Evolution of the glucagon-like system across fish.

In fishes, including the jawless lampreys, the most ancient lineage of extant vertebrates, plasma glucose levels are highly variable and regulation is more relaxed than in mammals. The regulation of glucose and lipid in fishes in common with mammals involves members of the glucagon (GCG)-like family of gastrointestinal peptides. In mammals, four peptides GCG, glucagon-like peptide 1 and 2 (GLP1 and GLP2) and glucose-dependent insulinotropic peptide (GIP) that activate four specific receptors exist. However, in lamprey and other fishes the glucagon-like family evolved differently and they retained additional gene family members (glucagon-related peptide, gcrp and its receptor, gcrpr) that are absent from mammals. In the present study, we analysed the evolution of the glucagon-like system in fish and characterized gene expression of the family members in the European sea bass (Dicentrarchus labrax) a teleost fish. Phylogenetic analysis revealed that multiple receptors and peptides of the glucagon-like family emerged early during the vertebrate radiation and evolved via lineage specific events. Synteny analysis suggested that family member gene loss is likely to be the result of a single gene deletion event. Lamprey was the only fish where a putative glp1r persisted and the presence of the receptor gene in the genomes of the elephant shark and coelacanth remains unresolved. In the coelacanth and elephant shark, unique proglucagon genes were acquired which in the former only encoded Gcg and Glp2 and in the latter, shared a similar structure to the teleost proglucagon gene but possessed an extra exon coding for Glp-like peptide that was most similar to Glp2. The variable tissue distribution of the gene transcripts encoding the ligands and receptors of the glucagon-like system in an advanced teleost, the European sea bass, suggested that, as occurs in mammals, they have acquired distinct functions. Statistically significant (p < .05) down-regulation of teleost proglucagon a in sea bass with modified plasma glucose levels confirmed the link between these peptides and metabolism. The tissue distribution of members of the glucagon-like system in sea bass and human suggests that evolution of the brain-gut-peptide regulatory loop diverged between teleosts and mammals despite the overall conservation and similarity of glucagon-like family members.

STC1 and PTHrP Modify Carbohydrate and Lipid Metabolism in Liver of a Teleost Fish.

Stanniocalcin 1 (STC1) and parathyroid hormone-related protein (PTHrP) are calciotropic hormones in vertebrates. Here, a recently hypothesized metabolic role for these hormones is tested on European sea bass treated with: (i) teleost PTHrP(1-34), (ii) PTHrP(1-34) and anti-STC1 serum (pro-PTHrP groups), (iii) a PTHrP antagonist PTHrP(7-34) or (iv) PTHrP(7-34) and STC1 (pro-STC1 groups). Livers were analysed using untargeted metabolic profiling based on proton nuclear magnetic resonance (1H-NMR) spectroscopy. Concentrations of branched-chain amino acid (BCAA), alanine, glutamine and glutamate increased in pro-STC1 groups suggesting their mobilization from the muscle to the liver for degradation and gluconeogenesis from alanine and glutamine. In addition, only STC1 treatment decreased the concentrations of succinate, fumarate and acetate, indicating slowing of the citric acid cycle. In the pro-PTHrP groups the concentrations of glucose, erythritol and lactate decreased, indicative of gluconeogenesis from lactate. Taurine, trimethylamine, trimethylamine N-oxide and carnitine changed in opposite directions in the pro-STC1 versus the pro-PTHrP groups, suggesting opposite effects, with STC1 stimulating lipogenesis and PTHrP activating lipolysis/ß-oxidation of fatty acids. These findings suggest a role for STC1 and PTHrP related to strategic energy mechanisms that involve the production of glucose and safeguard of liver glycogen reserves for stressful situations.