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The meeting, sponsored by the International Neuroendocrine Federation (INF), incorporated the Annual Meetings of the British Society for Neuroendocrinology (BSN), the French Society of NeuroEndocrinology (SNE), Hypothalamic Neuroscience and Neuroendocrinology Australasia (HNNA), and the Pan-American Neuroendocrine Society (PANS). The 10th International Congress of Neuroendocrinology (ICN) took place from the 7 to 10th August 2022 at the Scottish Events Campus in Glasgow, Scotland. In this exciting time for neuroendocrinology worldwide, I look forward to the international community assembling again for the 11th International Congress of Neuroendocrinology in 2026 in Nagoya, Japan, to again discuss our progress and potential. [Extracted from the article]

The purpose of the RegPep2020 Special Issue is to take note of recent developments in the field of regulatory peptides, and to emphasise the theme of RegPep2020, namely "Regulatory Peptides in Systems Physiology". It was hypothesised at the time that the RFamide motif is so highly conserved and widespread because it provides "punctation" for the passage through the large dense-core vesicle secretory system, which includes processing enzymes for prohormone conversion to mature small peptides, and for amidation, which in many cases is a requirement for peptide biological activity. This linkage is sought mainly by examining the phenomenology of dysfunction of hypothalamic orexigenic and anorexigenic peptides, at the level of peptide expression, in the PWS hypothalamus. [Extracted from the article]

Nutrition across the lifespan encompasses both preventative and treatment options to maintain health and vitality. This review will focus on the challenge of overconsumption of energy relative to energy expenditure and the consequent development of overweight and obesity, since they are responsible for much of the burden of chronic disease in the developed world. Understanding the mechanisms of hunger and satiety and how particular foodstuffs and nutrients affect appetite and motivation to eat is important for evidence-based interventions to achieve weight control and design of community-wide dietary strategies that reach across the lifespan. Food reformulation for appetite control and weight management requires a knowledge of the mechanisms of hunger and satiety, how food interacts with peripheral and central regulatory systems, and how these interactions change across the lifecourse, allied to the technical capability to generate, evaluate and develop new ingredients and foods with enhanced biological potency based on these mechanisms. Two European Union-funded research projects, Full4Health and SATIN, are adopting these complementary approaches. These research projects straddle the sometimes conflicted ground between justifiable public health concerns on the one hand and the food and drink industry on the other. These multi-disciplinary projects pull together expertise in nutrition, neuroimaging, psychology and food technology that combines with food industry partners to maximise expected impact of the research. Better knowledge of mechanisms regulating hunger/satiety will lead to evidence base for preventive strategies for the European population, to reduction of chronic disease burden and to increased competitiveness of European food industry through the development of new food products. [ABSTRACT FROM PUBLISHER]

Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation. Conclusion: This study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status. [ABSTRACT FROM AUTHOR]

Oxidative stress and endothelial dysfunction contribute to vascular complication in diabetes. Extracellular superoxide dismutase (SOD3) is one of the key antioxidant enzymes that obtains copper via copper transporter ATP7A. SOD3 is secreted from vascular smooth muscles cells (VSMCs) and anchors at the endothelial surface. The role of SOD3 and ATP7A in endothelial dysfunction in type 1 diabetes mellitus (T1DM) is entirely unknown. Here we show that the specific activity of SOD3, but not SOD, is decreased, which is associated with increased ... production in aortas of streptozotocin-induced and genetically induced Ins2Akita T1DM mice. Exogenous copper partially rescued SOD3 activity in isolated T1DM vessels. Functionally, acetylcholine-induced, endothelium-dependent relaxation is impaired in T1DM mesenteric arteries, which is rescued by SOD mimetic tempol or gene transfer of SOD3. Mechanistically, ATP7A expression in T1DM vessels is dramatically decreased whereas other copper transport proteins are not altered. T1DM-induced endothelial dysfunction and decrease of SOD3 activity are rescued in transgenic mice overexpressing ATP7A. Furthermore, SOD3-deficient T1DM mice or ATP7A mutant T1DM mice augment endothelial dysfunction and vascular ... production versus T1DM mice. These effects are in part due to hypoinsulinemia in T1DM mice, since insulin treatment, but not high glucose, increases ATP7A expression in VSMCs and restores SOD3 activity in the organoid culture of T1DM vessels. In summary, a decrease in ATP7A protein expression contributes to impaired SOD3 activity, resulting in ... overproduction and endothelial dysfunction in blood vessels of T1DM. Thus, restoring copper transporter function is an essential therapeutic approach for oxidant stress-dependent vascular and metabolic diseases. [ABSTRACT FROM AUTHOR]

Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved mRNA surveillance system that degrades mRNA transcripts that harbour a premature translation-termination codon (PTC), thus reducing the synthesis of truncated proteins that would otherwise have deleterious effects. Although extensive research has identified a conserved repertoire of NMD factors, these studies have been performed with a restricted set of genes and gene constructs with relatively few exons. As a consequence, NMD mechanisms are poorly understood for genes with large 39 terminal exons, and the applicability of the current models to large multi-exon genes is not clear. In this Commentary, we present an overview of the current understanding of NMD and discuss how analysis of nonsense mutations in the collagen gene family has provided new mechanistic insights into this process. Although NMD of the collagen genes with numerous small exons is consistent with the widely accepted exon-junction complex (EJC)-dependent model, the degradation of Col10a1 transcripts with nonsense mutations cannot be explained by any of the current NMD models. Col10a1 NMD might represent a fail-safe mechanism for genes that have large 39 terminal exons. Defining the mechanistic complexity of NMD is important to allow us to understand the pathophysiology of the numerous genetic disorders caused by PTC mutations. [ABSTRACT FROM AUTHOR]

Exposure to short days (SD) induces profound changes in the physiology and behaviour of Siberian hamsters, including gonadal regression and up to 30% loss in body weight. In a continuous SD environment after approximately 20 weeks, Siberian hamsters spontaneously revert to a long day (LD) phenotype, a phenomenon referred to as the photorefractory response. Previously we have identified a number of genes that are regulated by short photoperiod in the neuropil and ventricular ependymal (VE) cells of the hypothalamus, although their importance and contribution to photoperiod induced physiology is unclear. In this refractory model we hypothesised that the return to LD physiology involves reversal of SD expression levels of key hypothalamic genes to their LD values and thereby implicate genes required for LD physiology. Male Siberian hamsters were kept in either LD or SD for up to 39 weeks during which time SD hamster body weight decreased before increasing, after more than 20 weeks, back to LD values. Brain tissue was collected between 14 and 39 weeks for in situ hybridization to determine hypothalamic gene expression. In VE cells lining the third ventricle, expression of nestin, vimentin, Crbp1 and Gpr50 were down-regulated at 18 weeks in SD photoperiod, but expression was not restored to the LD level in photorefractory hamsters. Dio2, Mct8 and Tsh-r expression were altered by SD photoperiod and were fully restored, or even exceeded values found in LD hamsters in the refractory state. In hypothalamic nuclei, expression of Srif and Mc3r mRNAs was altered at 18 weeks in SD, but were similar to LD expression values in photorefractory hamsters. We conclude that in refractory hamsters not all VE cell functions are required to establish LD physiology. However, thyroid hormone signalling from ependymal cells and reversal of neuronal gene expression appear to be essential for the SD refractory response. [ABSTRACT FROM AUTHOR]

A substantial proportion of noncommunicable disease originates in habitual overconsumption of calories, which can lead to weight gain and obesity and attendant comorbidities. At the other end of the spectrum, the consequences of undernutrition in early life and at different stages of adult life can also have major impact on wellbeing and quality of life. To help address some of these issues, greater understanding is required of interactions with food and contemporary diets throughout the life course and at a number of different levels: physiological, metabolic, psychological, and emotional. Here we review the current literature on the effects of dietary manipulation on anxiety-like behaviour. This evidence, assembled from study of preclinical models of diet challenge from gestation to adult life, supports a role for diet in the important connections between psychology, physiology, and behaviour. Analogous processes in the human population in our current obesogenic environment are likely to contribute to individual and societal challenges in this area. [ABSTRACT FROM AUTHOR]

