Glucagon regulation of carbohydrate metabolism in rainbow trout: in vivo glucose fluxes and gene expression

Abstract

Glucagon increases fish glycemia, but how it affects glucose fluxes in vivo has never been characterized. The goal of this study was to test the hypothesis that glucagon stimulates hepatic glucose production (Ra) and inhibits disposal (Rd) of rainbow trout. Changes in the mRNA abundance of key proteins involved in glycolysis, gluconeogenesis, and glycogen breakdown were also monitored. Results show that glucagon increases glycemia (+38%) by causing a temporary mismatch between Ra and Rd before both fluxes converge below baseline (-17%). A novel aspect of the regulation of trout gluconeogenesis is also demonstrated: the completely different effects of glucagon on the expression of three Pepck isoforms (stimulation of pck1, inhibition of pck2a, and no response of pck2b). Glycogen phosphorylase was modulated differently among tissues, and muscle upregulated pygb and downregulated pygm. Glucagon failed to activate the cAMP-dependent protein kinase or FoxO1 signalling cascades. We conclude that trout hyperglycemia results from the combination of two responses: (i) an increase in Ra glucose induced by the stimulation of gluconeogenesis through transcriptional activation of pck1 (and possibly glycogen phosphorylase), and (ii) a decrease in Rd glucose via inhibition of glycogen synthase and glycolysis. The observed decrease in glucose fluxes after 4 h of glucagon administration may be caused by a counterregulatory response of insulin, potentially linked to the decrease in pygm transcript abundance. Overall, however, these integrated effects of glucagon only lead to modest changes in glucose fluxes that partly explain why trout seem to be unable to control glycemia very tightly.

Glucagon Promotes Gluconeogenesis through the GCGR/PKA/CREB/PGC-1α Pathway in Hepatocytes of the Japanese Flounder Paralichthys olivaceus

“…In the present study, in vitro incubation with glucagon activated gluconeogenesis and induced glucose production in hepatocytes of the Japanese flounder. In line with the present study, bovine glucagon intraperitoneally injected in blunt snout bream (Megalobrama amblycephala) and infused in rainbow trout increased the hepatic glucose production and the mRNA levels of gluconeogenesis-related genes [36,37]. Earlier studies concerning the glucagon signaling pathway in fish found that bovine glucagon bound GCGR (by measuring the radioactivity of hepatocyte-bound 125 I-labelled glucagon) and increased PKA activity in American eels (Anguilla rostrata) and brown bullheads (Ictalurus nebulosus) hepatocytes [38,39].…”

Effects of Adiponectin on Glucose Metabolism in the Hepatopancreas of Grass Carp (Ctenopharyngodon idella)

“…Carbohydrates are important ingredients in the diets of cultivated fish due to supplying energy at low cost and improving physical quality of feed. The endocrine regulatory network of glucose metabolism in fish has not been sufficiently elucidated, although the roles of pancreatic hormones insulin and glucagon in the glucose homeostasis of fish has been extensively explored [28][29][30]. Adiponectin and leptin are two major members of adipokines, which have a profound influence on insulin sensitivity and energy balance in mammals [31].…”

Metabolic Plasticity of Gilthead Seabream Under Different Stressors: Analysis of the Stress Responsive Hepatic Proteome and Gene Expression

“…It diffuses through the cell plasma membrane, binds to the glucocorticoid receptor (GR) and then translocates into the nucleus to induce the expression of gluconeogenic genes (Teles et al, 2013). Binding of other transcriptional regulators to these gene promoters is required to activate their transcription, such as those mediated by the hormone glucagon via a complex series of enzymatic reactions (Forbes et al, 2019). Plasma cortisol levels of fish handled 4 times a week (NET4 group from NET trial), published in another work (Raposo de Magalhães et al, 2020b), were significantly increased when compared with control fish.…”