Endocrinology · 2026
Hepatic translational rewiring in insulin deficiency identifies Reg3α as an insulin-independent glucoregulatory factor.
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D S Teixeira Pryscila, Vincent Sarah Mathilda, Meurs Romane, Ursino Gloria, Zahoran Szabolcs, Lucibello Giulia, M Authiat Marcella, Gavin Anne-Claude, Ramadori Giorgio, Coppari Roberto
Аннотация
CONTEXT: Insulin deficiency (ID) causes severe metabolic defects and death if untreated, while insulin therapy does not fully restore metabolic homeostasis. Leptin therapy corrects metabolic abnormalities and promotes survival in rodents unable to produce insulin, suggesting the existence of insulin-independent glucoregulatory mechanisms.
OBJECTIVE: To characterize hepatic translational remodeling in severe insulin deficiency and determine whether leptin-responsive translational changes can reveal novel glucoregulatory factors.
METHODS: We used mice with diphtheria toxin-induced pancreatic β-cell ablation, resulting in severe ID. We assessed hepatic translation by polysome profiling, ribosome profiling (Ribo-seq), and RNA sequencing. To identify leptin-responsive hepatic factors, we compared the hepatic translatome during intracerebroventricular leptin treatment and following leptin withdrawal. Regenerating islet-derived protein 3 alpha (Reg3α) was subsequently overexpressed in the liver of ID mice to assess its metabolic effects.
RESULTS: ID suppresses hepatic mechanistic target of rapamycin complex 1 (mTORC1) signaling and global protein synthesis while extensively remodeling the hepatic translatome. Translation of anabolic and glucose-metabolism pathways is reduced, whereas transcripts involved in lipid metabolism are selectively enhanced. Leptin treatment markedly increases hepatic Reg3α translation. Hepatic Reg3α overexpression significantly improves hyperglycemia in ID mice without altering insulin-stimulated AKT phosphorylation in key metabolic tissues. These findings identify hepatic translational rewiring as an important feature of ID and Reg3α as an insulin-independent glucoregulatory factor.
OBJECTIVE: To characterize hepatic translational remodeling in severe insulin deficiency and determine whether leptin-responsive translational changes can reveal novel glucoregulatory factors.
METHODS: We used mice with diphtheria toxin-induced pancreatic β-cell ablation, resulting in severe ID. We assessed hepatic translation by polysome profiling, ribosome profiling (Ribo-seq), and RNA sequencing. To identify leptin-responsive hepatic factors, we compared the hepatic translatome during intracerebroventricular leptin treatment and following leptin withdrawal. Regenerating islet-derived protein 3 alpha (Reg3α) was subsequently overexpressed in the liver of ID mice to assess its metabolic effects.
RESULTS: ID suppresses hepatic mechanistic target of rapamycin complex 1 (mTORC1) signaling and global protein synthesis while extensively remodeling the hepatic translatome. Translation of anabolic and glucose-metabolism pathways is reduced, whereas transcripts involved in lipid metabolism are selectively enhanced. Leptin treatment markedly increases hepatic Reg3α translation. Hepatic Reg3α overexpression significantly improves hyperglycemia in ID mice without altering insulin-stimulated AKT phosphorylation in key metabolic tissues. These findings identify hepatic translational rewiring as an important feature of ID and Reg3α as an insulin-independent glucoregulatory factor.