Skip to main content

Emerging roles of C1Q tumor necrosis factor-related proteins in metabolic diseases


Obesity and insulin resistance are key elements of the metabolic syndrome, which includes type 2 diabetes (T2D), dyslipidemia, systemic inflammation, hypertension, elevated risk for cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). C1Q Tumor necrosis factor-related proteins (CTRPs) have recently emerged as important regulators of metabolism as a core component in the interrelationship between insulin resistance, adiposity and inflammation. To date 15 CTRP members have been identified and most of the CTRPs are dysregulated in obesity, T2D, coronary artery disease and NAFLD. Pharmacological intervention and lifestyle modification alter expression of CTRPs in circulation and in metabolically active tissues. CTRPs enhance metabolism mainly through activation of AMPK/AKT dependent pathways and possess insulin sensitizing properties. Thus dysregulated expression of CTRPs in metabolic disorders could contribute to the pathogenesis of the disease. For these reasons CTRPs appear to be promising targets for early detection, prevention and treatment of metabolic disorders. This review article aims at exploring the role of CTRPs in metabolic syndrome.


Adipose tissue is a dynamic endocrine organ that stores excess of energy in the form of triglycerides and secretes bioactive molecules termed as adipokines/adipocytokines that, amongst other key functions, contribute to glucose homeostasis and fatty acid metabolism [1,2,3,4]. C1q protein family contains over thirty secreted multimeric proteins that share a C-terminal domain homologous to the globular domain of the immune complement C1q [5, 6]. This family also include the C1Q Tumor Necrosis Factor-Related Proteins (CTRPs) that are also implicated in the regulation of lipid and glucose metabolism [7].

Adiponectin, a key adipokine is a multivariate protein found in abundance in healthy individuals as an insulin sensitizer and its deficiency may play a role in the pathogenesis of the metabolic syndrome (MS) [8]. CTRPs are a group of fifteen proteins with a role similar to that of adiponectin in metabolism (Table 1) [7]. CTRPs contain four distinct domains, which include a short variable domain, a C-terminal C1q globular domain, a collagenous domain and an N-terminal signal peptide (Fig. 1) [7].

Table 1 Summary of CTRPs expression in pathophysiological states and their metabolic functions
Fig. 1

Structure of CTRP, a Structure of monomeric protein; b Homotrimeric protein structure

CTRPs are widely expressed in central and peripheral tissues such as adipose tissue, liver, skeletal muscle, and heart in both rodents and human. CTRPs have been implicated in the regulation of insulin sensitivity and fatty acid oxidation in major metabolic organs such as liver, heart, skeletal muscle and adipose tissue (Fig. 2) [38]. Dysfunction of CTRPs are associated with metabolic abnormalities such as obesity, insulin resistance (IR), type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD) and PCOS [67,68,69,70]. Recently studies are focused on the potential role of CTRPs on metabolic abnormalities [7]. This review aims at exploring the potential role and importance of CTRPs in metabolic abnormalities.

Fig. 2

Expression and functional role of CTRPs in major metabolic tissues and organs

Appetite regulation by CTRPs

The metabolic consequences of the obesity arise from imbalance between energy intake and energy expenditure as a result of complex and poorly understood interactions between genes and environmental factors that can be influenced by behavior. In some individuals excess energy intake leads to excessive fat accumulation in the abdominal region, visceral adiposity, with deleterious effects on health [71, 72]. Obesity rates continue to rise globally despite efforts from public campaign and personal efforts. This occurs due to abundant access to energy dense food, failure of homeostatic mechanisms to regulate appetite and metabolic adaptations to prevent further weight gain [73]. Efforts to curb food intake and increase physical activity are largely ineffective. Calorie restriction increases lifespan of rodents and unicellular organisms, the effect on humans remains uncertain despite the fact that surrogate markers of metabolic health improve dramatically [74, 75].

CTRP1 transgenic mice are obesity resistant; they gain less body weight on a high fat diet (HFD) compared to controls [9]. Over expression of CTRP1 enhances energy expenditure, fatty acid oxidation and reduced fat mass [9]. However, CTRP2 transgenic mice have no role in appetite regulation and are not protected from obesity when challenged with HFD. These transgenic mice have improved insulin tolerance and a greater capacity to handle acute lipid challenge relative to littermate controls. Deletion of CTRP2 leads to secretion of hepatic triglyceride and adipose tissue lipolysis [23, 24]. Similarly, CTRP3 transgenic mice also show no differences in appetite, glucose metabolism or body weight compared to the wild type, but are resistant to the onset of hepatic steatosis, have lower serum TNF-alpha levels, and demonstrate a mild improvement in systemic insulin sensitivity [27]. Caloric restriction enhances insulin sensitivity in young and senescent rats. Whereas adiponectin levels are increased only in young rats; the senescent animals show increased expression of CTRP2 and CTRP7 in skeletal muscles; however, this did not increase AMPK activation [25]. Thus, the improvement in insulin sensitivity by caloric restriction in the old animals is not due to adiponectin induction [25] this effect may be induced by some unidentified proteins. This could be one possible reason for the dampened insulin sensitivity associated with aging.

Other CTRP family members such as CTRP4, CTRP9 and CTRP13 are highly expressed in the hypothalamus and may regulate appetite and body weight (Fig. 2), [7, 50]. CTRP4 expression in the mouse hypothalamus is increased by refeeding after overnight dietary restriction [39]. Central administration of recombinant CTRP4 inhibits appetite and lowers body weight in HFD fed mice with decreased expression of neuropeptide-Y (NPY) and the agouti-related protein (Agrp) [39]. Deletion of CTRP 9 in mice increased food intake, decreased insulin sensitivity and promoted hepatic steatosis [76]. In contrast CTRP9 transgenic mice were lean and resisted weight gain induced by a high-fat diet, mainly through reduced food intake and improved basal metabolism [76]. Taken together the data indicate that both CTRP4 and CTRP9 may be important regulators of appetite and food intake in the mouse.

