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J G Mercer

Publications and source records attributed to J G Mercer.

At least 37 records · Page 2Linked to original sources

The regulation of body weight: lessons from the seasonal animal.

The hypothalamus is a major regulatory centre involved in the control of many important physiological axes. One of these axes is the regulation of ingestive behaviour. Recent work using a combination of genetic-mutant mouse models together with targeted gene deletions has contributed much to our understanding of how neural pathways of the hypothalamus are involved in the regulation of energy balance in animals. These pathways are also relevant to human energy homeostasis. as mutations in key genes are correlated with obesity. Many of the genes identified mediate the effects of leptin, and are therefore primarily involved in sensing and responding to peripheral signals. In seasonal animals, such as the Siberian hamster (Phodopus sungorus), there is evidence for a higher level of regulation. The systems involved regulate body weight around an apparent 'set-point' through the action of photoperiod via the neurohormone, melatonin. The ability to manipulate energy balance through photoperiod (and melatonin) in the seasonal-animal model offers novel opportunities to identify further fundamental aspects of the control mechanisms involved in the central control of energy homeostasis and body weight.

Animals↗

Seasonally inappropriate body weight induced by food restriction: effect on hypothalamic gene expression in male Siberian hamsters.

Male Siberian hamsters undergo physiological weight change in changing photoperiod. Weight loss was induced by food restriction in long days to mimic short-day weight loss, or by food restriction superimposed on short-day weight loss, to test the hypothesis that the hypothalamus differentiates between weight change induced by imposed negative energy balance (inappropriate body weight) and seasonal, appropriate, body weight change, even when these are of similar magnitude. Short-day weight loss was accompanied by reduced POMC and leptin receptor (OB-Rb) mRNA in the arcuate nucleus but elevated cocaine- and amphetamine-regulated transcript. Melanocortin 3-receptor gene expression was reduced in the arcuate nucleus but elevated in the ventromedial nucleus compared with ad libitum-fed long-day controls. Weight loss in long-day restricted animals generated a gene expression profile typical of negative energy balance with low cocaine- and amphetamine-regulated transcript mRNA and elevated OB-Rb. Melanocortin 3-receptor mRNA levels were indistinguishable in short-day and long-day food-restricted hamsters. The hypothalamic correlates of food restriction in short days included up-regulated anabolic neuropeptides and increased OB-Rb mRNA. Low plasma leptin is integrated differently in short-day and long-day restricted animals, and seasonally-inappropriate body weight in either photoperiod engages the compensatory neuropeptide systems involved in the defense of body weight.

Animals↗

Circulating leptin during ovine pregnancy in relation to maternal nutrition, body composition and pregnancy outcome.

This study examined the pattern of circulating leptin in age-matched sheep during adolescent pregnancy, and its relationship with maternal dietary intake, body composition and tissue expression of the leptin gene. Overfeeding the adolescent pregnant ewe results in rapid maternal growth at the expense of the placenta, leading to growth restriction in the fetus, compared with normal fed controls. Our results demonstrate that, in the adolescent ewe, overfeeding throughout pregnancy was associated with higher maternal leptin concentrations, when compared with moderately fed controls (P<0.05), with no peak in circulating leptin towards the end of pregnancy. There was a close correlation between indices of body composition and circulating leptin levels at day 104 of gestation and at term (P<0.03). Further, when the dietary intake was switched from moderate to high, or high to moderate, at day 50 of gestation, circulating leptin levels changed rapidly, in parallel with the changes in dietary intake. Leptin mRNA levels and leptin protein in perirenal adipose tissue samples, taken at day 128 of gestation, were higher in overfed dams (P<0.04), suggesting that adipose tissue was the source of the increase in circulating leptin in the overnourished ewes. Leptin protein was also detected in placenta but leptin gene expression was negligible. However, leptin receptor gene expression was detected in the ovine placenta, suggesting that the placenta is a target organ for leptin. A negative association existed between maternal circulating leptin and fetal birth weight, placental/cotyledon weight and cotyledon number. In conclusion, in this particular ovine model, hyperleptinaemia was not observed during late pregnancy. Instead, circulating leptin concentrations reflected increased levels of leptin secretion by adipose tissue primarily as a result of the increase in body fat deposition, due to overfeeding. However, there appears to be a direct effect of overfeeding, particularly in the short term. In the nutritional switch-over study, circulating leptin concentrations changed within 48 h of the change in dietary intake. The presence of leptin protein and leptin receptor gene expression in the placenta suggests that leptin could be involved in nutrient partitioning during placental and/or fetal development.

