Function and regulation of CTRP12 and CTRP13 in metabolic homeostasis.

摘要

Despite the prevalence of insulin resistance and Type 2 diabetes mellitus (T2DM), their underlying mechanisms remain incompletely understood. Many secreted endocrine factors and the inter-tissue crosstalk they mediate are known to be dysregulated in T2DM. In this thesis, the function and regulation of two adipokines, CTRP12 and CTRP13 are discussed. CTRP12 and CTRP13 are newly identified members of the C1q/TNF-related protein (CTRP) family and have significant metabolic functions. CTRP12 is an adipokine mainly expressed in the adipocytes. Recombinant CTRP12 protein administration lowered blood glucose in wild-type, leptin-deficient ob/ob, and diet-induced obese (D10) mice. A short-term elevation of serum CTRP12 by adenovirus-mediated expression improved insulin sensitivity. Enhancement of insulin signaling, reflected by increased phosphorylation of IRS-1 and Akt, was observed in the liver and adipose tissue of wild-type and obese mice overexpressing CTRP12. On the other hand, CTRP13 is largely expressed by cells of the stromal vascular compartment in adipose tissue and has sexually dimorphic expression pattern. Functional studies 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 pathway that impairs insulin signaling. Further, CTRP13 reduces glucose output in hepatocytes by inhibiting the expression of gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C). These results provided the first functional characterizations of CTRP12 and CTRP13 and established their importance in energy homeostasis.