The situation is complicated further by the observation that obese mice show increased hypothalamic CTRP13 expression that can be downregulated by calorie restriction and upregulated by high fat diet [63]. Intracerebroventricular (ICV) administration of recombinant CTRP13 in mice inhibits food intake and promotes weight reduction. This was accompanied with increased respiratory exchange ratio; this suggest increased free fatty acid (FFA) release from adipocytes may act as substrates for fatty acid oxidation in the skeletal muscle and liver. ICV administration of the orexigenic neuropeptide AgRP promoted CTRP13 expression. On the contrary administration of CTRP13 inhibited AgRP expression centrally. Calorie restriction inhibits hypothalamic Ctrp13 expression and increases the expression of NPY and Agrp [39, 63]. In contrast, when calorie restriction coupled with enhanced physical activity, both CTRP13 and Agrp were upregulated in the hypothalamus. This suggests that AgRP and CTRP13 regulate each other expression and form a local hypothamic feedback loop that regulates appetite [63].

CTRPs in skeletal muscle metabolism

The skeletal muscle plays an important role in fatty acid and glucose metabolism [77, 78]. Stimulation of skeletal muscle with insulin increases glucose uptake and glucose utilization; excess glucose is converted to stored energy in the form of glycogen [79]. IR in skeletal muscles is an important mechanism in T2D [80]. Several growth factors and myokines secreted from muscles modulate the metabolic and inflammatory processes [80, 81]. CTRP1 transgenic mice have increased fatty acid oxidation and energy expenditure in muscle cells through AMPK activation of acetyl co-enzyme A carboxylase (ACC) dependent pathway [9]. In muscle cells, CTRP5 and CTRP6 regulate glucose and lipid metabolism by promoting GLUT4 translocation and fatty acid oxidation through activation of AMPK [40, 41, 45] (Fig. 3).

Fig. 3

Illustration of possible signalling pathways and the physiological role of major CTRP family members in metabolic tissues

In murine C2C12 myocytes, CTRP9 activates p44/42 MAPK, Akt and AMPK signaling pathways, which are important mediators of insulin signaling [51]. Mice over-expressing CTRP9 had lower hepatic and skeletal muscle triglyceride levels, enhanced basal metabolic rate, suppressed food intake, increased body energy expenditure and were protected against diet induced obesity (DIO), IR and hepatic steatosis [76]. In adipose tissue, hepatocytes and skeletal muscle stimulation with CTRP15 enhanced fatty acid uptake without altering adipose tissue lipolysis [65, 82].

CTRPs in obesity and T2D

Obesity accompanied by IR is a key factor in the development of T2D and MS [83]. Current thinking is that adipose tissue secretes adipokine that regulate central and peripheral metabolic pathways thereby modulating homeostasis, blood pressure, lipid and glucose metabolism [42, 47, 84]. Most CTRPs are highly expressed in adipose tissues and have been implicated in the pathogenesis of obesity and T2D [38]. CTRP1, 2, 3, 4, 6 and 7 are also abundantly expressed in leptin-deficient ob/ob mice suggesting that leptin might regulate the expression of these family members (Table 1) [7, 26, 39]. In obese and T2D subjects circulating adiponectin levels are decreased. The adiponectin levels positively correlate with markers of insulin sensitivity and may protect against the MS [85,86,87]. Similar to adiponectin, CTRPs protects against obesity and T2D through enhancing insulin sensitivity and metabolism [10, 23, 76]. This explains why the members of the CTRP family are downregulated in tissues such as skeletal muscle, adipose tissue and liver in HFD-fed mice and also the circulatory levels are lower in obese and T2D compared to controls [26].

Circulating CTRP1 is higher in prediabetes, preeclampsia, T2D patients and positively correlates with fasting glucose, body mass index (BMI), glycated hemoglobin (HbA1C), low density lipoprotein (LDL), fibroblast growth factor (FGF21), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and negatively correlate with adiponectin [11,12,13,14, 88, 89]. This is in contrast to diet induced obese (DIO) mice that have significant reductions in circulating CTRP1 levels [9]. Unlike CTRP1, CTRP2 levels in the circulation are not significantly different in obese and control mice [23], whereas the circulating CTRP3 are lower in T2D and negatively correlates with IR. Elevated levels of CTRP3 were observed in women with gestational diabetes mellitus [28,29,30, 90,91,92]. CTRP3 levels are lower in DIO rodents than in control animals and the level increases after administration of a glucagon like peptide-1 (GLP-1) agonist [31]. CTRP3 is increased during fasting, inversely correlated with leptin and its levels are higher in leptin-deficient ob/ob mice [32]. CTRP3 added to human hepatocytes in vitro suppresses the gluconeogenic pathway thus showing a direct effect on gluconeogenesis [32]. Stimulation of pre-adipocytes with CTRP3 decreases adipogenic markers C/EBPα, PPARγ, FABP4 thereby inhibits adipogenesis and negatively regulates lipid metabolism [93].

Circulatory CTRP5 levels is abundantly expressed in murine adipose tissue and liver. CTRP5 KO mice have lower fasting insulin levels and when challenged with high fat diet these mice are more tolerant to lipid accumulation and are less prone for hepatic steatosis and have enhanced insulin action [42]. From this study it appears that CTRP5 may act as a negative regulator of glucose metabolism and promote IR. Further circulating CTRP5 shows sexual dimorphism, with higher levels found in female than male mice [26, 40]. CTRP6 was elevated in adipose tissue of obese T2D patients and this positively correlated with BMI [94]. CTRP7 is significantly elevated in obese subjects and positively correlates with marker of IR such as BMI, glucose, insulin and HOMA-IR [48]. CTRP7 deficient mice are protected from obesity and fatty liver [47] and its circulating levels are increased in the ob/ob mouse [26].

A significant reduction in circulating CTRP9 levels was observed in obese preeclampsia whereas in obese and T2D subjects it was found to be elevated [52,53,54, 95]. The circulating CTRP9 levels decreases with calorie restriction and increase upon re-feeding [76]. However, for CTRP11, both fasting and re-feeding have no effect on adipose tissue CTRP11 expression in DIO and ob/ob mice [59]. The circulatory and adipose tissue expression of CTRP12 were found to be lower in both DIO and leptin-deficient ob/ob mice [60, 61]. CTRP13 is expressed at relatively low levels in adipocytes compared to adiponectin, the most abundantly expressed adipokine [64]. Lean female mice have higher CTRP13 transcripts in adipose stromal vascular fraction compared to male. However, in obesity the expression pattern switches, obese male mice have higher circulating CTRP13 compared to lean and no significant difference were observed between lean and obese female mice suggesting a potential role in energy metabolism [63, 64]. Circulatory CTRP15 levels are lower in obese mice [65]. Food deprivation, exercise and gender influence circulatory levels of CTRP15. Furthermore, calorie restricted female mice had higher circulating CTRP15 compared to the males [65]. This suggests that circulating CTRPs might serve as novel biomarkers for the early detection and intervention for obesity-linked T2D [7, 96].

