Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.

Aims: This study aimed to examine the alterations in the serum CTRP7 and CTRP15 concentrations in patients newly diagnosed with type 2 diabetes mellitus (T2DM) and to assess the diagnostic potential of the log10 (CTRP7+CTRP15) for insulin resistance (IR) and T2DM. Methods: Serum CTRP7, CTRP15, and adiponectin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate CTRP7 and CTRP15-related genes and metabolic signaling pathways. Results: Log10 (CTRP7+CTRP15) levels were notably elevated in the impaired glucose tolerance (IGT) and T2DM cohorts compared with those in the normal control (NGT) cohort. Log10(CTRP7+CTRP15) exhibited positive correlations with HOMA-IR, area under the glucose curve (AUCg), HbA1c%, triglyceride (TG), visceral adiposity index (VAI), body mass index (BMI), and free fatty acid (FFA), levels but negative correlations with adiponectin. Multivariate stepwise regression analysis revealed that HOMA-IR, BMI, HbA1c and FFA levels were independent factors affecting the log10 (CTRP7+CTRP15). Logistic regression analysis revealed that log10 (CTRP7+CTRP15) was independently associated with T2DM and significantly associated with increased risk. Receiver operating characteristic (ROC) curve analysis indicated that the predictive value of log10 (CTRP7+CTRP15) for T2DM and IR was superior to that of CTRP7 or CTRP15 alone. Intervention studies demonstrated that insulin, FFAs and acute exercise contribute to the elevation of serum CTRP7 levels, while hyperglycemia inhibited CTRP7 secretion. Short-term changes in blood glucose, insulin, FFA and acute exercise had minimal effects on serum CTRP15 levels. Bioinformatics analysis revealed that CTRP7 and CTRP15 interact with multiple metabolism-related genes and are enriched in glucose and lipid metabolism-related pathways. Conclusion: Log10 (CTRP7+CTRP15) may serve as a valuable diagnostic marker for the management of metabolic-related diseases, particularly T2DM and IR.

CTRP15 promotes macrophage cholesterol efflux and attenuates atherosclerosis by increasing the expression of ABCA1

C1q tumor necrosis factor–related protein 15 (CTRP15), a newly identified myokine, is closely implicated in cardiovascular disease. However, the role of CTRP15 in atherosclerosis is still unclear. This study aims to determine the role of CTRP15 in atherosclerosis and explore the underlying mechanisms. Our findings revealed that lentivirus-mediated CTRP15 overexpression significantly decreased atherosclerotic plaque lesions and increased reverse cholesterol transport (RCT) efficiency and circulating HDL-C levels in apolipoprotein E-deficient (apoE−/−) mice. Consistently, in vitro, overexpression of CTRP15 also inhibited intracellular lipid accumulation and promoted cholesterol efflux from macrophages. Mechanistically, CTRP15 decreased the expression of miR-101-3p by upregulating T-cadherin, thereby facilitating ABCA1 expression and cholesterol efflux. In summary, these data indicate that CTRP15 inhibits the development of atherosclerosis by enhancing RCT efficiency and increasing plasma HDL-C levels via the T-cadherin/miR-101-3p/ABCA1 pathway. Targeting CTRP15 may serve as a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases. (AU)

CTRP15 promotes macrophage cholesterol efflux and attenuates atherosclerosis by increasing the expression of ABCA1.

C1q tumor necrosis factor-related protein 15 (CTRP15), a newly identified myokine, is closely implicated in cardiovascular disease. However, the role of CTRP15 in atherosclerosis is still unclear. This study aims to determine the role of CTRP15 in atherosclerosis and explore the underlying mechanisms. Our findings revealed that lentivirus-mediated CTRP15 overexpression significantly decreased atherosclerotic plaque lesions and increased reverse cholesterol transport (RCT) efficiency and circulating HDL-C levels in apolipoprotein E-deficient (apoE-/-) mice. Consistently, in vitro, overexpression of CTRP15 also inhibited intracellular lipid accumulation and promoted cholesterol efflux from macrophages. Mechanistically, CTRP15 decreased the expression of miR-101-3p by upregulating T-cadherin, thereby facilitating ABCA1 expression and cholesterol efflux. In summary, these data indicate that CTRP15 inhibits the development of atherosclerosis by enhancing RCT efficiency and increasing plasma HDL-C levels via the T-cadherin/miR-101-3p/ABCA1 pathway. Targeting CTRP15 may serve as a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.

Increased circulating level of CTRP15 in patients with type 2 diabetes mellitus and its relation with inflammation and insulin resistance.