Adipose Tissue↗

Dietary and genetic influences on susceptibility or resistance to weight gain on a high fat diet.

This paper outlines the concepts and objectives behind the Fifth Framework Programme 'Diet and Obesity', scheduled to run from February 2001 to January 2004 with financial support from the European Commission. The objective is to identify the causes of weight gain on an energy-dense, high fat diet, and apply findings in the diagnosis, prevention and management of obesity. Molecular, physiological, behavioural and clinical approaches will be applied to the study of the mechanisms underlying diet preferences and susceptibility to weight gain, in both humans and laboratory rodents. This strategy is based on the observation that not all individuals habitually eating a high fat diet are obese; some have a similar body mass index (BMI) to low fat consumers despite the consumption of substantially more fat (and energy). The project will investigate why some individuals preferentially select a high fat diet, and how genetic background interacts with diet to confer susceptibility or resistance to obesity. Improved diagnosis of individuals at risk may allow treatment and preventive measures, including advice during pregnancy, to be more targeted. The effect of early life nutrition on dietary preferences, susceptibility to obesity, and the programming of brain signalling systems will be investigated in parallel clinical and rodent studies.

Animals↗

Effect of leptin on hypothalamic GLP-1 peptide and brain-stem pre-proglucagon mRNA.

Leptin, the adipocyte-derived plasma hormone, and CNS GLP-1 neurons reduce food intake and body weight. GLP-1 is produced in the CNS by post-translational processing of pre-proglucagon. ICV leptin administration prevented the reduction in hypothalamic GLP-1 peptide content seen in pair-fed food-restricted rats (P < 0.05). There was a significant overall positive correlation between pre-proglucagon mRNA expression in the NTS and hypothalamic GLP-1 peptide content (r = +0.34, P < 0.05). Intraperitoneal leptin administration also increased hypothalamic GLP-1 peptide in food-restricted mice (P < 0. 05). This supports the hypothesis that the anorectic actions of leptin are in part due to stimulation of GLP-1 neurons. Reduced CNS GLP-1 neuronal activity during food deprivation may act to stimulate feeding behaviour, and perhaps also inhibit hypothalamic LHRH neurons, as part of the neuroendocrine response to starvation.

Animals↗

Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta.

Leptin is a 167-amino acid protein that is secreted from adipose cells and expressed in placental tissues. It is important nutritionally in the regulation of energy balance, but also has other functions such as a role in reproduction. To investigate the function of the leptin system in fetal development we examined, primarily by in-situ hybridization and immunohistochemistry, the expression (both mRNA and protein) of leptin and its receptor (including the signalling splice variant) in tissues from 11.5, 13.5, 16.5 and 18.5 d postcoitus murine fetuses and associated placentas. We detected leptin mRNA (at low levels) and protein predominantly in the cytotrophoblasts of the labyrinth part of the placenta, an area of nutrient exchange between the developing fetus and the placenta, and in the trophoblast giant cells situated in the junctional zone at the maternal interface. In addition, leptin was strongly expressed in the fetal cartilage-bone and at a lower level in the hair follicles, heart, and liver of the murine fetus at differing stages of development. The leptin receptor, including the signalling splice variant, was also identified in specific fetal tissues. The physiological importance of expression of both leptin and the leptin receptor (OB-R and OB-Rb) in the placenta remains to be determined. In addition, the high levels of expression of leptin and its receptor in discrete areas of the murine fetus suggest that leptin has a critical role in fetal development.

Animals↗

Anorexia in rats infected with the nematode, Nippostrongylus brasiliensis: experimental manipulations.