Pharmacological intervention of CTRPs in obesity and diabetes

The peripheral administration of CTRPs in obese and diabetic mice results in lower circulatory glucose levels and promotes insulin sensitivity (Table 1) [23, 32, 51, 76]. The administration of CTRP1 resulted in time dependent reduction of blood glucose levels [26]. Administration of recombinant CTRP3 to leptin deficient ob/ob mice lowers the blood glucose levels without altering glucagon, insulin and adiponectin levels in both wild type and ob/ob mice [32]. CTRP6 gene deletion increased the metabolic rate, improved action of insulin and energy expenditure in DIO mice [94]. The CTRP9 transgenic mice were lean, had lower insulin levels and maintained glucose load better compared to control littermates [76]. Recombinant CTRP9 administration improves the fatty oxidation by activating the AMPK pathway [50]. The administration of CTRP12 in mice decreased resistin levels but had no effect on other adipokines such as leptin, adiponectin and plasminogen activator inhibitor-1. Furthermore, CTRP12 suppressed gluconeogenesis and promotes glucose uptake by activating the PI3 kinase/Akt pathway [60]. The administration of myonectin (CTRP15) to obese mice has no effect on blood glucose and serum triacylglycerol levels [7, 65, 82]. This may be due to the shorter half-life leading to rapid degradation of CTRP15 in the circulation.

Insulin and metformin treatment does not alter the circulatory CTRP1 levels in T2D patients [12]. Administration of the GLP-1 receptor agonist exendin improves insulin sensitivity in IR and T2D rats by increasing CTRP3 levels in circulation and in the adipose tissue [31]. Furthermore, rosiglitazone treatment up-regulates circulating CTRP1 levels in diabetic subjects and also increases expression of CTRP12 and CTRP13 in adipose tissue explants thus providing the evidence for PPARγ mediated regulation of CTRPs [9, 64, 97].

CTRPs and cardiac function

Obesity is a major risk factor for CVD mortality [98]. Obesity linked complications such as glucose intolerance are associated with cardiac injury and prognosis of myocardial infarction (MI) [99, 100]. Distorted circulating CTRPs are linked to obesity and IR that are associated with the prevalence and progress of the CVD [12, 15, 16, 101]. In patients with coronary artery disease (CAD) and atherosclerosis, circulating CTRP1, CTRP2 and CTRP3 were elevated and increased further with severity of CAD [17,18,19, 88]. Patients with acute myocardial infarction had much higher CTRP1 compared to patients with stable/unstable angina. CTRP1 levels were further increased with severity of vessel disease. Patients having triple-vessel disease had significantly higher CTRP1 compared to subjects having single-vessel disease [17]. Moreover, CTRP1 in circulation positively correlate with the systolic blood pressure and triglycerides [16, 20]. Thus suggesting that elevated CTRP1 levels could be used as a potential biomarker for CAD and atherosclerosis in men [16, 20, 21].

Circulatory CTRP3 levels were lower in patients with both stable angina pectoris acute coronary syndrome and acute myocardial infarction [33]. Similarly, CTRP5 is a proatherogenic cytokine promoting oxidation of LDL and transcytosis in endothelial cells by upregulating a key molecule 12/15 lipooxygenase which mediates oxidation and LDL trafficking via STAT6 signaling [102]. Circulating CTRP5 levels is lower in patients with IR and CAD [43]. Another member of CTRP family CTRP6 is also highly expressed in adult rat cardiomyocytes, and the levels are significantly reduced in infarct tissue following MI in rats [46]. CTRP7 was found to be higher in CAD patients compared to non-CAD subjects. The CTRP7 levels was highest in patients with triple vessel lesion compared to single vessel lesion CAD patients [49].

The closest adiponectin paralog CTRP9 is expressed about 100-fold higher in mice cardiac tissue compared to adiponectin [55]. In individuals with acute MI and coronary atherosclerosis, the CTRP9 expression in adipocytes and in circulation was lower [103]. Similarly, in rodents, CTRP9 levels decreased significantly in adipose tissues following myocardial ischemic reperfusion [55, 56]. In patients with T2D and those coexisting with CAD along with T2D had lower circulating CTRP9 levels associated with the prevalence of the CAD [34]. This report is intriguing given study from Jia et al., reported CTRP9 levels to be elevated in T2D [53].There are controversial finding on CTRP15 and CAD. Nahrkhalaji et al., found elevated CTRP15 levels in CAD patients and elevated CTRP15 levels were associated with insulin resistance, BMI and disease severity [49, 66]. However recent findings from Zhang et al., showed lower level of CTRP15 in triple vessel lesion patients compared to single vessel lesion patients and non-CAD patients [49]. Further studies on large cohorts are required to elucidate the role of CTRP15 in CAD.

Pharmacological intervention of CTRPs in cardiac disease

The peripheral administration of CTRP1 prevents platelet adhesion, aggregation and thrombosis induced by collagen in rodents and in primates [22]. In contrast another study eluded that CTRP1 administration in mice promotes atherogenesis [20]. Further studies are needed to understand better to therapeutically exploit CTRP1 as potential antithrombotic agents in clinical settings.

The mice pre-treated with recombinant CTRP3 prior to induction of MI had improved post-MI survival rate, restored cardiac function, lesser cardiomyocyte apoptosis and improved revascularization compared to control mice subjected to MI [35]. In addition CTRP3 also enhanced AKT phosphorylation and increased the expression of vascular endothelial growth factor, and hypoxia inducing factor-1α genes that are key mediators required for promoting angiogenesis and mature vessel formation. These effects were mediated independent of nitric oxide production [35]. These observations have clinical relevance in patients with MI; CTRP3 may be useful in the future as an adjuvant to other drugs aimed to restore cardiac function after myocardial ischemia and MI [35]. The transforming growth factor-beta1 (TGF-β1) induces the expression of CTRP3 in vascular smooth muscles (VSMCs) following blood vessel injury and further promotes proliferation of VSMCs [36]. The recombinant CTRP3 administration enhances angiogenesis in rodents through activation ERK1/2 and p38 MAPK signaling dependent pathways (Table 1) [104].

