Glucose-dependent regulation of hepatic adipsin controls glucose uptake and tolerance

Complement factor D, also known as adipsin, is produced by adipose tissue, and the liver that links metabolic regulation with innate immunity. Despite its established systemic functions, the regulation of hepatic adipsin expression and its contribution to metabolic disease remain poorly defined. Here, we show that hepatic adipsin protein abundance is markedly increased in individuals with type 2 diabetes (T2D), and positively correlates with glycated hemoglobin, despite unchanged mRNA expression. Concordantly, hepatic adipsin protein levels were elevated in multiple murine models of hyperglycemia, including type 1 diabetes (T1D), T2D, and following fasting-refeeding transitions. In cultured hepatocytes, glucose exposure induced a rapid, dose-dependent increase in adipsin protein without altering transcript abundance, demonstrating post-transcriptional regulation. Mechanistically, glucose stimulates adipsin translation via dephosphorylation of eukaryotic initiation factor 2 (eIF2), and activation of the mammalian target of rapamycin, mediated by the 5' untranslated region of adipsin mRNA. Functionally, hepatocyte-specific depletion of adipsin impaired postprandial glucose tolerance, with reduced glucose uptake and a marked downregulation of glucose transporter type 2 (GLUT2). Taken together, these findings identify hepatic adipsin as a glucose-responsive translational target that couples nutrient availability to metabolic adaptation, revealing a new layer of regulation with potential relevance to diabetes pathogenesis. HighlightsO_LIHepatic adipsin protein increases in type 2 diabetes and correlates with glycemic status independent of mRNA expression. C_LIO_LIGlucose induces adipsin translation through eIF2 dephosphorylation and mTOR activation. C_LIO_LImTOR controls adipsin synthesis via structured 5'UTR of adipsin mRNA. C_LIO_LILiver-specific adipsin depletion impairs post-prandial glucose tolerance by downregulating GLUT2. C_LIO_LIHepatic adipsin acts as a glucose-responsive effector of glycemic control. C_LI