Nippostrongylus brasiliensis induces a biphasic anorexia in laboratory rats, the first phase coincident with lung invasion (ca day 2) and the second when the worms mature in the intestine (ca day 8). Using the anthelminthic, mebendazole (MBZ), N. brasiliensis infections of the rat were eliminated between the first and second anorexic episodes. This intervention prevented the expression of the second phase of anorexia. Rats exposed to a second infection with N. brasiliensis, 3 weeks after the primary infection, exhibited only a first phase anorexic response which was not influenced by MBZ termination of the primary infection. The lower cumulative food intake and weight gain of all infected rats after 8 days of infection were accompanied by elevated plasma insulin and, in some individuals, by elevated plasma leptin, compared with uninfected controls and previously-infected MBZ-treated rats. Messenger RNA levels for neuropeptide Y were higher in the hypothalamic arcuate nucleus of 8-day infected rats than in recovering MBZ-treated animals. Inoculation of rats with heat-killed N. brasiliensis larvae failed to induce anorexia and did not alter the severity of biphasic anorexia on subsequent injection of viable larvae. The first anorexic episode is therefore dependent upon viable migrating larvae. The second phase of anorexia clearly requires the continuing presence of the parasite beyond the lung phase. Viable migrating larvae are also required to confer 'resistance' to reinfection.

Animals↗

B219/OB-R 5'-UTR and leptin receptor gene-related protein gene expression in mouse brain and placenta: tissue-specific leptin receptor promoter activity.

Leptin receptor (OB-R) splice variants either encode proteins with different 3' cytoplasmic domains or have different 5' untranslated regions (UTR), indicative of dual promoters. The B219/OB-R promoter transcribes only OB-R transcripts, whereas the OB-R/GRP promoter initiates transcription of both OB-R and another protein of unknown function, called the leptin receptor gene-related protein (OB-RGRP). We compared expression of B219/OB-R 5'-UTR and OB-RGRP mRNAs by in situ hybridization. We thus assessed, by inference, the contributions of the two promoters to the leptin receptor transcript pool, in murine brain or in placenta, a tissue with abundant leptin receptor mRNA. Expression of B219/OB-R 5'-UTR mRNA (and thus by inference B219/OB-R promoter activity) in brain was similar in both distribution and relative intensity to OB-R mRNA. OB-RGRP mRNA (and thus by inference OB-R/GRP promoter activity) was widely distributed in murine brain, with elevated expression in the hypothalamic regions that express the leptin receptor mRNA, including the paraventricular nucleus. B219/OB-R 5'-UTR mRNA, but not OB-RGRP mRNA, was upregulated in hypothalamus of obese ob/ob mice. In placenta, B219/OB-R 5'-UTR mRNA was restricted to the maternal interface, and transcription of both long and short leptin receptor splice variants in the main body of the tissue thus proceeds via the OB-R/GRP promoter, strongly indicative of tissue-specific promoter usage.

5' Untranslated Regions↗

The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone.

The adipose hormone, leptin, not only restrains appetite, but also influences energy expenditure. One such influence is to promote sexual maturation and fertility. The neuromodulatory circuits that mediate this effect are not well known but the present study suggests that one mediator could be melanin-concentrating hormone (MCH). We show that the long-form receptor (Ob-Rb) is expressed in the zona incerta of the rat and that administration of leptin (both 0.5 microg and 1.0 microg/side) into this area of ovariectomized, oestrogen-primed rats stimulated the release of luteinizing hormone (LH) within 1 h, the effect enduring for a further 1 h. Injections of leptin into the arcuate nucleus induced a smaller, transient rise in LH while injections into the paraventricular and ventromedial nuclei were without effect. MCH neurones are present in the zona incerta and administration of this hormone into the medial preoptic area (mPOA) stimulates LH release, therefore we investigated the possibility that MCH might mediate this effect of leptin. An injection of MCH antiserum into mPOA prevented the rise in LH normally induced by leptin injected into the zona incerta. In addition, melanocortin receptor antagonists ([D-Arg8]ACTH(4-10) and [Ala6]ACTH(4-10)), previously shown to inhibit the stimulatory effect of MCH on LH release, also inhibited the effect of leptin. We propose that one route by which leptin may promote reproductive activity is by enhancing MCH release from fibres within the mPOA. Speculative mechanisms for the action of MCH include the following possibilities: MCH may be acting on the specific MCH receptor which in turn interacts with a melanocortin or melanocortin-like receptor; MCH may bind directly to one of the melanocortin receptors; or melanocortin antagonists may interact with the MCH receptor.

Alternative Splicing↗

Photoperiod differentially regulates the expression of Per1 and ICER in the pars tuberalis and the suprachiasmatic nucleus of the Siberian hamster.