Prenatal nutritional conditions can predispose to development of obesity and metabolic syndrome in adulthood. Gestation with its important modifications in hormonal status is a period of changes in normal feeding habits with pulses of consumption or avoidance of certain categories of food. We tried to mimic in an animal model some changes in food consumption patterns observed in pregnant women. For this purpose, Long-Evans female rats were fed during the dark period, their usual pre-gestational food quantity, and were allowed to complete their daily intake with either a restricted control (Cr), high-fat (HF), or high-carbohydrate (HC) diet available ad libitum during the light period. Dams fed a control diet ad libitum (Ca) served as controls. Body weight and composition, food intake, and metabolic hormones (insulin, leptin) were recorded in male offspring until 20weeks after birth. Cr and HC females ate less than Ca females (-16%; p <0.001) and their offspring presented a weight deficit from birth until 6 (HC group) and 10 (Cr group) weeks of age (p <0.05 or less). Plasma leptin corresponded to low body weight in Cr offspring, but was increased in HC offspring that in addition, had increased plasma insulin, blood glucose, and subcutaneous adipose tissue mass. HF dams ate more than Ca dams (+13%; p <0.001), but plasma leptin and insulin were similar in their offspring. Hypothalamic Ob-Rb expression was increased in Cr, HC, and HF offspring (+33-100% vs Ca; p <0.05 or less). HC supplement ingestion during gestation therefore leads to insulin and leptin resistance in adult offspring independently of lower birth weight. These hormonal changes characterize obesity-prone animals. We therefore suggest that attention should be paid to the carbohydrate snacking and overall carbohydrate content in the diet during the last weeks (or months) preceding delivery to limit development of later metabolic disorders in offspring. [ABSTRACT FROM AUTHOR]

The Siberian hamster, Phodopus sungorus, undergoes a striking seasonal cycle of leptin sensitivity and body weight regulation, but the molecular mechanism and relevance to human leptin insensitivity are unknown. Here we show that nuclear translocation of phospho-STAT3 in the hypothalamus is rapidly stimulated by leptin to a greater extent in hamsters held in short-day length (SD) as compared to long-day length (LD). Intriguingly, effects of leptin on STAT3 appeared to be in part limited to nuclear translocation of phospho-STAT3 associated with the cell surface rather than phosphorylation of STAT3. The number of phospho-ERK cells within the hypothalamus was unaffected by either photoperiod or leptin. However, proximal to ERK phosphorylation, hypothalamic SH2-containing tyrosine phosphatase (SHP2) and the small growth factor receptor-binding protein (GRB2), which act as competitive negative modulators on binding of SOCS3 to leptin receptor (LRb)-associated Tyr, were increased in SD compared to LD. Our findings suggest that activation of STAT3 by leptin may be dependent on interaction of stimulatory SHP2/GRB2 as well as inhibitory SOCS3 on the level of competitive binding to LRb-associated Tyr. This hypothetical mechanism may represent the molecular identity of seasonally induced adjustments in leptin sensitivity and may be applied to investigating leptin sensitivity in other rodent models. [ABSTRACT FROM AUTHOR]

Copper transport and accumulation were studied in virgin and lactating C57BL/6 mice, with and without expression of ceruloplasmin (Cp), to assess the importance of Cp to these processes. One hour after i.p. injection of tracer Cu, liver and kidney accounted for 80% of the radioactivity, and mammary gland 1%, while in lactating Cp+/+ mice 2-4 days post partum, uptake by mammary gland was 9-fold higher and that of liver and other organs was decreased, with Cu rapidly appearing in milk. Parallel studies in Cp−/− mice (siblings from same colony) gave virtually identical results. However, their milk contained less Cu, and actual copper contents determined by furnace atomic absorption were less than half those for milk from normal dams. Liver copper concentrations of pups born to Cp−/− dams also were half those of pups from wild type dams. Copper in pup brains was unaffected; but iron concentrations were reduced. We conclude that absence of Cp, while not affecting entry of exchangeable copper from the blood into the mammary gland, does have a significant effect on the availability of this metal to the newborn through the milk and in the form of stores accumulating in gestation. [ABSTRACT FROM AUTHOR]

Background: ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinuminduced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks. Results: In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals. Conclusions: In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin. [ABSTRACT FROM AUTHOR]

We report the neuronal expression of copper transporter 1 (CTR1) in rat dorsal root ganglia (DRG) and its association with the neurotoxicity of platinum-based drugs. CTR1 expression was studied by immunohistochemistry and RT-PCR. The toxicity of platinum drugs to CTR1-positive and CTR1-negative neurons was compared in DRG from animals treated with maximum tolerated doses of oxaliplatin (1.85 mg/kg), cisplatin (1 mg/kg) or carboplatin (8 mg/kg) twice weekly for 8 weeks. Abundant CTR1 mRNA was detected in DRG tissue. CTR1 immunoreactivity was associated with plasma membranes and cytoplasmic vesicular structures of a subpopulation (13.6 ± 3.1%) of mainly large-sized (mean cell body area, 1,787 ± 127 μm2) DRG neurons. After treatment with platinum drugs, the cell bodies of these CTR1-positive neurons became atrophied, with oxaliplatin causing the greatest percentage reduction in the mean cell body area relative to controls (42%; P < 0.05), followed by cisplatin (18%; P < 0.05) and carboplatin causing the least reduction (3.2%; P = NS). CTR1-negative neurons, with no immunoreactivity or only diffuse cytoplasmic staining, showed less treatment-induced cell body atrophy than CTR1-positive neurons. CTR1 is preferentially expressed by a subset of DRG neurons that are particularly vulnerable to the toxicity of platinum drugs. These findings, together with its neuronal membrane localization, are suggestive of CTR1-related mechanisms of platinum drug neuronal uptake and neurotoxicity. [ABSTRACT FROM AUTHOR]

