Leptin: a possible metabolic signal affecting reproduction

Since its discovery in 1994, leptin, a protein hormone synthesized and secreted by adipose tissue, has been shown to regulate feed intake in several species including sheep and pigs. Although a nimiety of information exists regarding the physiological role of leptin in rodents and humans, the regulation and action of leptin in domestic animals is less certain. Emerging evidence in several species indicates that leptin may also affect the hypothalamo-pituitary-gonadal axis. Leptin receptor mRNA is present in the anterior pituitary and hypothalamus of several species, including sheep. In rats, effects of leptin on GnRH, LH and FSH secretion have been inconsistent, with leptin exhibiting both stimulatory and inhibitory action in vivo and in vitro. Evidence to support direct action of leptin at the level of the gonad indicates that the leptin receptor and its mRNA are present in ovarian tissue of several species, including cattle. These leptin receptors are functional, since leptin inhibits insulin-induced steroidogenesis of both granulosa and thecal cells of cattle in vitro. Leptin receptor mRNA is also found in the testes of rodents. As with the ovary, these receptors are functional, at least in rats, since leptin inhibits hCG-induced testosterone secretion by Leydig cells in vitro. During pregnancy, placental production of leptin may be a major contributor to the increase in maternal leptin in primates but not rodents. However, in both primates and rodents, leptin receptors exist in placental tissues and may regulate metabolism of the fetal-placental unit. As specific leptin immunoassays are developed for domestic animals, in vivo associations may then be made among leptin, body energy stores, dietary energy intake and reproductive function. This may lead to a more definitive role of leptin in domestic animal reproduction.     

Altered “set-point” of the hypothalamus determines effects of cortisol on food intake,adiposity, and metabolic substrates in sheep

Chronic elevation of glucocorticoid concentrations is detrimental to health. We investigated effects of chronic increase in plasma cortisol concentrations on energy balance and endocrine function in sheep. Because food intake and reproduction are regulated by photoperiod, we performed experiments in January (JAN) and August (AUG), when appetite drive is either high or low, respectively. Ovariectomized ewes were treated (intramuscularly) daily with 0.5 mg Synacthen Depot® (synthetic adrenocorticotropin: ACTH) or saline for 4 wk. Blood samples were taken to measure plasma concentrations of cortisol, luteinising hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), leptin, insulin, and glucose. Adrenocorticotropin treatment increased concentrations of cortisol. During JAN, treatment reduced food intake transiently, but increased food intake in AUG. Leptin concentrations were reduced and glucose concentrations were greater in AUG, and insulin concentrations were similar throughout the year. Treatment with ACTH increased leptin concentrations in AUG only, whereas insulin concentrations increased in JAN only. Synacthen treatment increased glucose concentrations, with a greater effect in JAN. Changes in truncal adiposity and ACTH-induced cortisol secretion were positively correlated in JAN and negatively correlated in AUG. Treatment reduced the plasma LH pulse frequency in JAN and AUG, with an effect on pulse amplitude in JAN only. Treatment did not affect plasma GH or FSH concentrations. We conclude that chronically elevated cortisol concentrations can affect food intake, adiposity, and reproductive function. In sheep, effects of chronically elevated cortisol concentrations on energy balance and metabolism depend upon metabolic setpoint, determined by circannual rhythms.     

Intracerebroventricular Infusion of Leptin into Mature Merino Rams of Different Metabolic Status: Effects on Blood Concentrations of Glucose and Reproductive and Metabolic Hormones

