopus Google Scholar). In have a role for CTRP6 in C. Chen Yang G.S. of CTRP6 and Biol. PubMed Scopus Google fat M.J. fatty the activation of the AMP-activated protein PubMed Scopus Google expression M.J. the expression of in PubMed Scopus Google and CTRP6 in human PubMed Scopus Google Scholar). In Ctrp6 is in adipose tissue 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). of Ctrp6 in the adipose tissue is up-regulated in leptin-deficient a of obesity and insulin resistance 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 mice is down-regulated by the of an anti-diabetic drug 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). lacking an have serum of CTRP6 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 of human as a gene that to type of type 2008; PubMed Scopus Google Scholar). In the we to the metabolic role of CTRP6 and mouse We provide the and evidence that CTRP6 as a secreted regulator of glucose metabolism and inflammation in to the mouse gene 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 human CTRP6 is in adipose tissue To adipose expression of CTRP6 is in human obesity, we in and fat of CTRP6 in both and fat depots was with body mass and with CTRP6 expression was up-regulated in both the and fat depots of obese with and type 2 and We in humans for diet-induced obese mouse to human expression of mouse Ctrp6 was up-regulated in both the and white adipose tissue of obese mice a high-fat to a control low-fat Ctrp6 is in adipose tissue and mice To the fat to in Ctrp6 expression in response to obesity, we Ctrp6 in adipocytes and of the stromal vascular both adipocytes and Ctrp6 expression was in in both and fat depots of mice to cells, such as macrophages, as as and that of macrophages are to the fat in the obese (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 CTRP6 in obesity produced by adipose tissue In of cultured macrophages to the diabetic expression of Ctrp6 was is by and as an A mouse was used to the metabolic role of Ctrp6 of to a 2 of the and a the deletion in the gene to the of and from of the Ctrp6 was from epididymal white adipose tissue inguinal white adipose tissue and bone marrow-derived macrophages of mice The Ctrp6 gene is for is 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 mice the and with To the of CTRP6 to energy metabolism in the and obese Ctrp6 and mice an or a control for of an LFD, we in body body and metabolic energy or Ctrp6 and mice with an HFD, Ctrp6 and mice in body body or metabolic rate as by the of and production much in Ctrp6 mice with and exchange the of fat and as a source. 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