Review
Feature Review
CTRP family: linking immunity to metabolism

https://doi.org/10.1016/j.tem.2011.12.003Get rights and content

It is well known that infectious and inflammatory diseases such as sepsis and severe inflammatory response syndrome are accompanied by metabolic alterations such as insulin resistance. Conversely, metabolic diseases such as visceral obesity and type 2 diabetes are characterized by high levels of proinflammatory cytokines. Metabolism and immunity are linked by proteins of dual function. Adiponectin, a member of the C1q/TNF-related protein (CTRP) family, has attracted much interest because of its anti-inflammatory and insulin-sensitizing effects. To date, 15 additional CTRP family members have been identified that might also play a role in metabolism and immunity. This review focuses on the biochemistry and pleiotropic physiological functions of CTRPs as new molecular mediators connecting inflammatory and metabolic diseases.

Section snippets

Structure and function of CTRPs

The term CTRP, originally introduced by Harvey Lodish and coworkers, describes a new family of secreted proteins that were cloned on the basis of sequence homology between CTRPs and adiponectin [1]. Adiponectin controls whole-body energy metabolism by enhancing insulin sensitivity in muscle and liver (Box 1). Hence, the recently discovered family of adiponectin paralogs might have important implications in energy homeostasis and might provide novel pharmacological targets in type 2 diabetes

Tissue expression, serum levels and multimerization

CTRP1 mRNA is expressed in heart, placenta, liver, muscle, kidney, prostate, and ovary [9], with highest expression levels in adipose tissue 10, 11. Stromal vascular cells (SVC) composed of adipose-tissue macrophages, preadipocytes and endothelial cells are the major source of CTRP1, but so far the exact cells which synthesize CTRP1 have not been identified. Rosiglitazone, a drug with anti-inflammatory properties and a high-affinity ligand for the adipogenic transcription factor peroxisome

Tissue expression, serum levels and multimerization

CTRP2 mRNA is mainly synthesized in SVC but the respective cell type has not yet been identified. mRNA expression levels are similar in male and female tissues [10]. In ob/ob mice, CTRP1 mRNA is increased in the fat tissue of 8-week-old but not 12-week-old animals.

Thiazolidinediones (TZDs) such as rosiglitazone are antidiabetic drugs that ameliorate insulin resistance partly by inducing adiponectin [18]. It was found that daily administration of rosiglitazone for 3 weeks, which significantly

Tissue expression, serum levels and multimerization

CTRP3 (synonyms CORS-26, cartducin and cartonectin) was cloned by Maeda et al. using suppression subtractive hybridization between transforming growth factor β1 (TGFβ1)-treated and untreated multipotential mesenchymal C3H10T1/2 cells [7].

In mammalian cell lines, recombinant CTRP3 forms homotrimers and higher-order oligomers via disulfide bonding mediated by N-terminal cysteine residues [10]. When expressed using the baculovirus system, CTRP3 forms stable homotrimeric protein structures [20].

CTRP4

CTRP4 has not been as extensively studied as the previously discussed isoforms, and most of the existing data come from the use of heterologous cells as model systems. CTRP4 mRNA levels show low expression in the hepatoma cell line HepG2 and the human colon cancer cell line HT 29, and in tissues such as the liver and pancreas. Overexpression of CTRP4 in human endothelial cells [34] and in HEK293 increases nuclear factor κB (NFκB) activity. In addition, TNF and IL-6 expression, and

Tissue expression, serum levels and multimerization

CTRP5 is expressed in adipocytes 10, 36 with the highest expression in the SVC fraction, in basement membrane, retinal pigment and ciliary epithelium 37, 38, and in myocytes [39]. Despite similar mRNA levels in the fat of female and male mice, CTRP5 protein is present at significantly higher levels in the serum of female mice. CTRP5 is not increased in adipose tissue of ob/ob mice, nor is it increased in rosiglitazone-treated animals [10]. However, another study reported that serum CTRP5