In mature Merino rams, nutrition is one of the external cues that most strongly affects the reproductive centres of the preoptic-hypothalamic continuum. The signalling pathways that link dietary status and the activity of the neurones that produce gonadotrophin-releasing hormone signals are thought to be partly hormonal in nature to reflect the amount of body reserves. Among the hormones thought to be involved are insulin and leptin. This study tested whether recombinant bovine leptin infused (0.4 microg/h) into the third cerebral ventricle would stimulate pulsatile luteinizing hormone (LH) secretion in mature Merino rams when their energy status was low or decreasing, during both chronic (fasting) and acute reductions of energy balance. Leptin may interact with other hormones that depend on energy availability, so we also monitored changes in circulating concentrations of insulin, thyroid hormones, growth hormone, prolactin and adrenocorticotrophin. Overall, our data do not support this hypothesis. The dietary regimes induced clear responses in the metabolic profiles of the animals but there was no clear effect of central leptin administration on LH pulse frequency. The relationships between the hormonal systems measured in the present study add weight to the contention that leptin plays only a permissive role in the nutritional control of the reproductive axis and that other hormonal signals (particularly insulin) or pathways are acting in concert with leptin to stimulate the reproductive axis.     

Biology of leptin in the pig

The recently discovered protein, leptin, which is secreted by fat cells in response to changes in body weight or energy, has been implicated in regulation of feed intake, energy expenditure and the neuroendocrine axis in rodents and humans. Leptin was first identified as the gene product found deficient in the obese ob/ob mouse. Administration of leptin to ob/ob mice led to improved reproduction as well as reduced feed intake and weight loss. The porcine leptin receptor has been cloned and is a member of the class 1 cytokine family of receptors. Leptin has been implicated in the regulation of immune function and the anorexia associated with disease. The leptin receptor is localized in the brain and pituitary of the pig. The leptin response to acute inflammation is uncoupled from anorexia and is differentially regulated among swine genotypes. In vitro studies demonstrated that the leptin gene is expressed by porcine preadipocytes and leptin gene expression is highly dependent on dexamethasone induced preadipocyte differentiation. Hormonally driven preadipocyte recruitment and subsequent fat cell size may regulate leptin gene expression in the pig. Expression of CCAAT-enhancer binding protein (C/EBP) mediates insulin dependent preadipocyte leptin gene expression during lipid accretion. In contrast, insulin independent leptin gene expression may be maintained by C/EBP auto-activation and phosphorylation/dephosphorylation. Adipogenic hormones may increase adipose tissue leptin gene expression in the fetus indirectly by inducing preadipocyte recruitment and subsequent differentiation. Central administration of leptin to pigs suppressed feed intake and stimulated growth hormone (GH) secretion. Serum leptin concentrations increased with age and estradiol-induced leptin mRNA expression in fat was age and weight dependent in prepuberal gilts. This occurred at the time of expected puberty in intact contemporaries and was associated with greater LH secretion. Further work demonstrated that leptin acts directly on pituitary cells to enhance LH and GH secretion, and brain tissue to stimulate gonadotropin releasing hormone secretion. Thus, development of nutritional schemes and (or) gene therapy to manipulate leptin secretion will lead to practical methods of controlling appetite, growth and reproduction in farm animals, thereby increasing efficiency of lean meat production.     

Signals of adiposity

Adipose tissue, a reserve of energy, has played an essential role in mammalian evolution. Adipose tissue differs from other tissues in that its mass has considerable capacity to expand, which while beneficial in decreasing the risk of starvation, increases the risk of predation. Adipose tissue mass is thus under tight control in nondomestic species. Adipose tissue secretes a variety of factors, some of which (leptin, tumor necrosis factor (TNF) , resistin) are thought to be involved in modulation of adipose mass. Leptin has a variety of functions, primarily targetting the hypothalamus where it acts to decrease appetite and increase energy expenditure. Leptin is also involved in the adaptations to fasting, and leptin is also required for normal reproductive and immune function. TNF and resistin appear to have key paracrine roles, attenuating the anabolic effects of insulin on adipose tissue metabolism.     

