Katarzyna Kirsz

Ghrelin-mediated appetite regulation in the central nervous system

The gut hormone and neuropeptide ghrelin was initially identified in the periphery as a compound released in the bloodstream in response to a negative energetic status. In the central nervous system (CNS), ghrelin mainly acts on the hypothalamus and the limbic system, with its best-known biological role being the regulation of appetitive functions. Recent research has shown that ghrelin is not an indispensable factor in the regulation of food intake. However, it plays a key role in the metabolic changes of lipids, mainly those involving hypothalamic NOS, AMPK, CaMKK2, CPT1 and UCP2 proteins. Ghrelin participates in the regulation of memory processes and the feeling of pleasure resulting from eating, both of which are metabolism-dependent and may be essential for the successful achievement of adaptive appetitive behavior. Ghrelin exerts its biological effect through a complicated network of neuroendocrine links, including the melanocortin and endocannabinoid systems. The activity of ghrelin is connected with circadian and annual fluctuations, which depend on seasons and food availability.

Effects of orexigenic peptides and leptin on melatonin secretion during different photoperiods in seasonal breeding ewes: An in vitro study

The pineal gland (PG) acts as a neuroendocrine transducer of daily and seasonal time through the nocturnal release of melatonin. Here, we examined the interaction of season, orexin, ghrelin, and leptin on melatonin secretion by pineal explants in short-term culture. Glands were collected after sunset from 12 ewes during long days (LD; April and May) and from an additional 12 ewes during short days (SD; October and November). Glands were transected sagittally into strips, with each equilibrated in 2.5 mL of Dulbeccos modified Eagles medium for 60 min, followed by a 2-h incubation in control medium or medium containing orexin B (10 and 100 ng/mL), ghrelin (10 and 100 ng/mL), or 50 ng/mL of leptin. After a 3-h incubation, some PG explants treated previously with lower doses of orexin or ghrelin were challenged with 50 ng/mL of leptin and those treated with both doses of orexin were challenged with 300 nM of the β-agonist isoproterenol. One milliliter of medium was harvested and replaced from each well every 30 min. Treatment with the low dose of orexin during LD increased melatonin secretion about 110% (P<0.01); treatment with a high dose increased melatonin secretion about 47% (P<0.001). During the SD period, leptin stimulated (P < 0.05) melatonin secretion slightly compared with mean melatonin concentration in controls. However, together, orexin and leptin depressed (P<0.01) melatonin secretion. Both doses of ghrelin reduced (P < 0.01) melatonin concentration during the SD season compared with control culture. Addition of ghrelin and leptin to culture medium increased (P<0.01) melatonin concentration compared with ghrelin-treated culture and decreased melatonin concentration (P<0.01) compared with leptin-treated culture during SD. Isoproterenol stimulated (P<0.01) melatonin secretion compared with values observed during the pretreatment period. We conclude that orexigenic peptides (orexin B and ghrelin) and an anorectic peptide (leptin) affect PG directly. The responses of PG to those hormones depend on day length. Moreover, secretion of melatonin from the ovine PG is under an adrenergic regulation.

