Abstract
FAM3C, a member of FAM3 gene family, has been shown to improve insulin resistance and hyperglycemia in obese mice. This study further determined whether FAM3C functions as a hepatokine to suppress hepatic gluconeogenesis of type 1 diabetic mice. In STZ-induced type 1 diabetic mouse liver, the FAM3C-HSF1-CaM signaling axis was repressed. Hepatic FAM3C overexpression activated HSF1-CaM-Akt pathway to repress gluconeogenic gene expression and ameliorate hyperglycemia of type 1 diabetic mice. Moreover, hepatic HSF1 overexpression also activated CaM-Akt pathway to repress gluconeogenic gene expression and improve hyperglycemia of type 1 diabetic mice. Hepatic FAM3C and HSF1 overexpression had little effect on serum insulin levels in type 1 diabetic mice. In cultured hepatocytes, conditioned medium of Ad-FAM3C-infected cells induced Akt phosphorylation. Moreover, Akt activation and gluconeogenesis repression induced by FAM3C overexpression were reversed by the treatment with anti-FAM3C antibodies. Treatment with recombinant FAM3C protein induced Akt activation in a HSF1- and CaM-dependent manner in cultured hepatocytes. Furthermore, recombinant FAM3C protein repressed gluconeogenic gene expression and gluconeogenesis by inactivating FOXO1 in a HSF1-dependent manner in cultured hepatocytes. In conclusion, FAM3C is a new hepatokine that suppresses hepatic gluconeogenic gene expression and gluconeogenesis independent of insulin by activating HSF1-CaM-Akt pathway.
Highlights
Diabetes has become a severe worldwide epidemic affecting more than 400 million people [1]
To directly evaluate the effects of FAM3CHSF1-CaM pathway on hepatic gluconeogenesis and hyperglycemia of type 1 diabetic mice, FAM3C or heat shock factor 1 (HSF1) was overexpressed in STZ-treated mouse livers via tail vein injection of Ad-FAM3C or HSF1 plasmid
We provided new evidences that FAM3C activated HSF1-CaM-Akt pathway to repress hepatic gluconeogenic gene expression and attenuate hyperglycemia of type 1 diabetic mice
Summary
Diabetes has become a severe worldwide epidemic affecting more than 400 million people [1]. Excessive hepatic gluconeogenesis due to insulin resistance or insulin deficiency plays crucial roles in the development of diabetes [2]. Type 1 diabetes is mainly due to auto-immune-mediated pancreatic beta cell destruction, resulting in the deficiency of circulating insulin [3]. FOXO1 is the key transcriptor regulating gluconeogenesis, and it is phosphorylated and inactivated by insulin-mediated Akt activation in physiological condition [4]. Overactivation of hepatic FOXO1 due to insulin deficiency or insulin resistance will trigger excessive gluconeogenesis and hyperglycemia. It had been revealed that drugs that suppress hepatic gluconeogenesis help reduce blood glucose levels in type 1 diabetic patients. Identifying new genes or pathways that activate Akt to repress hepatic FOXO1 activity independent of insulin will shed light on the treatment of both type 1 and type 2 diabetes
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