Central regulation of energy balance in seasonal mammals such as the Siberian hamster is dependent on the precise integration of short-term satiety information arising from the gastrointestinal tract with long-term signals on the status of available energy reserves (e.g. leptin) and prevailing photoperiod. Within the central nervous system, the brainstem nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN) are major relay nuclei that transmit information from the gastrointestinal tract to higher forebrain centres. We extended studies on the seasonal programming of the hypothalamus to examine the effect of the photoperiod on neuropeptidergic circuitries of this gut–brain axis. In the NTS and PBN we performed gene expression and immunoreactivity (-ir) studies on selected satiety-related neuropeptides and receptors: alpha-melanocyte stimulating hormone, melanocortin-3 receptor, melanocortin-4 receptor (MC4-R), growth hormone secretagogue-receptor, cocaine- and amphetamine-regulated transcript, preproglucagon (PPG), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY, galanin, neurotensin, and corticotrophin releasing hormone (CRH). Gene expression of PPG and MC4-R, and -ir of CCK and GLP-1, in the NTS were up-regulated after 14 weeks in long-day photoperiod (16 h light:8 h dark) compared to short-days (8 h light:16 h dark), whereas CRH-ir and NT-ir were increased in short-days within the PBN. We suggest that brainstem neuroendocrine mechanisms contribute to the long-term regulation of body mass in the Siberian hamster by a photoperiod-related modulation of satiety signalling. [ABSTRACT FROM AUTHOR]

In the Siberian hamster, seasonal weight loss occurs gradually over many weeks during autumn and winter. This is driven by a regulatory mechanism that is able to integrate duration of exposure to short days (SDs) with the size of body energy reserves. After food restriction in SDs, followed by ad libitum refeeding, body weight of the hamster does not return to its former level; rather, it increases to a level defined by the length of time spent in SDs. In this report, we show that components of the thyroid hormone system that are involved in seasonal weight loss change expression in response to 48 h of starvation. Eight weeks in an SD photoperiod induced weight loss in the Siberian hamster. In the hypothalamus of these hamsters, type II deiodinase expression was decreased and type III deiodinase expression was induced, but there was no change in hypothalamic neuropeptide Y or thyrotropinreleasing hormone gene expression. For the first time, we show that the thyroid hormone transporter monocarboxylate transporter 8 is expressed in tanycytes and is increased in response to an SD photo- period. Food restriction (48 h of starvation) reversed the direction of gene expression change for type II and III deiodinase and monocarboxylate transporter 8 induced by SD photoperiods. Furthermore, fasting increased neuropeptide Y expression and decreased thyrotropin-releasing hormone expression. VGF, a gene upregulated in SDs in the dorsal region of the medial posterior area of the arcuate nucleus, was not changed by starvation. These data point to a mechanism whereby energy deprivation can interact with an SD photoperiod on hypothalamic tanycytes to regulate components of the thyroid hormone system involved in photoperiodic regulation of seasonal physiology. [ABSTRACT FROM AUTHOR]

The proportion of the child and adolescent population that is in appropriate energy balance is declining throughout the developed world, and childhood obesity is a particular problem in the UK relative to other northern European countries. Assessment of the underlying causes of obesity, and the different routes to its development, may assist in the definition of successful intervention strategies. The network of peripheral and central (brain) regulatory systems that underlie energy balance and body weight and composition can, for the most part, only be approached experimentally through the study of appropriate laboratory animal models. This problem is particularly acute when the target is overweight and obesity in the young. Some of the mechanisms underlying the development of energy imbalance and specifically the onset of overweight and obesity in the young, and the metabolic health consequences of obesity, can be addressed by examination of experimental rodent models in which mutation of a single gene causes early-onset extreme obesity, genetic susceptibility to obesity is revealed in an obesogenic environment or early-life nutritional experience programmes susceptibility to obesity or metabolic problems in later life. These studies highlight genes that are essential to normal body-weight regulation in rodents and man, the impact of diet and diet-induced obesity on regulatory systems in the young and the potential sensitivity of developing regulatory systems to nutritional experiences in utero and during early life. [ABSTRACT FROM PUBLISHER]

