Loss of CTRP1 disrupts glucose and lipid homeostasis

Abstract

C1q/TNF-related protein 1 (CTRP1) is a conserved plasma protein of the C1q family with notable metabolic and cardiovascular functions. We have previously shown that CTRP1 infusion lowers blood glucose and that transgenic mice with elevated circulating CTRP1 are protected from diet-induced obesity and insulin resistance. Here, we used a genetic loss-of-function mouse model to address the requirement of CTRP1 for metabolic homeostasis. Despite similar body weight, food intake, and energy expenditure, Ctrp1 knockout (KO) mice fed a low-fat diet developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1 KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter glucose transporter 4 levels and AMP-activated protein kinase activation. Loss of CTRP1 enhanced the clearance of orally administered lipids but did not affect intestinal lipid absorption, hepatic VLDL-triglyceride export, or lipoprotein lipase activity. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1 KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet to induce obesity, Ctrp1 KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue; these phenotypes were linked to elevated FGF-21 levels. Due in part to increased hepatic AMP-activated protein kinase activation and reduced expression of lipid synthesis genes, Ctrp1 KO mice fed a high-fat diet also had reduced liver and serum triglyceride and cholesterol levels. Taken together, these results provide genetic evidence to establish the significance of CTRP1 to systemic energy metabolism in different metabolic and dietary contexts.

Myonectin deletion promotes adipose fat storage and reduces liver steatosis

“…It is known that female mice on a C57BL/6 genetic background are much less susceptible to diet-induced obesity (75,76). Many studies (77), including our previous studies (54)(55)(56) and the present study, reinforce the importance of sex as a biologic variable that can influence the impact and phenotypic outcomes of a given genotype. Intriguingly, although our current study and previous findings (62) do not support a major role for myonectin in regulating glucose metabolism, recent reports suggest that circulating myonectin in human blood is correlated with insulin resistance, impaired glucose metabolism, and type 2 diabetes (60,61).…”

Late‐onset renal hypertrophy and dysfunction in mice lacking CTRP1

“…These data indicate that late‐onset renal hypertrophy in Ctrp1 ‐KO mice fed a control LFD is associated with aging and not overt renal injury (eg, diabetic nephropathy, renal fibrosis, and inflammation). We previously showed that Ctrp1 ‐KO mice fed an LFD also develop fatty liver . Although the link between liver steatosis and glomerular hypertrophy is unclear, we cannot rule out the possibility that kidney enlargement in aged CTRP1‐deficient animals is indirectly due to metabolic dysfunction in the liver.…”

“…7 In vivo studies using recombinant protein infusion or genetic gain-and loss-offunction mouse models have established CTRP1's role in regulating systemic glucose and lipid metabolism. 14,19,24 Correlative human studies also support a role for CTRP1 as an adipokine with cardio-metabolic function. Elevated plasma levels of CTRP1 are found in patients with type 2 diabetes and metabolic syndrome, [41][42][43][44][45] non-alcoholic fatty liver disease, 46 coronary artery and heart disease, 33,[47][48][49][50][51] and hypertension.…”

“…The Ctrp1/C1qtnf1 KO (−/−) mice generated for this study were previously described. 19 Both wild-type (WT) and knockout (KO) mice are on C57BL6/J genetic background. All Ctrp1-KO (−/−) and WT (+/+) littermate controls were generated by intercrossing Ctrp1 heterozygous (+/−) mice.…”

“…Our efforts to identify novel regulators of metabolism have led to the identification and characterization of C1q/TNF-related proteins (CTRP1-15), secreted proteins of the C1q family conserved from fish to human. [6][7][8] In vivo animal studies highlight important metabolic, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] cardiovascular, [26][27][28][29][30][31][32][33][34][35][36] and inflammatory 12,13,[37][38][39][40] functions for multiple family members.…”