Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish

Abstract

Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.leptin | zebrafish | glucose homeostasis | adipostasis T he hormone leptin was identified in mammalian adipocytes (1) and well characterized in mice and humans as an adipostatic hormone. It is secreted into the serum in proportion to adipose mass and homeostatically regulates adipose mass primarily via binding to a distinct leptin receptor expressed in behavioral, endocrine, and autonomic control circuits in the central nervous system (2, 3). Failure of leptin signaling, due to mutations in leptin or leptin receptor genes, results in hyperphagia and hypometabolism to produce extreme obesity, diabetes, and infertility. Leptin and leptin receptor are highly conserved across mammalian species. Mouse and human leptin proteins are 83% identical, and leptin receptor proteins are 75% identical. However, the mammalian leptin and leptin receptor amino acid sequences are less well conserved with those of lower vertebrates. Indeed, the use of primary sequence homology failed to identify the leptin gene in fish or birds; chromosomal synteny was ultimately used to identify the gene in these vertebrate classes (4). For example, the zebrafish leptin protein is only 19% identical to the human protein.Although the amino acid sequences are divergent, the basic structural features and intracellular signaling mechanisms of leptin and its receptor appear to be conserved throughout vertebrates (4). Furthermore, administration of mammalian leptin in birds...

Control of leptin by metabolic state and its regulatory interactions with pituitary growth hormone and hepatic growth hormone receptors and insulin like growth factors in the tilapia ( Oreochromis mossambicus )

“…Similar to reports in other fishes (Froiland et al, 2012; Michel et al, 2016), leptin does not appear to serve as an adipostat in tilapia, since neither hepatic gene expression nor circulating hormone correlate with hepatic energy stores as measured by HSI (Fig. 1) or with peritoneal fat, which changed little over 3-weeks of food deprivation in the present investigation (data not shown).…”

The leptin system and its expression at different nutritional and pregnant stages in lined seahorse (Hippocampus erectus)

“…These results demonstrate that the function of leptin at the peripheral tissues as a paracrine/autocrine factor is capable of modifying energy metabolism. In zebrafish, a leptin receptor knockout study showed that leptin played a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence (Michel et al, 2016). …”

The Neuroendocrine Regulation of Food Intake in Fish: A Review of Current Knowledge

“…In topmouth culter Culter alburnus (Cyprinoforme), leptin mRNA expression is lower in wild populations, who have more muscle fat content than cultured fish (Wang et al, 2013), in grass carp, fish fed high fat diets have higher leptin expression (Li A. et al, 2016) than control fish, and in medaka, leptin receptor null-mutants have higher food intake and larger deposits of visceral fat than that of wild-type fish (Chisada et al, 2014), suggesting a correlation between leptin levels and fat. However, results from other studies seem to contradict this hypothesis: leptin receptor null adult zebrafish do not exhibit increased feeding or adiposity (Michel et al, 2016); In rainbow trout, leptin levels are higher in lean fish than fat fish (Salmeron et al, 2015; Johansson et al, 2016; Pfundt et al, 2016), and in Arctic charr, neither hepatic leptin expression nor plasma leptin levels correlate with fish adiposity (Froiland et al, 2012; Jørgensen et al, 2013); In murray cod Maccullochella peelii peelii (Perciforme), fish fed different experimental diets containing fish oil with or without vegetable oil have similar leptin levels (Ettore et al, 2012; Varricchio et al, 2012); In yellow catfish (Siluriforme), IP injections of human leptin reduce hepatic lipid content and the activities of lipogenic enzymes (Song et al, 2015) but Zn deficiency, which tends to increase hepatic and muscle lipid contents, does not affect leptin mRNA levels (Zheng et al, 2015). …”