Metabolic Regulation by C1q/TNF-related Protein-13 (CTRP13)

Abstract

Members of the C1q/TNF family play important and diverse roles in the immune, endocrine, skeletal, vascular, and sensory systems. Here, we identify and characterize CTRP13, a new and extremely conserved member of the C1q/TNF family. CTRP13 is preferentially expressed by adipose tissue and the brain in mice and predominantly by adipose tissue in humans. Within mouse adipose tissue, CTRP13 is largely expressed by cells of the stromal vascular compartment. Due to sexually dimorphic expression patterns, female mice have higher transcript and circulating CTRP13 levels than males. CTRP13 transcript and circulating levels are elevated in obese male mice, suggesting a potential role in energy metabolism. The insulin-sensitizing drug rosiglitazone also increases the expression of CTRP13 in adipocytes, which correlates with the insulin-sensitizing action of CTRP13. In a heterologous expression system, CTRP13 is secreted as a disulfide-linked oligomeric protein. When co-expressed, CTRP13 forms heteromeric complexes with a closely related family member, CTRP10. This heteromeric association does not involve conserved N-terminal Cys residues. Functional studies using purified recombinant protein demonstrated that CTRP13 is an adipokine that promotes glucose uptake in adipocytes, myotubes, and hepatocytes via activation of the AMPK signaling pathway. CTRP13 also ameliorates lipid-induced insulin resistance in hepatocytes through suppression of the SAPK/JNK stress signaling that impairs the insulin signaling pathway. Further, CTRP13 reduces glucose output in hepatocytes by inhibiting the mRNA expression of gluconeogenic enzymes, glucose-6-phosphatase and the cytosolic form of phosphoenolpyruvate carboxykinase. These results provide the first functional characterization of CTRP13 and establish its importance in glucose homeostasis.

The Circulating CTRP13 in Type 2 Diabetes and Non-Alcoholic Fatty Liver Patients

“…This difference remained significant even after adjustment for age, BMI and serum adiponectin for NAFLD and NAFLD+T2DM groups. Our result is inconsistent with observations reported by Peterson JM et al and Byerly MS et al They found that plasma level of CTRP13 decreased in in leptin-deficient mice [8,9]. This discrepancy may arise due to differences in sample type.…”

“…According to the previous studies, AMPK function leads to beta-oxidation induction [21]. Since, AMPK can be induced by CTRP13 [8]; it seems that reduced CTRP13 serum levels have a negative effect on beta oxidation. However, molecular mechanistic studies are required to establish this concept.…”

“…Subsequently, it was found that this protein decreases gluconeogenesis [8]. CTRP13 consist of C-terminal globular domain homologous to the immune complement protein C1q, two highly conserved Cys residues and 17 Gly-X-Y repeats in collagen domain.…”

“…CTRP13 consist of C-terminal globular domain homologous to the immune complement protein C1q, two highly conserved Cys residues and 17 Gly-X-Y repeats in collagen domain. In human, most of CTRP13 was expressed by adipose tissue and secreted as a multimeric protein [8]. This is also worth mentioning that caloric restriction decreases, and high calorie diet increases expression level of CTRP13 mRNA in brain tissue of mice [9].…”

Adipolin/C1qdc2/CTRP12 Protein Functions as an Adipokine That Improves Glucose Metabolism

“…However, both adipolin and adiponectin are down-regulated in obese states. In contrast to adipolin and adiponectin, the expression of other members of this family in fat tissues is either increased or unchanged in obese states (25,26). For instance, a recent report showed that CTRP13 in fat tissue is up-regulated in obese states, but this factor stimulates glucose uptake in muscle and reduces hepatic glucose output in vitro, indicating a role in glucose homeostasis (25).…”