Ionic copper entering blood plasma binds tightly to albumin and the macroglobulin transcuprein. It then goes primarily to the liver and kidney except in lactation, where a large portion goes directly to the mammary gland. Little is known about how this copper is taken up from these plasma proteins. To examine this, the kinetics of uptake from purified human albumin and α2-macroglobulin, and the effects of inhibitors, were measured using human hepatic (HepG2) and mammary epithelial (PMC42) cell lines. At physiological concentrations (3-6 µM), both cell types took up copper from these proteins independently and at rates similar to each other and to those for Cu-dihistidine or Cu-nitrilotriacetate (NTA). Uptakes from α2-macroglobulin indicated a single saturable system in each cell type, but with different kinetics, and 65-80% inhibition by Ag(I) in HepG2 cells but not PMC42 cells. Uptake kinetics for Cu-albumin were more complex and also differed with cell type (as was the case for Cu-histidine and NTA), and there was little or no inhibition by Ag(I). High Fe(II) concentrations (100-500 µM) inhibited copper uptake from albumin by 20-30% in both cell types and that from α2-macroglobulin by 0-30%, and there was no inhibition of the latter by Mn(II) or Zn(II). We conclude that the proteins mainly responsible for the plasma-exchangeable copper pool deliver the metal to mammalian cells efficiently and by several different mechanisms. α2-Macroglobulin delivers it primarily to copper transporter 1 in hepatic cells but not mammary epithelial cells, and additional as-yet-unidentified copper transporters or systems for uptake from these proteins remain to be identified. [ABSTRACT FROM AUTHOR]

Hypothalamic energy balance genes have been examined in the context of seasonal body weight regulation in the Siberian hamster. Most of these long photoperiod (LD)/short photoperiod (SD) comparisons have been of tissues collected at a single point in the light-dark cycle. We examined the diurnal expression profile of hypothalamic genes in hamsters killed at 3-h intervals throughout the light-dark cycle after housing in LD or SD for 12 wk. Gene expression of neuropeptide Y, agouti-related peptide, proopiomelanocortin, cocaine- and amphetamine-regulated transcript, long-form leptin receptor, suppressor of cytokine signaling-3, melanocortin-3 receptor, melanocortin-4 receptor, and the clock gene Perl as control were measured by in situ hybridization in hypothalamic nuclei. Effects of photoperiod on gene expression and leptin levels were generally consistent with previous reports. A clear diurnal variation was observed for Pen in the suprachiasmatic nucleus in both photoperiods. Temporal effects on expression of energy balance genes were restricted to long-form leptin receptor in the arcuate nucleus and ventromedial nucleus, where similar diurnal expression profiles were observed, and melanocortin-4 receptor in the paraventricular nucleus; these effects were only observed in LD hamsters. There was no variation in serum leptin concentration. The 24-h profiles of hypothalamic energy balance gene expression broadly confirm photoperiodic differences that were observed previously, based on single time point comparisons, support the growing consensus that these genes have a limited role in seasonal body weight regulation, and further suggest limited involvement in daily rhythms of food intake. [ABSTRACT FROM AUTHOR]

The protein affected in Menkes disease, ATP7A, is a copper (Cu)-transporting P-type ATPase that plays an important role in Cu homeostasis, but the full extent of this role has not been defined at a systemic level. Transgenic mice that overexpress the human ATP7A from the chicken beta-actin composite promoter (CAG) were used to further investigate the physiological function of ATP7A. Overexpression of ATP7A in the mice caused disturbances in Cu homeostasis, with depletion of Cu in some tissues, especially the heart. To investigate the effect of overexpression of ATP7A when dietary Cu intake was markedly increased, normal and transgenic mice were exposed to drinking water containing 300 mg/L of Cu as Cu acetate for 3 mo. Cu exposure resulted in partial restoration of heart Cu concentrations in male transgenic mice. Despite the extended period of Cu exposure, Cu concentrations in the liver remained relatively unaffected, with a significant increase in male nontransgenic mice. Liver pathology was unremarkable except for small areas of fibrosis that were detected only in livers of the Cu-exposed transgenic mice. Intracellular localization of ATP7A in various tissues was not affected by Cu exposure. Plasma Cu concentration and ceruloplasmin oxidase activity were reduced in both Cu-exposed transgenic and nontransgenic mice. The expression levels of other candidate Cu homeostatic proteins, endogenous Atp7b, ceruloplasmin, Ctr1, and transgenic ATP7A were not altered significantly by Cu exposure. Overall, mice are remarkably resistant to high Cu loads and the overexpression of ATP7A has only moderate effects on the response to Cu exposure. [ABSTRACT FROM AUTHOR]

