Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

Abstract

Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

“…Samples were washed with ice-cold ethanol twice. The glycogen pellets were resuspended in distilled water and analyzed with a ␤-counter, as described previously (14).…”

Energy Homeostasis by the Peripheral Serotonergic System

“…Furthermore, serotonin inhibits glycogen synthesis at micromolar concentrations but stimulates it at nanomolar concentrations in hepatocytes [22]. Thus, there are several reports on the control of hepatic glucose uptake by serotonin.…”

Role of Serotonin in the Regulation of Respiration and Bile Secretory Function of the Liver

“…Слід відзначити, що із семи родин серотонінових рецепторів у різних клітинних популяціях печінки найбільш інтенсивно експресуються 5-НТ 2 -рецепто-ри, які опосередковують вплив аутокоїда на метаболічні та регенеративні процеси в тканині цього органа [6][7][8][9]. Нині більшість досліджень гепатотропних ефектів серото-ніну спрямовані на з'ясування його дії на регенерацію і канцерогенез у печінковій тканині [10].…”

“…Як зазначалось вище, із семи родин серо-тонінових рецепторів, виявлених у печінці, найбільш інтенсивно експресуються і, до того ж, опосередковують дію серотоніну на мета-болічні процеси в залозі 5-НТ 2 -рецептори [6,9]. Тому ми вирішили з'ясувати їхню роль у реалізації стимулювальної дії серотоніну на тканинне дихання печінки.…”