Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold

• Published in: Metabolism, clinical and experimental clinical and experimental, 2024-08, Vol.157, p.155940, Article 155940
• Main Authors: Morgan, Henrique J.N., Delfino, Heitor B.P., Schavinski, Aline Z., Malone, Samuel A., Charoy, Camille, Reis, Natany G., Assis, Ana P., Lautherbach, Natalia, Silveira, Wilian A., Heck, Lilian C., Guton, Dan, Domingos, Ana I., Kettelhut, Isis C., Montminy, Marc, Navegantes, Luiz C.C.
• Format: Article
• Language: English
• Subjects: Adrenergic Neurons - metabolism; Adrenergic Neurons - physiology; Animals; Calcium pathway; Cold Temperature; Cyclic AMP Response Element-Binding Protein - metabolism; Gluconeogenesis - physiology; Hepatic glucose production; Hepatocytes - metabolism; Liver; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Noradrenaline; Norepinephrine - metabolism; Signal Transduction - physiology; Sympathetic nervous system; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2024.155940

Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease. •Acute cold stress activates noradrenergic fibres in mouse liver, increasing blood glucose by activating gluconeogenesis.•Norepinephrine directly stimulates gluconeogenesis through the induction of PEPCK and G6Pase genes.•Norepinephrine operates through the CREB/CRTC2 pathway to activate gluconeogenesis in the liver.•Norepinephrine stimulates CREB/CRTC2 and gluconeogenesis program via induction of Ca2+-dependent signalling in hepatocytes.