Expression of leptin and its receptors in various tissues of ruminants

The energy metabolism of domestic animals is under the control of hormonal factors, which include thyroid hormones and leptin. Leptin signals from the periphery to the centre. It is mostly produced in the white adipose tissue and informs the central nervous system (CNS) about the total fat depot of the body. Low and high levels of leptin induce anabolic and catabolic processes, respectively. Besides controlling the food uptake and energy expenditure leptin is also involved in regulation of the reproduction and the immune system. Leptin is produced in several tissues other than fat. In the present paper the leptin expression of ruminant (Egyptian water buffalo, cow, and one-humped camel) tissues are examined. The mammary gland produces leptin in each species investigated. The local hormone production contributes to milk leptin and most probably helps to maintain lactation. Considerable leptin receptor expression was observed in the milk-producing epithelial cells, which is the same cell type that produces most of the udder leptin. Based on the results tissues participating in production have an autoregulative mechanism through which tissues can be relatively independent of the plasma leptin levels in order to maintain the desired function.     

Genetics and physiology of leptin in periparturient dairy cows

In dairy cattle, the increase in milk yield has been accompanied by a more negative energy balance (EB) during early lactation and a decrease in fertility. As the hormone leptin is involved in regulation of nutritional status and reproductive function this hormone is an interesting protein to investigate during the periparturient period in dairy cattle. This study was performed to get insight into the function of leptin during the periparturient period and to perform an association study between polymorphisms in the bovine leptin gene and leptin receptor gene and fertility as well as production traits. Leptin concentrations in the periparturient cow undergo remarkable changes; leptin concentrations were high during late pregnancy and declined to a nadir at parturition. Genetic analysis of the leptin gene indicated that a combination of three polymorphisms located at a 135 bp region of the leptin promoter explained most of the variance in prepartum leptin concentrations. The two extreme genotype combinations could be used to investigate the function of leptin concentrations in pregnant cows. A polymorphism located on intron 2 of the leptin gene explained a significant part of the variation in milk yield. On the promoter region of the leptin gene an SNP was detected that was associated with first postpartum luteal activity (FPLA). This SNP could be a candidate marker for fertility in dairy cows. Another SNP on the leptin promoter was associated with energy balance and dry matter intake (DMI) where a higher dry matter intake occurred together with a higher energy balance. Two genotype combinations of the aforementioned three associated SNPs were defined which had a good milk yield together with a good energy balance and fertility. Calculations of an economical value per trait have to validate if one of these genotype combinations would be a possible candidate to be used in selection.     

瘦素对动物生殖调控的研究进展

瘦素是由白色脂肪细胞分泌的一种蛋白类激素,对动物的采食量及能量平衡调控具有明显的作用。除此之外,瘦素对生殖系统也有着重要的调节作用。瘦素通过JAK-STAT途径及与KiSS-1/GPR54系统的相互作用,对动物初情期的启动,下丘脑—垂体—性腺(HPG)轴及胎盘与子宫等产生广泛的影响。     

瘦素基因的研究进展

瘦素（leptin,LEP）是白色脂肪分泌的一种蛋白质激素,在哺乳动物中,LEP是一种16-ku的肽类激素,在能量平衡的神经内分泌和外周调节中发挥重要作用,是反应体脂含量和调节体重、摄食的重要信号因子。在人类疾病方面,LEP基因的表达对很多疾病的发生起着重要的调控作用,尤其是LEP基因的突变可能导致肥胖、糖尿病和乳腺癌等疾病;在畜牧生产上,LEP基因的表达对牛、羊和猪的采食和生长性状影响显著。为了加深对LEP基因的认识,作者对LEP基因的结构及LEP的分布、结构和功能进行了总结,并对近几年LEP基因在疾病和畜牧生产方面的研究进展进行了综述。     

瘦素在动物繁殖上的研究进展

瘦素（ｌｅｐｔｉｎ）是１４６个氨基酸组成的分子量为１４６ｋＤａ的多肽,由脂肪细胞所分泌。瘦素作为内分泌因子,通过阿片促黑激素皮质素原（ＰＯＭＣ）和神经多肽Ｙ（ＮＰＹ）影响丘脑下部（ＧｎＲＨ）释放,从而影响着生殖激素的产生和释放,动物初情期的发动伴随着瘦素水平的不断提高,成年动物繁殖功能的维持也有赖于瘦素发挥作用。瘦素对性腺和垂体的作用机理尚不明确。     