Obesity has recently become a focus of research to elucidate diet and lifestyle factors as important risk factors for colon cancer. Altered levels of insulin, leptin, and adiponectin have been identified as potential candidates increasing colon cancer risk within the prevailing obesogenic environment. There has been considerable research to characterize signaling via these hormones in the brain, liver, and adipose tissue; however, very little is known of their emerging role in peripheral signaling, particularly in epithelial tissues. This study profiles insulin, leptin, and adipokine receptors in the rat colon, revealing novel microanatomical location of these receptors and thereby supporting a potential role in regulating colonic tissue. Potential involvement of insulin, leptin, and adiponectin receptors in increased risk of colon cancer was investigated using Sprague-Dawley rats, either resistant or susceptible to diet-induced obesity. Regulation of insulin, leptin, and adiponectin receptors as a consequence of differing levels of adiposity was assessed regionally in the colon in response to treatment with the chemical carcinogen 1,2-dimethylhydrazine (DMH). However, significantly increased fat mass, increased levels of plasma insulin, leptin, and triglycerides, previously associated with an increased risk of colon cancer, were not associated with promotion of precancerous lesions in the experimental rats or deregulation of insulin, leptin, or adiponectin receptors. These findings do not support a direct link between the deregulation of insulin and adipokine levels observed in obese rats and an increased risk of colon carcinogenesis. [ABSTRACT FROM AUTHOR]

Previously, 40% food restriction of male Siberian hamsters over 21 days in short-day (SD) photoperiod induced characteristic changes in expression of hypothalamic arcuate nucleus energy balance genes; mRNAs for neuropeptide Y, agouti-related peptide, and leptin receptor were upregulated, and those of proopiomelanocortin and cocaine- and amphetamine-regulated transcript were depressed. The present study examined the effect of refeeding hamsters for 6 days (~50% recovery of weight differential) or 19 days (resumption of appropriate weight trajectory). Hyperphagia continued throughout refeeding, but differences in fat pad weights and leptin levels had disappeared after 19 days. Cocaine- and amphetamine-regulated transcript gene expression was depressed by prior restriction in both refed groups. The depressive effect of prior restriction on proopiomelanocortin gene expression had disappeared after 19 days of refeeding. There was no effect of prior food restriction on neuropeptide Y or agouti-related peptide gene expression. Expression of the anorexigenic brain-derived neurotrophic factor was down- regulated in the ventromedial nucleus after SD exposure for 12 wk. In the SD food restriction study, there were effects of photoperiod on brain-derived neurotrophic factor gene expression but not of prior food restriction. Hypothalamic energy balance genes in the hamster respond asynchronously to return to a seasonally appropriate body weight. The achievement of this weight rather than the weight at which caloric restriction was imposed is the critical factor. The differential responses of hypothalamic energy balance genes to food restriction and refeeding are poorly characterized in any species, a critical issue given their potential relevance to human weight loss strategies that involve caloric restriction. [ABSTRACT FROM AUTHOR]

Contemporary foods and beverages that constitute the diets of adults and children almost certainly contribute to the obesity problem. To develop a model of childhood obesity, we examined the effects of feeding juvenile rats 2 solid diets, either alone or in combination [nonpurified control diet (C), high-energy (HE), or C+HE] with or without the liquid supplement Ensure (EN). Rats were fed C until 4 wk of age and then were assigned to 1 of 6 weight-matched groups that were fed C, HE, C+HE, C+EN, HE+EN, or C+HE+EN for 5 wk. EN accelerated weight gain and increased energy intake and adiposity irrespective of the solid diet consumed. Serum leptin concentrations were increased after the consumption of all diets when compared with C rats, but there was dissociation between leptin levels and adiposity. The type of solid diet had no effect on the expression of a panel of hypothalamic genes except for glutamate-decarboxylase-67. EN decreased mRNA for agouti-related peptide and neuropeptide Y in the arcuate nucleus and DYN in the paraventricular nucleus. Dynorphin and CART mRNA were decreased in the supraoptic retrochiasmatic nucleus. The reduction in orexigenic signaling in the hypothalamus suggests that overconsumption of EN is sensed by the hypothalamus but that any initiated physiological responses fail to compensate effectively and may be negated or overwhelmed by other systems. Providing diets in solid and liquid form, with choice, mimics more closely the human environment. Understanding the interactions between these diets and peripheral and central energy balance systems could be crucial in unraveling the events underlying human obesity and its early development. [ABSTRACT FROM AUTHOR]