The knockdown of CTRP6 promotes TGF-β1-induced expression of cardiac fibrosis and over expression inhibits TGF-β1 suggesting TGF-β1 may be critically important for regulation of CTRP6 [46]. Furthermore, over expression of CTRP6 in rats through adenoviral- mediated delivery promotes activation of AMPK and AKT-dependent pathways, reduces cardiac hypertrophy, alleviated cardiac fibrosis, hampered myofibroblast differentiation and improves cardiac function post-MI [46]. CTRP9 knockout mice subjected to myocardial ischemia/reperfusion (MI/R) had severe tissue injury and increased cell death compared to controls. This was reversed by either overexpression or through the administration of recombinant CTRP9 which reduced gp91phox expression attenuated superoxide production and oxidative stress [105]. Furthermore in high fat diet fed mice subjected to MI/R, CTRP9 administration also improved cardiac function [105]. This report was further supported by findings where administration of CTRP9 reduces the hypoxia of MI/R through activation of AMPK pathway; thus, protecting the heart from cardiac ischemic injury and decreasing infarct size in response to the ischemic reperfusion [106].

Furthermore, in the apolipoprotein-E KO mice which are susceptible to develop atherosclerosis, administration of CTRP9 stabilized carotid plaques, probably via reduction in the secretion of macrophage proinflammatory cytokines (TNFα and MCP-1) [107]. CTRP9 might also be associated with the regulation of arterial stiffness in humans [108], as it was shown to promote vasorelaxation in human vascular endothelial cells and aortic rings via activation of the AMPK/eNOS/NO-dependent pathway (Table 1) [109]. It also prevents VSMCs proliferation via cAMP-dependent mechanism following arterial injury [110]. Interestingly treatment of a mouse model of acute myocardial infarction with CTRP9 ameliorates cardiomyocyte apoptosis, improves cardiac function and survival through activation of AMPK, PKA and AKT-dependent pathways (Fig. 2) (Table 1) [55]. Taken together these findings suggest that CTRPs might be useful biomarker for the diagnosis and treatment of CVD [7, 111].

CTRPs and non-alcoholic fatty liver disease

NAFLD is linked to IR, obesity and metabolic syndrome [112]. The IR in obese individuals leads to de novo synthesis of lipid and its accumulation in the liver [113, 114]. Disrupted levels of adipokines such as adiponectin, visfatin, TNFα and IL-6 have been found in NAFLD patients, some of which play a key role in the pathophysiology of NAFLD [115, 116]. Therefore, circulating adipokines are currently being used as a surrogate biomarker to determine the prognosis of the disease [117]. Unlike adiponectin, which is lower in NAFLD patients [116], circulating CTRP1 levels were higher in patients with NAFLD and also in patients who had both T2D with NAFLD (Table 1) [15]. CTRP1 levels in these patients positively correlated with fasting blood glucose, BMI, HOMA-IR, γ-glutamyl transpeptidase, alanine transaminase and liver stiffness [15].

CTRP3 plays an important role in regulation of hepatic glucose production. CTRP3 transgenic mice are resistant to hepatic steatosis when fed on HFD and hepatic glucose-6 phosphatase expression was significantly reduced. However, no change was observed in the expression of PPARγ, Cpt1a, Acoxs, Acads and AMPK pathway between wild type and CTRP3 transgenic mice [27]. Administration of CTRP3 reduced blood glucose without altering glucagon, insulin and adiponectin levels in wild type, DIO and ob/ob mice. In hepatoma cells, CTRP3 stimulation reduced lipid accumulation and fatty acid synthesis by suppressing triglyceride synthesis genes (Agpat, Gpat, and Dgat) expression. In hepatocytes, CTRP3 suppressed gluconeogenesis by activating Akt pathway and decreasing the gluconeogenesis enzymes PEPCK and G6Pase independent of insulin (Fig. 3) [27, 32]. Circulatory levels of CTRP5 can be an independent risk factor for determining IR states such as T2D and NAFLD. In small group of human subjects circulating levels of CTRP5 were significantly reduced in T2D, NAFLD and patients with both T2D and NAFLD. From this study lower circulating CTRP5 appears to be an independent risk factor for IR states such as NAFLD, T2D and NAFLD with T2D in human subjects [44].

Genetic deletion of CTRP9 makes mice more prone to develop hepatic steatosis, these CTRP9 KO mice have higher appetite, increased lipid accumulation in the liver, decreased AKT phosphorylation, impaired hepatic insulin signaling and IR [50]. Expression of lipogenic genes Srebp-1c and acetyl-CoA carboxylase were higher in CTRP9 KO mice thus promoting lipid accumulation in the liver. However the fatty acid synthase and fatty acid oxidation regulatory genes (Lcad and Mcad) were unaltered. The administration of recombinant CTRP9 to these KO mice reduced hepatic lipid levels supporting the hypothesis CTRP9 can be important therapeutic target for NAFLD [50].

CTRP9 transgenic mice have lower hepatic and skeletal muscle triglyceride levels, these mice have improved metabolic profile and are protected from metabolic syndrome phenotypes such as IR, high fat diet-induced obesity and hepatic steatosis [50, 76]. Furthermore adenovirus-mediated CTRP9 overexpression in HFD-fed mice leads to suppression of ER stress markers, fatty acid metabolic genes SREBP-1c, lipid accumulation via activation of AMPK dependent pathway [57].

CTRPs and polycystic ovary syndrome

Polycystic Ovary Syndrome (PCOS) is one of the common hormonal disorders in women of reproductive stage [118]. It is a chronic pro-inflammatory state, commonly associated with menstrual dysfunction, diabetes-like phenotype, dyslipidemia, cardiovascular complications, obesity and metabolic syndrome [119]. Obese women are more likely to develop PCOS due to the accumulation of fat, which leads to the development of hyperinsulinemia and IR [120]. The circulating level of adiponectin has been suggested to be possible biomarker in PCOS individuals [121]. CTRP family members are differentially expressed in PCOS subjects. Circulating CTRP9 levels were similar in PCOS and control subjects and positively correlate with serum total cholesterol and LDL-C, the unfavorable lipids [58]. CTRP3 and CTRP12 might have a similar function in PCOS women since CTRP3 expression in adipose tissue and in circulation were lower in women with PCOS and augmented following metformin treatment [37]. In addition glucose stimulation reduced circulating CTRP12 levels while metformin treatment increased the CTRP12 expression in adipose tissue explants, at least in part through activation of AMPK dependent pathway [62].


