C1q/TNF-related Protein-3 (CTRP3), a Novel Adipokine That Regulates Hepatic Glucose Output

Jonathan M Peterson,Zhikui Wei,G William Wong

doi:10.1074/jbc.m110.180695

Abstract

Adipose tissue-derived adipokines play important roles in controlling systemic insulin sensitivity and energy balance. Our recent efforts to identify novel metabolic mediators produced by adipose tissue have led to the discovery of a highly conserved family of secreted proteins, designated as C1q/TNF-related proteins 1-10 (CTRP1 to -10). However, physiological functions regulated by CTRPs are largely unknown. Here we provide the first in vivo functional characterization of CTRP3. We show that circulating levels of CTRP3 are inversely correlated with leptin levels; CTRP3 increases with fasting, decreases in diet-induced obese mice with high leptin levels, and increases in leptin-deficient ob/ob mice. A modest 3-fold elevation of plasma CTRP3 levels by recombinant protein administration is sufficient to lower glucose levels in normal and insulin-resistant ob/ob mice, without altering insulin or adiponectin levels. The glucose-lowering effect in mice is linked to activation of the Akt signaling pathway in liver and a marked suppression of hepatic gluconeogenic gene expression. Consistent with its effects in mice, CTRP3 acts directly and independently of insulin to regulate gluconeogenesis in cultured hepatocytes. In humans, alternative splicing generates two circulating CTRP3 isoforms differing in size and glycosylation pattern. The two human proteins form hetero-oligomers, an association that does not require interdisulfide bond formation and appears to protect the longer isoform from proteolytic cleavage. Recombinant human CTRP3 also reduces glucose output in hepatocytes by suppressing gluconeogenic enzyme expression. This study provides the first functional evidence linking CTRP3 to hepatic glucose metabolism and establishes CTRP3 as a novel adipokine.

Highlights

Consistent with its effect in mice, CTRP3 acts independently of insulin to reduce glucose output in rat H4IIE hepatocytes by suppressing the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in gluconeogenesis
No differences were observed in the circulating levels of CTRP3 when mice were fed a high or low fat diet for 9 weeks (Fig. 1A), we observed a significant decrease in the serum levels of CTRP3 in mice fed a high fat diet for 12 weeks (Fig. 1B)
A 2-fold increase in plasma levels of adiponectin is sufficient to ameliorate many metabolic abnormalities associated with insulin resistance and/or diabetes in various animal models (25, 36 –39)

Summary

Introduction

We show that recombinant mouse CTRP3 administration lowered blood glucose in both normal and insulin-resistant ob/ob mice, an effect linked to activation of the Akt signaling pathway and a marked suppression of gluconeogenic gene expression in mouse liver. Recombinant Protein Administration Reduces Blood Glucose Levels—To address the potential metabolic function of CTRP3, we purified recombinant protein from the supernatant of HEK 293 mammalian cells overexpressing CTRP3 (Fig. 2A) and evaluated its in vivo effect when administered to mice.

Results

Conclusion