2031-LB: Serotonin Is a Novel Player in Selective Hepatic Insulin Resistance

• Published in: Diabetes (New York, N.Y.) Vol. 73; p. 1
• Main Authors: Nam, Jung Eun, Hwang, Inseon, Choi, Won-Il, Lee, Minju, Choi, Wongun, Choi, Wonsuk, Moon, Young-Ah, Kim, Hail
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2024
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Calcium (intracellular); Cell activation; Cyclic AMP response element-binding protein; Fatty liver; Glucagon; Gluconeogenesis; Hepatocytes; Homeostasis; Injection; Insulin resistance; Intracellular signalling; Lipogenesis; Liver; Molecular modelling; Phosphorylation; Portal vein; Serotonin; Signal transduction; Steatosis; Sterol regulatory element-binding protein
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-2031-LB

Insulin is known to induce lipogenesis and inhibit gluconeogenesis in the liver. Therefore, hepatic lipogenesis is supposed to be downregulated in insulin resistance, but, in reality, hepatic lipogenesis is paradoxically upregulated. Recently, Serotonin (5-HT) has been implicated in both hepatic lipogenesis and gluconeogenesis. However, the molecular mechanism and the potential crosstalk between 5-HT and insulin signaling pathways have not been explored yet. Here, we investigated the multifaceted roles of 5-HT in the liver which may provide new insights into the complex regulatory networks governing hepatic glucose and lipid homeostasis. AML-12 cells were incubated with 5-HT in the presence or absence of various inhibitors. Signaling pathways were explored in liver specific Htr2a (HTR2ALKO), Htr2b (HTR2BLKO), Insr (LIRKO) and both Htr2a and Insr (HTR2A/IRLKO) knockout mice after injection of 5-HT or insulin via portal vein. In AML-12 cells, 5-HT activates AKT phosphorylation through PI3K and intracellular calcium flux resulting in the activation of SREBP-1c. Direct injection of 5-HT through portal vein induced activation of AKT and SREBP-1c, which were diminished specifically in HTR2ALKO mice. When the hepatic insulin signaling was inhibited by LIRKO or S961, 5-HT induced AKT phosphorylation but insulin could not. According to HFD fed condition, weight and size of liver and hepatic steatosis are decreased in HTR2A/IRLKO mice, comparing LIRKO mice. In terms of gluconeogenesis, 5-HT phosphorylates CREB via HTR2B which was mediated by PKG, not by PKA and 5-HT injection could not induce CREB activation in HTR2BLKO mice. These results suggest that during insulin resistance 5-HT can increase both lipogenesis and gluconeogenesis in the liver via HTR2A-PI3K-AKT-SREBP1c signaling and HTR2B-PKG-CREB signaling, respectively. Therefore, the selective hepatic insulin resistance could be attributed to the 5-HT induced activation of lipogenesis and gluconeogenesis, independently from insulin and glucagon.