The metabolic syndrome is a major global health problem associated with T2D, NAFLD and CVD. During the last decade many members of CTRPs were identified in many metabolic tissues and the CTRP family seems to be rapidly expanding. The CTRPs have diverse physiological functions regulates food intake, protects against hepatic steotosis, improves IR and protect against ischemic reperfusion injury and MI in rodents. However, the limitations are controversial findings from different studies showing opposite effects on circulating levels in certain pathophysiological conditions. The lack of clinical studies to translate findings from animals to human. Furthermore, in relationship to CTRP receptor identification it has been suggested CTRPs may partially function through AdipoR1. However, till date no exclusive receptors CTRPs has been identified. Identification and functional characterization of putative receptor and novel agonists for CTRPs may provide important insights that could lead to novel treatments for metabolic diseases.

Availability of data and materials

Because this is a review article, no individual data in any form is included inside the manuscript.



Acetyl co-enzyme A carboxylase


Adiponectin receptor 1


Agouti-related protein


Body Mass Index


Coronary artery disease


C1Q Tumor Necrosis Factor-Related Protein


Cardiovascular disease


Diet induced obese mice


Free fatty acid


Fibroblast growth factor


Glucagon like peptide-1


High fat diet


Homeostatic Model Assessment of Insulin Resistance




Insulin resistance


Low density lipoprotein


Myocardial infarction


Myocardial ischemia/reperfusion


Non-alcoholic fatty liver disease




Polycystic Ovary Syndrome


Type 2 Diabetes


Transforming growth factor-beta1


Vascular smooth muscles


  1. 1.

    Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444(7121):847–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Verhagen SN, Buijsrogge MP, Vink A, van Herwerden LA, van der Graaf Y, Visseren FL. Secretion of adipocytokines by perivascular adipose tissue near stenotic and non-stenotic coronary artery segments in patients undergoing CABG. Atherosclerosis. 2014;233(1):242–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Fernandez-Real JM, McClain D, Manco M. Mechanisms linking glucose homeostasis and Iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care. 2015;38(11):2169–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin--a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006;8(3):264–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Peterson JM, Wei Z, Wong GW. CTRP8 and CTRP9B are novel proteins that hetero-oligomerize with C1q/TNF family members. Biochem Biophys Res Commun. 2009;388(2):360–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Shah D, Romero F, Zhu Y, Duong M, Sun J, Walsh K, et al. C1q deficiency promotes pulmonary vascular inflammation and enhances the susceptibility of the lung endothelium to injury. J Biol Chem. 2015;290(49):29642–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Seldin MM, Tan SY, Wong GW. Metabolic function of the CTRP family of hormones. Rev Endocr Metab Disord. 2014;15(2):111–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Peterson JM, Aja S, Wei Z, Wong GW. CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition. J Biol Chem. 2012;287(2):1576–87.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Wong GW, Wang J, Hug C, Tsao TS, Lodish HF. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A. 2004;101(28):10302–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Pan X, Lu T, Wu F, Jin L, Zhang Y, Shi L, et al. Circulating complement-C1q TNF-related protein 1 levels are increased in patients with type 2 diabetes and are associated with insulin sensitivity in Chinese subjects. PLoS One. 2014;9(5):e94478.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Xin Y, Lyu X, Wang C, Fu Y, Zhang S, Tian C, et al. Elevated circulating levels of CTRP1, a novel adipokine, in diabetic patients. Endocr J. 2014;61(9):841–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Han S, Kim JD, Lee S, Jeong AL, Park JS, Yong HJ, et al. Circulating CTRP1 levels in type 2 diabetes and their association with FGF21. Int J Endocrinol 2016;2016:5479627.

  14. 14.

    Bai B, Ban B, Liu Z, Zhang MM, Tan BK, Chen J. Circulating C1q complement/TNF-related protein (CTRP) 1, CTRP9, CTRP12 and CTRP13 concentrations in type 2 diabetes mellitus: in vivo regulation by glucose. PLoS One. 2017;12(2):e0172271.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Shabani P, Naeimi Khaledi H, Beigy M, Emamgholipour S, Parvaz E, Poustchi H, et al. Circulating level of CTRP1 in patients with nonalcoholic fatty liver disease (NAFLD): is it through insulin resistance? PLoS One. 2015;10(3):e0118650.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Shen Y, Lu L, Liu ZH, Wu F, Zhu JZ, Sun Z, et al. Increased serum level of CTRP1 is associated with low coronary collateralization in stable angina patients with chronic total occlusion. Int J Cardiol. 2014;174(1):203–6.

    PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Wang H, Wang R, Du D, Li F, Li Y. Serum levels of C1q/TNF-related protein-1 (CTRP-1) are closely associated with coronary artery disease. BMC Cardiovasc Disord. 2016;16:92.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Wang S, Ling Y, Liang W, Shen L. Association of serum C1q/TNF-related protein-3 (CTRP-3) in patients with coronary artery disease. BMC Cardiovasc Disord. 2017;17(1):210.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Ilbeigi D, Khoshfetrat M, Afrisham R, Rahimi B, Gorgani-Firuzjaee S. Serum C1q/TNF-related Protein-2 (CTRP2) levels are associated with coronary artery disease. Arch Med Res. 2020;51(2):167–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Lu L, Zhang RY, Wang XQ, Liu ZH, Shen Y, Ding FH, et al. C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis. Eur Heart J. 2016;37(22):1762–71.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  21. 21.