Seasonal changes in the interactions among leptin, ghrelin, and orexin in sheep

The adaptation of the physiology of an animal to changing conditions of light and food availability is evident at the behavioral and hormonal levels. Melatonin, leptin, ghrelin, and orexin, which exhibit rhythmic secretion profiles under ad libitum feeding conditions, are sensitive to changes in daylength, forming a tight web of interrelationships in the regulation of energy balance. The aim of this study was to determine the effects of central injections of leptin, ghrelin, and orexin on the reciprocal interactions among these hormones and the influence of photoperiod on these responses. Twenty-four ovariectomized and estradiol-implanted ewes were used in a replicated switchback design. The ewes were assigned randomly to 1 of 6 treatment groups, and the treatments were infused into their third ventricles 3 times at 0, 1, and 2 h, with 0 h being at dusk. The treatments were as follows: 1) control, Ringer-Locke buffer; 2) leptin, 0.5 μg/kg BW; 3) ghrelin, 2.5 μg/kg BW; 4) orexin B, 0.3 μg/kg BW; 5) leptin antagonist, 50 μg/kg BW, then ghrelin, 2.5 μg/kg BW; and 6) leptin antagonist, 50 μg/kg BW, then orexin B, 0.3 μg/kg BW. Blood samples (5 mL) were collected at 15-min intervals for 6 h. The administration of leptin increased (P < 0.05) plasma concentrations of melatonin during short-day (ShD) photoperiods and decreased (P < 0.05) them during long-day (LD) photoperiods, whereas ghrelin decreased (P < 0.05) melatonin concentrations during ShD photoperiod, and orexin had no effect (P > 0.1). Leptin attenuated (P < 0.05) ghrelin concentrations relative to the concentration in controls during ShD. The plasma concentrations of orexin were reduced (P < 0.05) after leptin infusions during LD and ShD photoperiods; however, ghrelin had the opposite effect (P < 0.05) on orexin concentration. Orexin increased (P < 0.05) ghrelin concentrations during LD. Ghrelin and orexin concentrations were increased (P < 0.05) after leptin antagonist infusions. Our data provide evidence that the secretion of leptin, ghrelin, and orexin are seasonally dependent, with relationships that are subject to photoperiodic regulation, and that leptin is an important factor that regulates ghrelin and orexin releases in sheep.

A review on the effect of the photoperiod and melatonin on interactions between ghrelin and serotonin

Ghrelin and serotonin, which exhibit rhythmic secretion profiles under feeding/fasting conditions, are sensitive to increases and decreases in the day length and form a close web of interrelationships in the regulation of energy homeostasis. Ghrelin and serotonin are biochemically and functionally linked to the suprachiasmatic nucleus, which is a circadian pacemaker, and melatonin, which is an internal transducer of photic environmental changes. Ghrelin and serotonin might be candidates for integrating photic and nonphotic signals, such as light and food availability in the central nervous system. The mechanisms that convert a light signal into a variety of physiological and behavioral rhythms remain unknown. However, we know that the conversion of light signals is necessary to maximize an animals chances of survival and reproduction.

Cross-talk between leptin, ghrelin and orexins in the central nervous system of seasonal animals – a review

Abstract The maintenance of energy homeostasis is achieved with ‘detectors’ that receive signals from the external and internal environment and with multidirectional ‘communication routes’ including neuronal networks and body fluids, such as blood and cerebrospinal fluid. Changes in the energy demands of organisms are caused by current physiological status and environmental conditions, including season and food availability. Little is known about the interactions between the metabolic indicators involved in the maintenance of energy homeostasis, e.g., leptin, orexins and ghrelin. Sheep and other seasonal animals are highly adaptable to their environments because of the plasticity of their neural and endocrine systems. Sheep exhibit leptin resistance and are thus an extremely interesting model for research on the relationship between hormonal indicators of energy metabolism. The paper is focused mainly on the anatomical and functional communication between leptin, ghrelin and orexins, which play principal roles in the adaptation of energetic demands to environmental fluctuations.

Photoperiod Influences the Effects of Ghrelin and Serotonin Receptor Agonist onGrowth Hormone and Prolactin Secretion in Sheep

Objective: Recent studies have identified a novel heterodimer involving the ghrelin receptor (GHS-R1A) and the 5-HT2C receptor, a subtype of serotonin receptors. Whether or not interactions between GHS-R1A and the 5-HT2C receptor exist and how they are modulated by photoperiod and nutritional status in seasonally animals remains unknown. The aims of this study were to determine the effects of ghrelin and a 5-HT2B/2C serotonin receptor agonist, 1-(3-chlorophenyl) piperazine hydrochloride (m-CPP), on GH and PRL secretion under the influence of nutritional status and photoperiod. Methods: Normally fed (n=12) or fasted (n=12) ewes were assigned to one of 4 groups and treatments: 1) control (saline); 2) ghrelin (2.5 μg/kg); 3) m-CPP (2.5 mg/kg); 4) ghrelin followed by m-CPP were infused once at the beginning of the study for groups 1, 2 and 3; in group 4, ghrelin was administered at 15 min, and m-CPP at 30 min. Blood samples were collected at 15 min intervals for 3 h during the short day (SD) and long day (LD) season. Results: Ghrelin and m-CPP enhanced (p<0.05) GH secretion in fasted ewes during LD. The m-CPP significantly decreased GH concentrations in fasted ewes during SD. Prolactin concentrations were lower (p<0.01) in normally fed ewes after the ghrelin+m-CPP treatment compared to treatment with m-CPP alone. Conclusion: There were interactions among ghrelin, serotonin, photoperiod and metabolic status that influenced GH and PRL secretion in ewes. Using an ovine model, our work provides a basis for future studies of the pathogenesis of metabolic disorders associated with alterations in nutritional status and day length.