Rodent models of diet-induced obesity (DIO) mimic common human obesity more accurately than obese single-gene mutation lines, such as the ob/ob mouse. Sprague-Dawley rats sourced in the UK develop obesity when fed a high-energy diet, but susceptibility to DIO is normally distributed, as might be anticipated for a polygenic trait in an outbred population, in contrast to reports in the literature using ostensibly the same strain of rats sourced in the USA. Nevertheless, the responses of these rats to solid and liquid obesogenic diets are very similar to those reported elsewhere, and this model of DIO has much to commend it as a vehicle for the mechanistic study of susceptibility to DIO, development and reversal of obesity on solid and liquid diets and the response of peripheral and central energy balance systems to the development of obesity and to the obesogenic diets themselves. In general, hypothalamic energy-balance-related systems respond to obesogenic diets and developing obesity with activity changes that appear designed to counter the further development of the obese state. However, these hypothalamic changes are apparently unable to maintain body weight and composition within normal limits, suggesting that attributes of the obesogenic diets either evade the normal regulatory systems and/or engage with reward pathways that override the homeostatic systems. Since diets are a risk factor in the development of obesity, it will be important to establish how obesogenic diets interact with energy-balance pathways and whether there is potential for diets to be manipulated with therapeutic benefit. [ABSTRACT FROM PUBLISHER]

During the last 5 years it has been well established that photoperiod-induced changes in body weight in the seasonal hamster, Phodopus sungorus, are accompanied by a marked seasonal cycle in leptin sensitivity. In the present study, we investigated the possible involvement of insulin signaling in seasonal body weight regulation. We analyzed the expression pattern and relative intensity of insulin receptor (IR), phosphatidylinositol 3-kinase (PI3-kinase), and protein tyrosine phosphatase IB (PTPIB) mRNAs by in situ hybridization in the brains of juvenile female hamsters acclimated to either long-(LD) or short-day length (SD) for 8 wk, with or without superimposed food deprivation for 48 h. Furthermore, the hypothalamic concentration and distribution of phospho-AKT, a marker of PI3-kinase activity was determined by immunoblotting and immunohistochemistry. Eight weeks of acclimation to SD led to a substantial downregulation of IR, PTPIB gene expression, and phospho-AKT concentration in this brain region, whereas PI3-kinase mRNA was unchanged. Food deprivation induced a decrease in PTPIB and a trend toward lowered IR gene expression in LD but not in SD. Additionally, a striking increase in PTPIB gene expression in the thalamus was observed after food deprivation in both photoperiods. The direction of change in neuronal insulin signaling contrasts to the central catabolic nature of this pathway described in other species. SD-induced reduction in insulin signaling may be due to decline in body fat stores mediated by enhanced central leptin sensitivity. Increased anorexigenic tone of leptin may overwrite central insulin signaling to prevent catabolic overdrive. [ABSTRACT FROM AUTHOR]

The article presents a scientific research which focuses on the alteration of copper physiology in mice overexpressing ATP7A, a human Menkes protein. Transgenic mice expressing ATP7A from chicken β -actin composite promoter were used to fully examine the role of ATP7A. Researchers gave special interest in the topic due to the importance of copper homeostatic mechanisms in genetic disorders like Menkes and Wilson diseases.

The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane. [ABSTRACT FROM AUTHOR]

Neuromedin-U (NMU) has been reported to drive several physiological or behavioural responses following i.c.v. injection of the peptide into the third ventricle of rodent brains. Many of these responses are mediated through a change in corticotrophin-releasing factor (CRF) output from the paraventricular nucleus (PVN). A number of the physiological or behavioural responses are regulated in a circadian manner, e.g. feeding. We have previously reported NMU gene expression in the suprachiasmatci nucleus (SCN) and NMU-2 receptor expression in the PVN, dorsal medial hypothalamus (DMH) and other regions of the mouse brain. We therefore hypothesized that NMU would be regulated by the circadian clock and may consequently drive a circadian rhythm of CRF expression in the PVN. Here we report that NMU is regulated in a circadian manner with peak expression during the light phase of a light–dark cycle. In C3H mice held in constant darkness, the NMU rhythm free runs with a period predicted by the free running period of locomotor activity in this mouse. The NMU mRNA transcript colocalizes with cells expressing AVP in the SCN and shows a coincident rhythm of expression with AVP. On the other hand, CRF did not express a circadian rhythm of expression in a light–dark cycle, although a rhythm was evident in constant darkness with a peak of expression prior to the rise of NMU in the same conditions. This would suggest that the circadian rhythm in NMU expression in the SCN does not drive a circadian rhythm in CRF in the PVN to be translated into physiological and behavioural responses mediated by NMU. [ABSTRACT FROM AUTHOR]