    Yuasa D, Ohashi K, Shibata R, Takeshita K, Kikuchi R, Takahashi R, et al. Association of circulating C1q/TNF-related protein 1 levels with coronary artery disease in men. PLoS One. 2014;9(6):e99846.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Lasser G, Guchhait P, Ellsworth JL, Sheppard P, Lewis K, Bishop P, et al. C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen. Blood. 2006;107(2):423–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Peterson JM, Seldin MM, Tan SY, Wong GW. CTRP2 overexpression improves insulin and lipid tolerance in diet-induced obese mice. PLoS One. 2014;9(2):e88535.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Lei X, Wong GW. C1q/TNF-related protein 2 (CTRP2) deletion promotes adipose tissue lipolysis and hepatic triglyceride secretion. J Biol Chem. 2019;294(43):15638–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Rohrbach S, Aurich AC, Li L, Niemann B. Age-associated loss in adiponectin-activation by caloric restriction: lack of compensation by enhanced inducibility of adiponectin paralogs CTRP2 and CTRP7. Mol Cell Endocrinol. 2007;277(1–2):26–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF. 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(2):161–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Peterson JM, Seldin MM, Wei Z, Aja S, Wong GW. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism. Am J Physiol Gastrointest Liver Physiol. 2013;305(3):G214–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Deng W, Li C, Zhang Y, Zhao J, Yang M, Tian M, et al. Serum C1q/TNF-related protein-3 (CTRP3) levels are decreased in obesity and hypertension and are negatively correlated with parameters of insulin resistance. Diabetol Metab Syndr. 2015;7:33.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Ban B, Bai B, Zhang M, Hu J, Ramanjaneya M, Tan BK, et al. Low serum cartonectin/CTRP3 concentrations in newly diagnosed type 2 diabetes mellitus: in vivo regulation of cartonectin by glucose. PLoS One. 2014;9(11):e112931.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Qu H, Deng M, Wang H, Wei H, Liu F, Wu J, et al. Plasma CTRP-3 concentrations in Chinese patients with obesity and type II diabetes negatively correlate with insulin resistance. J Clin Lipidol. 2015;9(3):289–94.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Li X, Jiang L, Yang M, Wu YW, Sun SX, Sun JZ. Expression of CTRP3, a novel adipokine, in rats at different pathogenic stages of type 2 diabetes mellitus and the impacts of GLP-1 receptor agonist on it. J Diabetes Res 2014;2014:398518.

  32. 32.

    Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem. 2010;285(51):39691–701.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Choi KM, Hwang SY, Hong HC, Choi HY, Yoo HJ, Youn BS, et al. Implications of C1q/TNF-related protein-3 (CTRP-3) and progranulin in patients with acute coronary syndrome and stable angina pectoris. Cardiovasc Diabetol. 2014;13:14.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Ahmed SF, Shabayek MI, Abdel Ghany ME, El-Hefnawy MH, El-Mesallamy HO. Role of CTRP3, CTRP9 and MCP-1 for the evaluation of T2DM associated coronary artery disease in Egyptian postmenopausal females. PLoS One. 2018;13(12):e0208038.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Yi W, Sun Y, Yuan Y, Lau WB, Zheng Q, Wang X, et al. C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart. Circulation. 2012;125(25):3159–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Maeda T, Wakisaka S. CTRP3/cartducin is induced by transforming growth factor-beta1 and promotes vascular smooth muscle cell proliferation. Cell Biol Int. 2010;34(3):261–6.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Tan BK, Chen J, Hu J, Amar O, Mattu HS, Adya R, et al. Metformin increases the novel adipokine cartonectin/CTRP3 in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(12):E1891–900.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Schaffler A, Buechler C. CTRP family: linking immunity to metabolism. Trends Endocrinol Metab. 2012;23(4):194–204.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Byerly MS, Petersen PS, Ramamurthy S, Seldin MM, Lei X, Provost E, et al. 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(7):4055–69.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Schmid A, Kopp A, Aslanidis C, Wabitsch M, Muller M, Schaffler A. Regulation and function of C1Q/TNF-related protein-5 (CTRP-5) in the context of adipocyte biology. Exp Clin Endocrinol Diabetes. 2013;121(5):310–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Park EJ, Kim MJ, Lee W, Park SY. Ets-2 is involved in transcriptional regulation of C1qTNF-related protein 5 in muscle cells. Mol Biol Rep. 2012;39(10):9445–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Lei X, Rodriguez S, Petersen PS, Seldin MM, Bowman CE, Wolfgang MJ, et al. Loss of CTRP5 improves insulin action and hepatic steatosis. Am J Physiol Endocrinol Metab. 2016;310(11):E1036–52.

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Moradi N, Fadaei R, Rashidbeygi E, Bagheri Kargasheh F, Malek M, Shokoohi Nahrkhalaji A, et al. Evaluation of changing the pattern of CTRP5 and inflammatory markers levels in patients with coronary artery disease and type 2 diabetes mellitus. Arch Physiol Biochem. 2020:1–6.

  44. 44.

    Emamgholipour S, Moradi N, Beigy M, Shabani P, Fadaei R, Poustchi H, et al. The association of circulating levels of complement-C1q TNF-related protein 5 (CTRP5) with nonalcoholic fatty liver disease and type 2 diabetes: a case-control study. Diabetol Metab Syndr. 2015;7:108.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Lee W, Kim MJ, Park EJ, Choi YJ, Park SY. C1qTNF-related protein-6 mediates fatty acid oxidation via the activation of the AMP-activated protein kinase. FEBS Lett. 2010;584(5):968–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Lei H, Wu D, Wang JY, Li L, Zhang CL, Feng H, et al. C1q/tumor necrosis factor-related protein-6 attenuates post-infarct cardiac fibrosis by targeting RhoA/MRTF-A pathway and inhibiting myofibroblast differentiation. Basic Res Cardiol. 2015;110(4):35.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  47. 47.

    Petersen PS, Lei X, Wolf RM, Rodriguez S, Tan SY, Little HC, et al. CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress. Am J Physiol Endocrinol Metab. 2017:ajpendo 00344 2016.

  48. 48.

    Petersen PS, Lei X, Wolf RM, Rodriguez S, Tan SY, Little HC, et al. CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress. Am J Physiol Endocrinol Metab. 2017;312(4):E309–E25.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Zhang Y, Liu C, Liu J, Guo R, Yan Z, Liu W, et al. Implications of C1q/TNF-related protein superfamily in patients with coronary artery disease. Sci Rep. 2020;10(1):878.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Wei Z, Lei X, Petersen PS, Aja S, Wong GW. 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(7):E779–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Ge G, Spooner E, Hug C, et al. 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(1):241–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Hwang YC, Woo Oh S, Park SW, Park CY. Association of serum C1q/TNF-related Protein-9 (CTRP9) concentration with visceral adiposity and metabolic syndrome in humans. Int J Obes. 2014;38(9):1207–12.