Tissue expression, serum levels and multimerization

CTRP6 is found in serum and its expression in fat tissues is enhanced in obese, ob/ob and adiponectin null-mice [10]. However, mRNA levels are fairly low in fat tissue, where CTRP6 in mainly produced by SVC. Rosiglitazone treatment decreases CTRP6 expression in adipose tissue [10]. The mRNA levels in fat are about fivefold higher in female compared to male mice. Serum CTRP6 also seems to be increased in female mice and CTRP6 mRNA is highest in placenta. CTRP6 forms homotrimers and higher-order

CTRP7

CTRP7 is highly expressed in the SVC fraction of adipose tissue and in the lung in mice. No gender difference in adipose tissue mRNA levels has been observed and expression is not consistently increased in the fat of ob/ob animals. CTRP7 can form heteromeric complexes with CTRP2 [10]. In a psychiatric genome-wide association study, two markers lying within the CTRP7 gene locus were reported to be associated with conduct disorder. Furthermore, six single-nucleotide polymorphisms in CTRP7 were

CTRP8

Human CTRP8 [54] is expressed in lung and testis and forms homotrimers as well as heteromeric complexes with C1q-related factor (CRF) when both proteins are coexpressed in mammalian cell lines. CRF is a secreted multimeric protein known to form heteromeric structures with CTRP1, CTRP and CTRP10 [55]. There is no ortholog of the CTRP8 gene in the mouse genome [54], and this complicates the analysis of CTRP8 function.

Tissue expression, serum levels and multimerization

CTRP9 is the closest adiponectin paralog of the CTRP family. Its expression is highest in adipose tissue and is similar between the SVC and adipocyte fractions. CTRP9 mRNA levels are higher in SVC of female rodents, and systemic levels are increased in 8-week-old female mice. Moreover, 8-week obese mice have higher CTRP9 mRNA in fat and higher protein in serum [13]. CTRP9 principally forms trimers when expressed in HEK293T cells, and the trimeric form of CTRP is the predominant form in serum.

CTRP10

CTRP10 is highly expressed in brain, placenta and the eye. mRNA levels in adipose tissue are fairly low, and here CTRP10 is mainly produced by SVC. CTRP10 in fat is upregulated by rosiglitazone treatment. Levels are also increased in epididymal fat of 8-week-old but not 12-week-old ob/ob mice. CTRP10 forms homotrimers and higher-order oligomers via disulfide bonding mediated by N-terminal cysteine residues [10]. CTRP10 may form heterooligomeric complexes with CTRP13 [58], which is also produced

Tissue expression, serum levels and multimerization

CTRP13 mRNA expression in humans is highest in adipose tissue, whereas in mice mRNA levels are comparable in fat and brain. In adipose tissue, SVC is the main source of CTRP13. Similar to most adipokines, circulating CTRP13 is increased in female mice [58]. In ob/ob mice, adipose tissue mRNA levels are elevated; however, systemic levels are higher only in male and not female obese mice. CTRP13 is similarly expressed in preadipocytes and differentiated 3T3-L1 cells. In mature adipocytes,

CTRP11, -12, -14 and -15

Future studies are required to elucidate the regulation and function of CTRP11, -12, -14 and -15.

Putative role of CTRP–adiponectin heterodimers and interference with the adiponectin receptor pathway

Several of the CTRPs analyzed so far exert insulin-sensitizing effects similar to adiponectin. Therefore, these proteins might compensate for adiponectin deficiency, explaining why adiponectin knockout mice have only mild metabolic disturbances, even when fed a high-fat diet 13, 61. Adiponectin may form heterotrimers with CTRP2 and CTRP9, and such trimeric isoforms have been detected [10]. However, these trimers can only be generated when proteins are coexpressed in the same cell [10].

Concluding remarks

The family of CTRPs is rapidly growing and these proteins are widely expressed in human and murine systems. CTRPs are pleiotropic proteins and, similar to adiponectin, have many different physiologic functions and are of high clinical interest as drug targets in various diseases. From an evolutionary viewpoint, their highly conserved structural homologies suggest that these proteins might have arisen from a common ancient precursor with pleiotropic functions. Indeed, diversity, modularity and

Acknowledgments

The authors are grateful to Prof. Dr C. Aslanidis for critical reading of the manuscript.