Leptin expression in ruminants: nutritional and physiological regulations in relation with energy metabolism

Leptin, mainly produced in adipose tissue (AT), is a protein involved in the central and/or peripheral regulation of body homeostasis, energy intake, storage and expenditure, fertility and immune functions. Its role is well documented in rodent and human species, but less in ruminants. This review is focused on some intrinsic and extrinsic factors which regulate adipose tissue leptin gene expression and leptinemia in cattle, sheep, goat and camel: age, physiological status (particularly pregnancy and lactation) in interaction with long-term (adiposity) and short-term effects of feeding level, energy intake and balance, diet composition, specific nutrients and hormones (insulin, glucose and fatty acids), and seasonal non-dietary factors such as photoperiod. Body fatness strongly regulates leptin and its responses to other factors. For example, leptinemia is higher after underfeeding or during lactation in fat than in lean animals. Physiological status per se also modulates leptin expression, with lactation down-regulating leptinemia, even when energy balance (EB) is positive. These results suggest that leptin could be a link between nutritional history and physiological regulations, which integrates the animal's requirements (e.g., for a pregnancy-lactation cycle), predictable food availability (e.g., due to seasonal variations) and potential for survival (e.g., body fatness level). Reaching permissive leptin thresholds should be necessary for pubertal or postpartum reproductive activity. In addition to the understanding of leptin yield regulation, these data are helpful to understand the physiological significance of changes in leptin secretion and leptin effects, and how husbandry strategies could integrate the adaptative capacities of ruminant species to their environment.     

Investigation of the leptin levels in the blood serum of Cyprinus carpio (Linnaeus, 1758) and Capoeta trutta (Heckel, 1843)

Leptin is a peptide hormone secreted by adipose tissues in the various teleost fish and vertebrates. Leptin has been suggested to have an important role in a range physiological function, including regulation of food intake, reproduction, immune function, energy expenditure, lipid and carbohydrate metabolism. In this study, leptin levels in the blood serum of Cyprinus carpio and Capoeta trutta were determined. Then the results were compared between two species and between sexes of each species. In addition, leptin levels were also compared with the body weight and length of both C. carpio and C. trutta. Leptin level was analysed using available enzyme‐linked immunoassay (ELISA) kit (Rat leptin ELISA kit, catalog no: SK00050‐08). Leptin levels showed no significant difference (p > 0.05) that in relation to between two species and between sexes of each species. It has been shown that not significantly correlated when examined correlations between the leptin level in blood serum and body weight (r = 0.192, p = 0.380) or length (r = 0.102, p = 0.644) of C. carpio. Similarly, the correlations between leptin level in blood serum and body weight (r = 0.021, p = 0.959) or length (r = 0.123, p = 0.595) of C. trutta were also not significant.     