    CAS  Article  Google Scholar 

  53. 53.

    Jia Y, Luo X, Ji Y, Xie J, Jiang H, Fu M, et al. Circulating CTRP9 levels are increased in patients with newly diagnosed type 2 diabetes and correlated with insulin resistance. Diabetes Res Clin Pract. 2017;131:116–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Wolf RM, Steele KE, Peterson LA, Zeng X, Jaffe AE, Schweitzer MA, et al. C1q/TNF-related Protein-9 (CTRP9) levels are associated with obesity and decrease following weight loss surgery. J Clin Endocrinol Metab. 2016;101(5):2211–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Sun Y, Yi W, Yuan Y, Lau WB, Yi D, Wang X, et al. C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase a activation. Circulation. 2013;128(11 Suppl 1):S113–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Kambara T, Ohashi K, Shibata R, Ogura Y, Maruyama S, Enomoto T, et al. CTRP9 protein protects against myocardial injury following ischemia-reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism. J Biol Chem. 2012;287(23):18965–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Jung TW, Hong HC, Hwang HJ, Yoo HJ, Baik SH, Choi KM. C1q/TNF-related protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress. Mol Cell Endocrinol. 2015;417:131–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Forouhi N, Saedisomeolia A, Djalali M, Eshraghian MR, Morshedzadeh N, Zabetian-Targhi F, et al. Serum C1q and tumor necrosis factor (TNF)-related protein 9 in women with polycystic ovary syndrome. Diab Metab Syndr. 2016;10(2 Suppl 1):S131–4.

    Article  Google Scholar 

  59. 59.

    Wei Z, Seldin MM, Natarajan N, Djemal DC, Peterson JM, Wong GW. C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis. J Biol Chem. 2013;288(15):10214–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Wei Z, Peterson JM, Lei X, Cebotaru L, Wolfgang MJ, Baldeviano GC, et al. 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(13):10301–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Enomoto T, Shibata R, Ohashi K, Kambara T, Kataoka Y, Uemura Y, et al. Regulation of adipolin/CTRP12 cleavage by obesity. Biochem Biophys Res Commun. 2012;428(1):155–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Tan BK, Chen J, Adya R, Ramanjaneya M, Patel V, Randeva HS. Metformin increases the novel adipokine adipolin/CTRP12: role of the AMPK pathway. J Endocrinol. 2013;219(2):101–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Byerly MS, Swanson R, Wei Z, Seldin MM, McCulloh PS, Wong GW. A central role for C1q/TNF-related protein 13 (CTRP13) in modulating food intake and body weight. PLoS One. 2013;8(4):e62862.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Wei Z, Peterson JM, Wong GW. 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(18):15652–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Seldin MM, Peterson JM, Byerly MS, Wei Z, Wong GW. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem. 2012;287(15):11968–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Shokoohi Nahrkhalaji A, Ahmadi R, Fadaei R, Panahi G, Razzaghi M, Fallah S. Higher serum level of CTRP15 in patients with coronary artery disease is associated with disease severity, body mass index and insulin resistance. Arch Physiol Biochem. 2019:1–5.

  67. 67.

    Otvos L Jr, Kovalszky I, Olah J, Coroniti R, Knappe D, Nollmann FI, et al. Optimization of adiponectin-derived peptides for inhibition of cancer cell growth and signaling. Biopolymers. 2015;104(3):156–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol. 2013;19(6):802–12.

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Kawano J, Arora R. The role of adiponectin in obesity, diabetes, and cardiovascular disease. J Cardiometab Syndr. 2009;4(1):44–9.

    PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Jardé T, Caldefie-Chézet F, Goncalves-Mendes N, Mishellany F, Buechler C, Penault-Llorca F, et al. Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies. Endocr Relat Cancer. 2009;16(4):1197–210.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  71. 71.

    Burgio E, Lopomo A, Migliore L. Obesity and diabetes: from genetics to epigenetics. Mol Biol Rep. 2015;42(4):799–818.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Murakami K, Livingstone MB. Eating frequency is positively associated with overweight and central obesity in US adults. J Nutr. 2015;145(12):2715–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Marti A, Moreno-Aliaga MJ, Hebebrand J, Martinez JA. Genes, lifestyles and obesity. Int J Obes Relat Metab Disord. 2004;28(Suppl 3):S29–36.

    PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Taormina G, Mirisola MG. Calorie restriction in mammals and simple model organisms. Biomed Res Int 2014;2014:308690.

  75. 75.

    Baumeier C, Kaiser D, Heeren J, Scheja L, John C, Weise C, et al. Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. Biochimica Biophysica Acta (BBA). 2015;1851(5):566–76.

    CAS  Article  Google Scholar 

  76. 76.

    Peterson JM, Wei Z, Seldin MM, Byerly MS, Aja S, Wong GW. CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol. 2013;305(5):R522–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev. 2009;61(3):373–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Marette A, Liu Y, Sweeney G. Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome. Rev Endocr Metab Disord. 2014;15(4):299–305.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Jensen J, Rustad PI, Kolnes AJ, Lai YC. The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Front Physiol. 2011;2:112.

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32(Suppl 2):S157–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Pedersen BK. Muscles and their myokines. J Exp Biol. 2011;214(Pt 2):337–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Peterson JM, Mart R, Bond CE. Effect of obesity and exercise on the expression of the novel myokines, Myonectin and Fibronectin type III domain containing 5. PeerJ. 2014;2:e605.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21(12):1443–55.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne). 2013;4:71.

    Article  Google Scholar 

  85. 85.

    Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med. 2008;14(11–12):741–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Okauchi Y, Kishida K, Funahashi T, Noguchi M, Ogawa T, Ryo M, et al. Changes in serum adiponectin concentrations correlate with changes in BMI, waist circumference, and estimated visceral fat area in middle-aged general population. Diabetes Care. 2009;32(10):e122.

    PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J. 2004;68(11):975–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Lang Y, Ran X, Wang L, Li W. Risk factors of death in patients with acute ST-segment elevation myocardial infarction after PCI and the combined application of CTRP-1 with GRACE score in prognosis evaluation of PCI treated patients. Sichuan Da Xue Xue Bao Yi Xue Ban. 2019;50(6):941–5.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Yagmur E, Buergerhausen D, Koek GH, Weiskirchen R, Trautwein C, Koch A, et al. Elevated CTRP1 Plasma Concentration Is Associated with Sepsis and Pre-Existing Type 2 Diabetes Mellitus in Critically Ill Patients. J Clin Med. 2019;8:5.

    Google Scholar 

  90. 90.

    Wurm S, Neumeier M, Weigert J, Schaffler A, Buechler C. 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;6:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Gęca T, Kwiatek M, Krzyżanowski A, Kwaśniewska A. C1q/TNF-Related Protein-3 (CTRP-3) and Pigment Epithelium-Derived Factor (PEDF) Concentrations in Patients with Gestational Diabetes Mellitus: A Case-Control Study. J Clin Med. 2020;9:8.

    Google Scholar 

  92. 92.

    Moradi N, Najafi M, Sharma T, Fallah S, Koushki M, Peterson JM, et al. Circulating levels of CTRP3 in patients with type 2 diabetes mellitus compared to controls: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2020:108453.

  93. 93.

    Nishimoto H, Yamamoto A, Furukawa S, Wakisaka S, Maeda T. C1q/TNF-related protein 3 expression and effects on adipocyte differentiation of 3T3-L1 cells. Cell Biol Int. 2016;41:197–203.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  94. 94.

    Lei X, Seldin MM, Little HC, Choy N, Klonisch T, Wong GW. C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance. J Biol Chem. 2017;292(36):14836–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Aksin Ş, Andan C. Protein-9 (CTRP9) levels associated with C1q tumor necrosis factor in obese preeclamptic, non-obese preeclamptic, obese and normal pregnant women. J Matern Fetal Neonatal Med. 2020:1–8.

  96. 96.

    Inadera H. The usefulness of circulating adipokine levels for the assessment of obesity-related health problems. Int J Med Sci. 2008;5(5):248–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Tan BK, Lewandowski KC, O'Hare JP, Randeva HS. Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects. J Endocrinol. 2014;221(1):111–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Akin I, Nienaber CA. "obesity paradox" in coronary artery disease. World J Cardiol. 2015;7(10):603–8.

    PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Steinberger J, Daniels SR, American Heart Association Atherosclerosis H, Obesity in the Young C, American Heart Association Diabetes C. Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Circulation. 2003;107(10):1448–53.

    PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the obesity Committee of the Council on nutrition, physical activity, and metabolism. Circulation. 2006;113(6):898–918.

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Lago F, Gomez R, Gomez-Reino JJ, Dieguez C, Gualillo O. Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci. 2009;34(10):500–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Li C, Chen JW, Liu ZH, Shen Y, Ding FH, Gu G, et al. CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis. Atherosclerosis. 2018;278:197–209.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Wang J, Hang T, Cheng XM, Li DM, Zhang QG, Wang LJ, et al. Associations of C1q/TNF-related Protein-9 levels in serum and Epicardial adipose tissue with coronary atherosclerosis in humans. Biomed Res Int 2015;2015:971683.

  104. 104.

    Akiyama H, Furukawa S, Wakisaka S, Maeda T. CTRP3/cartducin promotes proliferation and migration of endothelial cells. Mol Cell Biochem. 2007;304(1–2):243–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Su H, Yuan Y, Wang XM, Lau WB, Wang Y, Wang X, et al. Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFalpha-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice. Basic Res Cardiol. 2013;108(1):315.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  106. 106.

    Kambara T, Shibata R, Ohashi K, Matsuo K, Hiramatsu-Ito M, Enomoto T, et al. C1q/tumor necrosis factor-related protein 9 protects against acute myocardial injury through an Adiponectin receptor I-AMPK-dependent mechanism. Mol Cell Biol. 2015;35(12):2173–85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Li J, Zhang P, Li T, Liu Y, Zhu Q, Chen T, et al. CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. Biochem Biophys Res Commun. 2015;458(4):890–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Jung CH, Lee MJ, Kang YM, Jang JE, Leem J, Lee YL, et al. Association of serum C1q/TNF-related protein-9 concentration with arterial stiffness in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2014;99(12):E2477–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Zheng Q, Yuan Y, Yi W, Lau WB, Wang Y, Wang X, et al. C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol. 2011;31(11):2616–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Uemura Y, Shibata R, Ohashi K, Enomoto T, Kambara T, Yamamoto T, et al. Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J. 2013;27(1):25–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Shibata R, Ouchi N, Murohara T. Adiponectin and cardiovascular disease. Circ J. 2009;73(4):608–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009;13(1):9–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Privitera G, Spadaro L, Alagona C, Calanna S, Piro S, Rabuazzo AM, et al. Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components. Acta Diabetol. 2015;53(3):449–59.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  115. 115.

    Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum Adipokines. Medicine (Baltimore). 2016;95(5):e2630.

    CAS  Article  Google Scholar 

  116. 116.

    Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1062–79.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184–223.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Sharpless JL. Polycystic ovary syndrome and the metabolic syndrome. Clinical Diabetes. 2003;21(4):154–61.

    Article  Google Scholar 

  119. 119.

    Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014;2014:943162.

  120. 120.

    Sam S. Obesity and polycystic ovary syndrome. Obes Manag. 2007;3(2):69–73.

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar QM. Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res. 2014;7:18.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references


The authors would like to thank Medical research Center, Qatar metabolic institute and Translational Research Institute, Hamad Medical Corporation, Doha, Qatar for the support.


No funding.

Author information




MR and JJ wrote the manuscript. IB and KSS helped in preparing the figures and tables. ABAS helped in writing and review the manuscript. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Manjunath Ramanjaneya or Abdul-Badi Abou-Samra.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors give their consent for publication.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ramanjaneya, M., Jerobin, J., Bettahi, I. et al. Emerging roles of C1Q tumor necrosis factor-related proteins in metabolic diseases. transl med commun 6, 5 (2021).

Download citation


  • Obesity
  • Type 2 diabetes (T2D)
  • Metabolic syndrome (MS)
  • Polycystic ovarian syndrome (PCOS)
  • Non-alcoholic fatty liver disease (NAFLD)
  • Adipose tissue and C1Q tumor necrosis factor-related proteins (CTRPs)