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.

Hepatic adipsin expression was examined in liver biopsies from non-diabetic individuals and patients with type 2 diabetes (T2D), in murine models of type 1 diabetes (T1D) and T2D, during the fasted-to-fed transition, and in primary hepatocytes exposed to glucose. Translational regulation was assessed by glucose stimulation and pharmacological inhibition of mTOR signaling. Hepatocyte-specific adipsin knockdown was performed using liver-targeted shRNA to determine its metabolic function.

We show that hepatic adipsin protein abundance is markedly increased in individuals with type 2 diabetes, 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), type 2 diabetes (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 2α (eIF2α), 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).

These findings identify hepatic adipsin as a glucose-responsive translational target that couples nutrient availability to metabolic adaptation, revealingpreviously unrecognised regulation with potential relevance to diabetes pathogenesis.