References (87)

  • J. Weigert

    The adiponectin paralog CORS-26 has anti-inflammatory properties and is produced by human monocytic cells

    FEBS Lett.

    (2005)
  • Q. Li

    Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-kappaB pathways and promotes cell survival in human cancer cells

    Cancer Lett.

    (2011)
  • S.Y. Park

    C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase

    J. Biol. Chem.

    (2009)
  • J.M. Peterson

    CTRP8 and CTRP9B are novel proteins that hetero-oligomerize with C1q/TNF family members

    Biochem. Biophys. Res. Commun.

    (2009)
  • N.G. Berube

    Cloning and characterization of CRF, a novel C1q-related factor, expressed in areas of the brain involved in motor function

    Brain Res. Mol. Brain Res.

    (1999)
  • S.A. Chacko

    Magnesium supplementation, metabolic and inflammatory markers, and global genomic and proteomic profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals

    Am. J. Clin. Nutr.

    (2011)
  • Z. Wei

    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)
  • J. Wanninger

    Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes

    Biochim. Biophys. Acta

    (2011)
  • T.S. Tsao

    Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways

    J. Biol. Chem.

    (2003)
  • K. Maeda

    cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1)

    Biochem. Biophys. Res. Commun.

    (1996)
  • U.B. Pajvani

    Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity

    J. Biol. Chem.

    (2004)
  • H. Waki

    Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin

    J. Biol. Chem.

    (2003)
  • A. Barseghian

    Adiponectin and vulnerable atherosclerotic plaques

    J. Am. Coll. Cardiol.

    (2011)
  • P. Stenvinkel

    Adiponectin in chronic kidney disease: a complex and context sensitive clinical situation

    J. Ren. Nutr.

    (2011)
  • R. Fayad

    Adiponectin deficiency protects mice from chemically induced colonic inflammation

    Gastroenterology

    (2007)
  • L.A. Tartaglia

    Identification and expression cloning of a leptin receptor, OB-R

    Cell

    (1995)
  • T. Murakami et al.

    Cloning of rat obese cDNA and its expression in obese rats

    Biochem. Biophys. Res. Commun.

    (1995)
  • K. Shima

    Exercise training has a long-lasting effect on prevention of non-insulin-dependent diabetes mellitus in Otsuka Long–Evans–Tokushima fatty rats

    Metabolism

    (1996)
  • G.W. Wong

    A family of Acrp30/adiponectin structural and functional paralogs

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • L. Shapiro et al.

    The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor

    Curr. Biol.

    (1998)
  • G.W. Wong

    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)
  • J.H. Jeon

    A novel adipokine CTRP1 stimulates aldosterone production

    FASEB J.

    (2008)
  • G.W. Wong

    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)
  • A. Calmont

    Identification of a short cis-acting element in the human vasopressin type 2 receptor gene which confers high-level expression of a reporter gene specifically in collecting duct cells

    Mol. Endocrinol.

    (2000)
  • R.W. Schrier

    Optimal care of autosomal dominant polycystic kidney disease patients

    Nephrology (Carlton)

    (2006)
  • R. Cooper

    ACE, angiotensinogen and obesity: a potential pathway leading to hypertension

    J. Hum. Hypertens.

    (1997)
  • N. Maeda

    PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein

    Diabetes

    (2001)
  • J.M. Peterson

    C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output

    J. Biol. Chem.

    (2011)
  • S. Wurm

    Plasma levels of leptin, omentin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26) and adiponectin before and after oral glucose uptake in slim adults

    Cardiovasc. Diabetol.

    (2007)
  • R. Wiest

    Peritoneal fluid adipokines: ready for prime time?

    Eur. J. Clin. Invest.

    (2009)
  • C. Hofmann

    C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts

    Inflamm. Bowel Dis.

    (2011)
  • A. Kopp

    C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue

    Endocrinology

    (2010)
  • A. Schaffler

    Regulation and function of collagenous repeat containing sequence of 26-kDa protein gene product ‘cartonectin’

    Obesity (Silver Spring)

    (2007)
  • Cited by (258)

    • The emerging role of bile acids in white adipose tissue

      2023, Trends in Endocrinology and Metabolism
    View all citing articles on Scopus
    View full text