Introduction

C1q/TNF-related proteins (CTRP) are a family of secreted proteins [1]. The protein structures of the CTRP family are similar to that of adiponectin [2]. CTRP1, a 281 amino acids-glycoprotein, is an important adipokine closely related to metabolic and inflammatory pathways [3, 4]. CTRP1 is expressed in adipose, placenta, and many other tissues [2, 5, 6]. In clinical research, serum CTRP1 level was higher in metabolic syndrome and type II diabetes (T2DM) patients [7,8,28], which may cause different effects of CTRP1 on the appetite. More study is needed to investigate the mechanism of CTRP1 in appetite regulation and the causal relation between leptin and obesity after CTRP1 treatment.

CTRP1 significantly prevented the development of adipose hypertrophy and hepatic steatosis in HFD-fed mice (Fig. 2D, 3A), but it did not considerably lose weight in obese mice (Fig. 6G). The phosphorylation of AKT was upregulated in EWAT after CTRP1 treatment but not in the liver (Fig. 10B, E). Previous studies also observed controversial evidence between glucose metabolism and lipid clearance in Ctrp1 KO mice and transgenic mice: Ctrp1 transgenic mice maintained better glucose homeostasis and lipid homeostasis via AMPK and AKT pathways [13, 14]. Knockout of CTRP1 impaired glucose homeostasis and caused liver steatosis in LFD-fed mice [16]. However, the knockout of CTPR1 improved the lipid metabolism of HFD-fed mice, which may result from the up-regulation of Scd1, Cd36, and Pparγ [16]. We also found that some lipogenesis genes (Acly, Fas, Elovl6, and Pparγ1) were up-regulated in our study (Fig. 9A). In addition, the protein level of GLUT4, AMPK, and phosphorylation level of AMPK was decreased in skeletal muscle of LFD-fed CTRP1 KO mice, but phosphorylation level of AMPK was up-regulated in the liver in HFD-fed Ctrp1 KO mice [16]. These results suggested that the functions of CTRP1 in regulating lipid metabolism were various in different animal models and pathological statuses.

Hydrodynamic gene delivery of CTRP1 gene generated long-term anti-diabetic effects and beneficial effects in preventing HFD-induced obesity and fatty liver, indicating that CTRP1 has the therapeutic potential in maintaining glucose homeostasis and treating obesity-related metabolic disorders. However, the molecular mechanisms and clear signaling pathways of CTRP1 in preventing obesity, glucose tolerance, and fatty liver remain unclear, as well as the underlying mechanisms of CTRP1 in regulating food intake, inflammation, and thermogenesis. Further studies are needed to investigate the mechanisms of CTRP1 in regulating metabolic homeostasis and appetite. Moreover, the hydrodynamic injection strategy is a physical method of gene delivery to the liver [13, 14, 29]. The overexpressed CTRP1 protein can secrete into the blood and distribute to multiple tissues. CTRP1 was associated with adverse cardiovascular events [30] and was reported to prevent pathological vascular remodeling [31]. CTRP1 also prevented cardiac and renal disease [32, 33]. Further studies are needed to investigate the function of CTRP1 in different animal models, as well as the long-term effects and side effects of CTRP1 in multiple organs, such as cardiovascular systems, bone, muscle, and neurometabolic systems. This will help us better to understand its mechanism at deeper levels.

Conclusion

This study demonstrates that the hydrodynamic injection of CTRP1 improves glucose homeostasis and prevents HFD-induced obesity, adipose hypertrophy, and fatty liver due to upregulated energy expenditure, thermogenesis, lipolysis, and reduced inflammation and food intake. The beneficial effects of CTRP1 are related to modulation of the activity of AMPK, AKT, and upregulation of leptin, suggesting CTRP1 may serve as a target in treating metabolic diseases, as well as the potential use of CTRP1 by gene transfer for the treatment of metabolic diseases.