AIMS: Type 2 diabetes mellitus (T2DM) is a highly prevalence disease that has a close relation with secretory factors such as adipokines and myokines. C1q tumor necrosis factor-α (TNF-α)-related protein 15 (CTRP15) is a paralogue paralogue of adiponectin that has a close relation with insulin resistance and inflammation. The present study aimed to assess circulating levels of CTRP15 in patients with T2DM in comparison with controls and thier association with inflammatory cytokines. METHODS: This case-control study was performed on 80 T2DM patients and 80 controls which diagnosed according to the criteria of American Diabetes Association (ADA). Serum levels of CTRP15, adiponectin, TNF-α, and interleukin- 6 (IL-6) were determined using ELISA kits. RESULTS: The results indicated higher concentration of CTRP15 in T2DM patients (103.17 ± 27.99) compared to the controls (66.11 ± 20.46, p < 0.001), while adiponectin decreased considerably in the patients compared to the controls (p < 0.001). Moreover, circulating levels of IL-6 and TNF-α elevated in the patients compared to the controls (p < 0.001). CTRP15 indicated independent association with BMI and adiponectin in the controls while, in the patients it demonstrated independent association with HOMA-IR and TNF-α. CONCLUSIONS: Higher concentration of CTRP15 in the patients and its relation with insulin resistance and inflammation suggested a relation of CTRP15 with the pathogenesis of diabetes. In addition, it seems likely that patients with T2DM had a CTRP15 resistance; however, future studies are necessary to prove this concept.

Circulating C1q/TNF-related protein isoform 15 is a marker for the presence of metabolic syndrome.

BACKGROUND: C1q/TNF-related protein isoform 15 (CTRP15) has been reported to be related to glucose and lipid metabolism, but the results are inconsistent. Metabolic syndrome (MetS) is a cluster of metabolic disorders. The aim of this study is to determine circulating CTRP15 levels in individuals with MetS and investigate the association among circulating CTRP15 and markers for MetS as well as insulin resistance. METHODS: A total of 341 individuals were recruited for this cross-sectional study. These subjects were screened for MetS. Serum CTRP15 concentrations were measured by ELISA. RESULTS: Serum CTRP15 levels were significantly higher in MetS individuals relative to those of the healthy individuals. Circulating CTRP15 correlated positively with WHR, BMI, SBP, FAT %, 2 h-BG, FIns, 2 h-Ins, TG, FFA, HbA1c, HOMA-IR, and AUCglucose , while negatively with HDL-C and ISI. Multiple linear regression showed that HOMA-IR and HDL-C are independently related factors influencing serum CTRP15 concentrations. In addition, binary logistic regression analysis showed that serum CTRP15 concentrations were significantly related to MetS. When the mean concentrations of circulating CTRP15 in MetS subjects were stratified by the number of components of the MetS, circulating CTRP15 was found to increase progressively with increasing number of the MetS components. Finally, ROC curve analysis showed that the best cutoff values for circulating CTRP15 to predict MetS and insulin resistance were 63.6 and 64.0 µg/L. CONCLUSIONS: Serum CTRP15 concentrations were associated with the key components of MetS and insulin resistance.

Effect of obesity and exercise on the expression of the novel myokines, Myonectin and Fibronectin type III domain containing 5.

Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines, Myonectin and Fibronectin type III domain containing 5 (FNDC5), the precursor for Irisin. Methods. We performed immunoblot analysis and quantitative real-time PCR analysis of Myonectin and FNDC5 in the diaphragm muscles of obese Zucker rat (OZR) and lean Zucker rat (LZR) with 9 weeks of aerobic training on a motorized treadmill. Results. We show that myonectin gene expression is increased in the OZR model of obesity and decreases with exercise in both lean and obese Zucker rats. Conversely, myonectin protein concentration was elevated with exercise. Similarly, FNDC5 mRNA levels are significantly higher in the OZR, however exercise training had no effect on the expression level of FNDC5 in either the LZR or OZR. We did not observe any difference in muscle protein content of Irisin with obesity or exercise. Conclusion. Our data shows that exercise training does not increase either FNDC5 or myonectin gene expression, indicating that increased transcriptional regulation of these myokines is not induced by exercise. However, our data also indicates a yet to be explored disconnect between myonectin gene expression and protein content. Further, this report highlights the importance of verifying reference genes when completing gene expression analysis. We found that many commonly used reference genes varied significantly by obesity and/or exercise and would have skewed the results of this study if used to normalize gene expression data. The unstable reference genes include: beta-Actin, beta-2-microglobulin, Non-POU domain containing, octamer-binding, Peptidylprolyl isomerase H, 18S ribosomal RNA, TATA box binding protein and Transferrin receptor.

Regulation of tissue crosstalk by skeletal muscle-derived myonectin and other myokines.

The integrated control of animal physiology requires intimate tissue crosstalk, a vital task mediated by circulating humoral factors. As one type of these factors, adipose tissue-derived adipokines have recently garnered attention as important regulators of systemic insulin sensitivity and metabolic homeostasis. However, the realization that skeletal muscle also secretes a variety of biologically and metabolically active polypeptide factors (collectively called myokines) has provided a new conceptual framework to understand the critical role skeletal muscle plays in coordinating whole-body energy balance. Here, we highlight recent progress made in the myokine field and discuss possible roles of myonectin, which we have recently identified as a potential postprandial signal derived from skeletal muscle to integrate metabolic processes in other tissues, such as adipose and liver; one of its roles is to promote fatty acid uptake into cells. Myonectin is also likely an important mediator in inter-tissue crosstalk.