Previous studies demonstrated that the clock gene Per1 and the transcription factor ICER are expressed rhythmically in the suprachiasmatic nucleus (SCN) and in the pars tuberalis (PT). In the Syrian hamster the duration of photoperiod affects the amplitude of gene expression in the PT, and melatonin administered before lights-on suppressed the peak of Per1/ICER expression; these effects were not seen in the SCN. It was speculated that the inefficacy of melatonin was due to the low density of melatonin receptors in the SCN of this species. The aim of the present study was to determine whether this phenomenon also occurs in the Siberian hamster, which expresses a higher density of melatonin receptors in the SCN. Male Siberian hamsters were housed in long days (16 h light : 8 h dark) or short days (8 h light : 16 h dark) and expression of Per1 and ICER mRNA was studied by in situ hybridization. The expression of Per1 and ICER mRNA in the PT peaked 3 h following lights-on (ZT3) under both photoperiods. The amplitudes of these peaks were greatly attenuated under short photoperiod. In the SCN, the duration of Per1 gene expression was proportional to the length of the light phase, but only a modest amplitude effect was observed. Injections of melatonin (25 microg) 1 h before lights-on significantly reduced the expression of both genes in the PT at ZT3, but had no effect in the SCN. These data demonstrate that photoperiod-dependent amplitude modulation of Per1 and ICER gene expression in the PT is conserved across species, and reinforce the argument that this phenomenon is driven by melatonin.

Animals↗

Photoperiod regulates arcuate nucleus POMC, AGRP, and leptin receptor mRNA in Siberian hamster hypothalamus.

Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs. long day (LD) controls. Subsequent imposed food deprivation (FD; 24 h) caused a further 10% decrease. In the hypothalamic arcuate nucleus (ARC), SDs reduced proopiomelanocortin (POMC) gene expression and agouti-related protein (AGRP) mRNA was elevated, changes that summate to reduced catabolic drive through the melanocortin receptors. There was no effect of photoperiod on neuropeptide Y (NPY), melanin concentrating hormone, orexin, or corticotropin-releasing factor mRNAs. Superimposed FD increased AGRP gene expression and caused a localized elevation of NPY mRNA in the ARC. Both adipose tissue leptin and ARC leptin receptor (OB-Rb) mRNAs were downregulated in SDs, whereas FD increased OB-Rb gene expression. Thus OB-Rb mRNA is differentially regulated by acute and chronic changes in plasma leptin in this species. In a separate experiment in LDs, AGRP gene expression was increased by 24 or 48 h FD, whereas POMC mRNA was downregulated in the caudal ARC. AGRP and NPY mRNAs were extensively coexpressed in the ARC, and their differential regulation by photoperiod and FD is suggestive of transcript-specific regulation at the level of individual neurons.

Adipose Tissue↗

Photoperiod regulates growth, puberty and hypothalamic neuropeptide and receptor gene expression in female Siberian hamsters.

In seasonal mammals, both the growth and reproductive axes are regulated by photoperiod. Female Siberian hamsters were kept, for up to 12 weeks, in long-day (LD) or short-day (SD) photoperiod, from weaning at 3 weeks of age (Exp 1). LD hamsters had characteristically faster growth and higher asymptotic body weight, adiposity, and leptin gene expression in adipose tissue. Only LD females attained puberty. Gene expression in the hypothalamic arcuate nucleus for leptin receptor (OB-Rb), POMC, and melanocortin 3-receptor (MC3-R) was higher in LD but did not change from weaning levels in SD. In contrast, gene expression in the arcuate nucleus for cocaine and amphetamine-regulated transcript (CART) was higher in SD than LD, a difference that was apparent at 2 weeks post weaning. Transfer of SD females to LD at 15 weeks post weaning (Exp 2) increased body weight, leptin signal, and gene expression for POMC but failed to induce normal puberty onset or to increase gene expression for OB-Rb and MC3-R. Therefore, photoperiodic regulation of puberty may be modulated by age, by photoperiodic history, and by changes in leptin signaling and the activity of the leptin-sensitive hypothalamic melanocortin system (POMC, MC3-R). A role for CART in photoperiodic regulation of growth is suggested, because the changes in CART gene expression preceded significant divergence of growth trajectories in the opposite photoperiods.

Agouti Signaling Protein↗

Placental leptin.