The effects of leptin on plasma concentrations of prolactin, growth hormone, and melatonin vary depending on the stage of pregnancy in sheep1

The effects of hyperleptinemia and leptin resistance during gestation are unclear. Leptin, an important neuroendocrine regulator, has anorexic effects, but its interactions with other metabolic hormones during pregnancy are unclear. We examined potential roles of leptin in regulating prolactin (PRL), GH, and melatonin plasma concentrations during pregnancy in Polish Longwool ewes. Twelve estrus-synchronized ewes carrying twins after mating were randomly assigned to receive i.v. injections of saline or recombinant ovine leptin (2.5 or 5.0 µg/kg BW). Blood samples were collected (15-min intervals over 4 h) immediately before the first injection at dusk and kept under red light. Treatments were repeated at 2-wk intervals, starting before mating and continuing from days 30 to 135 of gestation. Concentrations of plasma PRL, GH, and melatonin were determined using a validated RIA. The effects of leptin on hormone plasma concentrations varied depending on pregnancy stage and leptin dose. PRL plasma concentrations were affected at most stages of pregnancy and before gestation. In non-, very early- (day 30), and late- (day 120 and 135) pregnant ewes, exogenous leptin stimulated PRL (P < 0.001) plasma concentrations, while during the second month of gestation, it decreased PRL concentrations (P < 0.01). Leptin affected GH plasma concentrations (P < 0.05) only during the first 2 mo of pregnancy, with no effects during the second part of gestation or before pregnancy. In early-pregnant ewes (day 30 and 45), leptin decreased melatonin plasma concentrations (P < 0.05), but at day 60, leptin stimulated melatonin plasma concentrations at low (P < 0.01) and high doses (P < 0.05), with no effects in ewes after 105 d of gestation. These data indicate specific pregnancy-induced endocrine adaptations to changes in energy homeostasis, supporting the hypothesis that leptin affects PRL, GH, and melatonin release during gestation.

Induction of the Secretion of LH and GH by Orexin A and Ghrelin is Controlled in Vivo by Leptin and Photoperiod in Sheep

Abstract The influence of leptin on orexin A and the interaction of leptin with ghrelin in regulating the gonadotropic and somatotropic axes in seasonally polyestrous animals are not well understood. This study examined the effects of these factors as well as the mediating roles of specific ovine leptin antagonist (SOLA; mutant D23L/L39A/D40A/F41A) and photoperiod on luteinizing hormone (LH) and growth hormone (GH) secretion. Twenty-four ovariectomized, estradiol-implanted ewes were used in a replicated switchback design. The ewes were assigned randomly to 1 of 6 treatments (infused into the third ventricle 3 times at 0 (dusk), 1, and 2 h) as follows: control, Ringer-Locke buffer; leptin, 0.5 μg/kg b.w.; orexin A, 0.3 μg/kg b.w.; ghrelin, 2.5 μg/kg b.w.; SOLA, 50 μg/kg b.w. + orexin A, 0.3 μg/kg b.w.; and SOLA, 50 μg/kg b.w. + ghrelin, 2.5 μg/kg b.w. Blood samples (5 ml) were collected at 15-min intervals for 4 h. SOLA + orexin A resulted in an increase (P<0.01) in the LH plasma concentration during short-day (SD) and long-day (LD) photoperiods. However, ghrelin and SOLA + ghrelin had the opposite effect. SOLA + orexin A resulted in an increase (P<0.001) in the GH concentration compared with leptin or orexin A during the LD season. Ghrelin and SOLA + ghrelin increased the GH concentration (P<0.01) regardless of the season. In summary, LH and GH secretion are seasonally dependent on relationships that are subject to photoperiodic regulation, and leptin is an important regulator of the effects of ghrelin and orexin A on the activities of the gonadotropic and somatotropic axes in sheep.