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 )

Abstract

Leptin is an important cytokine for regulating energy homeostasis, however, relatively little is known about its function and control in teleost fishes or other ectotherms, particularly with regard to interactions with the growth hormone (GH)/insulin-like growth factors (IGFs) growth regulatory axis. Here we assessed the regulation of LepA, the dominant paralog in tilapia (Oreochromis mossambicus) and other teleosts under altered nutritional state, and evaluated how LepA might alter pituitary growth hormone (GH) and hepatic insulin-like growth factors (IGFs) that are known to be disparately regulated by metabolic state. Circulating LepA, and lepa and lepr gene expression increased after 3-weeks fasting and declined to control levels 10 days following refeeding. This pattern of leptin regulation by metabolic state is similar to that previously observed for pituitary GH and opposite that of hepatic GHR and/or IGF dynamics in tilapia and other fishes. We therefore evaluated if LepA might differentially regulate pituitary GH, and hepatic GH receptors (GHRs) and IGFs. Recombinant tilapia LepA (rtLepA) increased hepatic gene expression of igf-1, igf-2, ghr-1, and ghr-2 from isolated hepatocytes following 24 h incubation. Intraperitoneal rtLepA injection, on the other hand, stimulated hepatic igf-1, but had little effect on hepatic igf-2, ghr1, or ghr2 mRNA abundance. LepA suppressed GH accumulation and gh mRNA in pituitaries in vitro, but had no effect on GH release. We next sought to test if abolition of pituitary GH via hypophysectomy (Hx) affects the expression of hepatic lepa and lepr. Hypophysectomy significantly increases hepatic lepa mRNA abundance, while GH replacement in Hx fish restores lepa mRNA levels to that of sham controls. Leptin receptor (lepr) mRNA was unchanged by Hx. In in vitro hepatocyte incubations, GH inhibits lepa and lepr mRNA expression at low concentrations, while higher concentration stimulates lepa expression. Taken together, these findings indicate LepA gene expression and secretion increases with fasting, consistent with the hormones function in promoting energy expenditure during catabolic stress. It would also appear that LepA might play an important role in stimulating GHR and IGFs to potentially spare declines in these factors during catabolism. Evidence also suggests for the first time in teleosts that GH may exert important regulatory effects on hepatic LepA production, insofar as physiological levels(0.05–1 nM) suppresse lepa mRNA accumulation. Leptin A, may in turn exert negative feedback effects on basal GH mRNA abundance, but not secretion.

Assessing the Functional Role of Leptin in Energy Homeostasis and the Stress Response in Vertebrates

“…The lipid regulatory activity of heterologous leptin on hepatocytes and ovarian follicular cells of yellow catfish ( P. fulvidraco ) is attenuated by JAK/STAT inhibitors, reiterating a role for this pathway in leptin signaling (39). Leptin has also been shown to act on the pituitary of tilapia ( O. mossambicus ) to stimulate prolactin (PRL) release through activation of the extracellular signal-related kinase (ERK) pathway (40) and on the liver of the hybrid striped bass [ Morone chrysops x Morone saxatilis (41)] and Mozambique tilapia [ O. mossambicus (42)] to regulate growth hormone (GH) receptors and insulin-like growth factors (IGFs), although the signaling pathways have yet to be determined. Albeit studies assessing the function of leptin in teleosts are limited, existing data suggest that the sites of leptin action and the signaling pathways responsible for eliciting its effects may be conserved with that of other vertebrate systems.…”

“…This mutant line showed consistently elevated hypothalamic activity of orexigenic neuropeptides, suppression of anorexigenic neuropeptides, and increased food intake, suggesting a similar regulatory role for leptin in appetite suppression in fishes. While the anorexigenic properties of leptin would also suggest potentially concurrent lipostatic properties as seen in mammals, no changes in adiposity were observed in leptin receptor-deficient strains of zebrafish (62), and other species exhibit inconsistent correlations between fat deposition and leptin expression, e.g., during fasting leptin rises in fish as adiposity declines, while it declines with fasting and lipid stores in mammals (38, 42, 63–65). Nonetheless, the anorexigenic properties of leptin appear well conserved among vertebrates.…”

“…No changes in circulating cortisol were observed in leptin-injected goldfish [ C. auratus (59)]; however, it is possible that leptin only inhibits glucocorticoid production when the HPI axis has been activated and circulating cortisol levels are elevated. In general, we do know that teleost pituitary glands are responsive to leptin (6, 26, 40, 42), and as such, it has been postulated that leptin may regulate the stress axis at the level of the pituitary (6, 113). …”

“…The preponderance of evidence in teleosts, however, points to fasting-induced increases in leptin synthesis and secretion (23, 42, 58, 72, 115, 116); albeit evidence in two species, the hybrid striped bass ( M. chrysops x M. saxatilis ) and red-bellied piranha ( Pygocentrus nattereri ) show that production of the hormone may decline with fasting (10, 117). The general increase in leptin during fasting found in most teleosts presents a functional paradox between the role of leptin as an anorexigenic endocrine signal and the drive to increase food intake during fasting.…”

“…Elevated leptin stimulates Na + retention and induces hypertension in rats and may be associated with hypertension induced kidney disease in humans (124). Few studies have investigated the role of leptin in osmoregulation in teleost fishes, despite its regulatory interactions with GH, IGFs, and PRL, hormones known to control salt and water balance (26, 40–42). In the Mozambique tilapia ( O. mossambicus ), acute seawater transfer induced significant increases in hepatic lepa and lepr mRNA levels (71).…”