Placental tissues from humans, rodents and farm animals contain leptin and its receptor. Leptin produced by the human placenta has the same size, charge and immunoreactivity as leptin produced by adipose tissue. However, the expression of human placental leptin appears to be regulated by a placenta-specific upstream enhancer. In this review the occurrence of leptin and its receptor in a range of species and placental types is described, and its significance during pregnancy discussed. Placental leptin contributes to the increase in maternal circulating concentrations of leptin during late pregnancy when it is likely to have an endocrine role in regulating maternal energy balance. Placental leptin may have angiogenic and immunomodulatory activities, which affect the placenta in an autocrine or paracrine manner. It also appears to affect fetal growth and development by binding to leptin receptors present in fetal organs.

Adipose Tissue↗

Appetite and parasite.

Molecular techniques have dramatically advanced our knowledge of the mechanisms that regulate appetite and body weight, yet human obesity, a significant healthcare problem, still lacks an effective science-based treatment. Infectious agents, including worm parasites, seem capable of overwhelming these regulatory systems. Can the study of parasites extend our understanding of what makes animals feed?

Animals↗

Parasite-induced anorexia: leptin, insulin and corticosterone responses to infection with the nematode, Nippostrongylus brasiliensis.

The nematode parasite, Nippostrongylus brasiliensis, induces a biphasic anorexia in its rat host. The mechanisms, underlying this anorexia and its possible advantages to the host or parasite are unknown. We have investigated the effect of acute (12-24 h) and chronic (2-17 days) infections on plasma concentrations of leptin, insulin and corticosterone, and on hypothalamic expression of neuropeptide Y, galanin and corticotrophin-releasing factor genes. Plasma leptin was elevated in infected rats relative to uninfected ad libitum-fed controls and pair-fed controls in 12 h infections initiated at dark onset and in infections of 2 days' duration. At other times prior to parasite expulsion, plasma leptin in infected and pair-fed rats was lower than that of uninfected ad libitum-fed controls, reflecting the existing state of negative energy balance. Elevated plasma leptin concentrations in infected rats at day 2 post-infection were accompanied by reduced neuropeptide Y gene expression in the hypothalamic arcuate nucleus compared with both ad libitum control and pair-fed animals, and by lowered corticotrophin-releasing factor gene expression in the paraventricular nucleus relative to pair-feds. Twelve hour infections were characterized by a substantial increase in plasma corticosterone that was independent of reduced food intake, and in 12 h infections initiated at dark onset, where plasma leptin was elevated, there was also increased plasma insulin concentration in infected rats. In longer infections, differences between the groups in plasma insulin and corticosterone concentration were only observed at day 4 post-infection. In summary, perturbations to leptin, insulin and corticosterone signals early in infection may have a causative role and might feed back onto hypothalamic gene expression, whereas subsequent changes in these parameters are more likely to be secondary to negative energy balance.

Animals↗

Leptin: fundamental aspects.

The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.

Adipose Tissue↗

Leptin receptor and neuropeptide Y gene expression in the sheep brain.

Leptin, a protein secretory product of adipocytes, is important in appetite control, energy balance and reproduction. In rodents, the physiological effects of leptin are centrally mediated, in part via the neuropeptide Y (NPY) system in the hypothalamus. The role of leptin in ruminants, where appropriate nutrition and reproductive status are of major economic concern, is largely unknown. To elucidate the function of leptin in sheep we have investigated putative sites of action for leptin in the brain and pituitary gland using both in-situ hybridization to detect expression of the signalling form of the leptin receptor (OB-Rb) and in-vitro autoradiography using (125I)leptin to detect sites of specific leptin binding. OB-Rb gene expression occurred in the hippocampus, cerebral cortex, preoptic area, stria terminalis and choroid plexus, and within the hypothalamus in the paraventricular (PVN), ventromedial (VHM) and arcuate (ARC) nuclei. OB-Rb gene expression in the ovine pituitary gland was not detected by in-situ hybridization. Sites of OB-Rb and NPY gene expression were compared using both in-situ hybridization on adjacent sections containing the arcuate and ventromedial nuclei, and dual in-situ hybridization on sections containing these areas. In serial sections, OB-Rb expression was found to correspond closely with that of NPY over the arcuate nuclei. Using dual in-situ hybridization, NPY expressing neurones in the arcuate nuclei were also positive for OB-Rb gene expression. Therefore, it appears that leptin may partly act via OB-Rb located on NPY neurones in the sheep hypothalamus as in the rodent.

Animals↗