Leptin and its role in the central regulation of reproduction in cattle

Leptin, a 16kDa product of the adipose obese (ob) gene, has been shown to contribute to the regulation of energy metabolism, feeding behavior, and reproduction in several monogastric species, including humans. Recent reports have provided evidence that the leptin gene is functionally relevant in cattle and sheep, and may contribute to an array of important reproductive events, including puberty. Leptin gene expression and circulating leptin increase markedly during sexual maturation in heifers reaching puberty during late spring or early summer. In addition, serum leptin concentrations increased by over 30% from early winter to the summer solstice in mature cows, and also increased with significant changes in adiposity. However, only limited changes in circulating leptin have been observed during the estrous cycle. Short-term fasting of growing peripubertal heifers causes marked reductions in leptin gene expression and circulating leptin, concomitant with declines in LH pulse frequency, and serum concentrations of insulin and IGF-1. Although short-term fasting of mature cows in excellent body condition is without effects on LH pulse frequency, it has remarkably similar metabolic effects to those observed in heifers. Moreover, ICV administration of recombinant oleptin resulted in a marked hypersecretion of LH in fasted cows, and in vitro studies using both hypothalamic and anterior pituitary explants have provided evidence that this effect is at the pituitary level. Paradoxically, ICV administration of oleptin normalized circulating insulin in fasted cows but hleptin was without effect on insulin in estradiol-implanted wethers. Collectively, work in cattle and sheep indicates that leptin can modulate both the hypothalamic-pituitary axis and endocrine pancreas under defined nutritional conditions. Additional work to more fully characterize these roles is clearly warranted and could lead to the development of novel strategies for modifying reproductive potential in food-producing species.     

Leptin的生物学功能研究进展

瘦蛋白（L-eptin)是由肥胖基因（obese gene)编码，脂肪细胞分泌的一种激素，具有调节摄食行为，减少能量消耗和降低动物采食量的作用，从而提高动物的生产性能和经济效益。作者综述了Leptin的生物学功能，作用机理，表达调控并展望了Leptin在畜牧业中的应用前景。     

Leptin的研究进展

Leptin是由脂肪细胞分泌的一种蛋白，自1994年被发现以来，对leptin的研究就成为最为的领域之一并取得了迅速进展，国外大量实验资料表明，leptin可以降低动物采量，维持动物能量平衡，调节动物 的繁殖机能，提高动物的免疫功能，本文就Leptin的研究进展和其应用前景作一综述。     

A rat model for the energetic regulation of gonadotropin secretion: role of the glucose-sensing mechanism in the brain

Energy availability has been considered to regulate gonadal activity by modulating the release of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) at various reproductive phases, such as lactation and puberty in domestic as well as wild animals. Experimental models with rats and sheep have demonstrated that fasting or glucoprivation suppresses pulsatile LH release. From those experiments, the information on energy deficiency is considered to be detected by specific central sensors and conveyed to the hypothalamus to regulate LH release as well as food intake. Noradrenergic neurons, originating in the medulla oblongata and projecting to the hypothalamic paraventricular nucleus (PVN), is reported to be one of the pathways mediating the response of LH release to energy deficiency. The other component is considered to be an energy-sensing mechanism in the brain. Glucose or other oxidizable fuels may function as a metabolic signal to regulate LH release. Previous studies suggest the presence of a glucose-sensing mechanism in the rat hindbrain. From our previous results in the rat, the ependymocytes lining the wall of the cerebroventricle could possibly serve as a glucose sensor to regulate GnRH/LH release. Greater understanding of the nature of the energy-sensing mechanism in the brain will contribute to the nutritional manipulation of reproductive performance in domestic animals in various conditions.     

Leptin inhibits mitogen-induced proliferation of peripheral T lymphocytes from Holstein cows

This study examined the mitogenic response of bovine peripheral T lymphocytes to leptin, a pleiotropic hormone regulating food intake and energy expenditure. Leptin alone slightly suppressed proliferation of T lymphocytes in the presence of concanavalin A (ConA). Leptin also inhibited proliferation of T lymphocytes induced by anti-CD3 antibody. ConA treatment activated some protein kinases, including p44/p42(MAPK) and Akt/PKB, while anti-CD3 antibody treatment increased mRNA expression of suppressor of cytokine signalling (SOCS) 3, interferon (IFN)gamma, interleukin (IL) 2 and IL4 in T lymphocytes. Leptin alone increased only SOCS3 mRNA expression. Simultaneous treatment with mitogens and leptin enhanced IFNgamma mRNA expression but decreased IL2 mRNA expression, without any synergistic effect on phosphorylation of protein kinases or mRNA expression of SOCS3 and IL4. These results suggest that leptin modulates bovine T lymphocyte functions.