Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway

Abstract

Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes. Diabetes: Signalling pathway interactions regulated by melatoninThe identification of a fundamental signalling process regulated by melatonin that can prevent excessive liver glucose metabolism during diabetes may offer a novel therapeutic approach. Both fasting and diabetic states trigger the elevation of a particular signalling pathway that significantly increases liver glucose metabolism, or 'hepatic gluconeogenesis', resulting in a rise in blood sugar levels. In experiments on mouse models and human patients, Yong Deuk Kim at Kyungpook National University in Daegu, South Korea, and co-workers have demonstrated that the hormone melatonin plays a vital role in suppressing hepatic gluconeogenesis. Melatonin upregulates another signaling cascade involving a stress regulation protein called sestrin-2 and its associated regulatory protein, SHP. The upregulation of SHP by melatonin repressed genes that are involved in gluconeogenesis, both in diabetic mice and in the human liver.