The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. Thetxmouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct thetxmouse phenotype.Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-oldtxmice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplantedtxmice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.Repopulation in recipienttxmice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g,n = 11) compared to non-repopulated animals (866 ± 62 µg/g,n = 14) and untreated controls (910 ± 103 µg/g,n = 6;P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain. [ABSTRACT FROM AUTHOR]

High circulating concentrations of leptin in obesity are associated with an apparent loss of its characteristic anorexic action within the hypothalamic region of the brain. Central insensitivity to leptin may therefore contribute to the aetiology of this disease, and an increased understanding of the underlying mechanisms will identify potential means of prevention and/or therapeutic targets. Seasonal animals such as sheep and Siberian hamsters (Phodopus sungorus) exhibit annual photoperiod-driven cycles of appetite and body weight. Increased food intake and weight gain in long days (summer) are associated with high circulating leptin, and decreased intake and weight loss in short days (winter) with low leptin. Critically, these cycles are associated with reversible changes in sensitivity to leptin. High sensitivity is seen in short days and relative insensitivity in long days, demonstrated both in sheep given leptin centrally via intracerebroventricular cannulas and in hamsters given leptin peripherally. In addition, primary hypothalamic appetite-regulating targets for leptin (i.e. neuropeptide Y, melanocortin and cocaine- and amphetamine-regulated transcript pathways) respond differently in these species to changes in circulating leptin and nutritional status induced by photoperiod as opposed to such changes induced by food restriction. Studies of seasonal animals will help to resolve causes of altered sensitivity to leptin and whether these changes reflect altered transport into the brain and/or altered signalling at the receptor or post-receptor level. Increased knowledge of the mechanism(s) and time-course for development and reversal of reduced central leptin sensitivity will provide new insights into the development and control of obesity. [ABSTRACT FROM AUTHOR]

High circulating concentrations of leptin in obesity are associated with an apparent loss of its characteristic anorexic action within the hypothalamic region of the brain. Central insensitivity to leptin may therefore contribute to the aetiology of this disease, and an increased understanding of the underlying mechanisms will identify potential means of prevention and/or therapeutic targets. Seasonal animals such as sheep and Siberian hamsters (Phodopus sungorus) exhibit annual photoperiod-driven cycles of appetite and body weight. Increased food intake and weight gain in long days (summer) are associated with high circulating leptin, and decreased intake and weight loss in short days (winter) with low leptin. Critically, these cycles are associated with reversible changes in sensitivity to leptin. High sensitivity is seen in short days and relative insensitivity in long days, demonstrated both in sheep given leptin centrally via intracerebroventricular cannulas and in hamsters given leptin peripherally. In addition, primary hypothalamic appetite-regulating targets for leptin (i.e. neuropeptide Y, melanocortin and cocaine- and amphetamine-regulated transcript pathways) respond differently in these species to changes in circulating leptin and nutritional status induced by photoperiod as opposed to such changes induced by food restriction. Studies of seasonal animals will help to resolve causes of altered sensitivity to leptin and whether these changes reflect altered transport into the brain and/or altered signalling at the receptor or post-receptor level. Increased knowledge of the mechanism(s) and time-course for development and reversal of reduced central leptin sensitivity will provide new insights into the development and control of obesity. [ABSTRACT FROM PUBLISHER]

Oxidized fats affect animal metabolism in several ways. To gain a comprehensive understanding of the molecular mechanisms underlying the effects of dietary oxidized fats in rats at varying dietary vitamin E concentrations, the gene expression profile of the liver was monitored with an array containing 1176 binding sites for cDNAs. Rats were fed diets with a fresh fat and vitamin E concentrations of 25 or 250 mg αtocopherol/kg (FF25, FF250 rats) or a fat heated at 50°C for 38 d, with vitamin E concentrations of 25 or 250 mg αtocopherol/kg (OF25, OF250 rats) for 63 d. Differences in gene expression were considered to be significant at a ratio of at least 1.4. In the OF25 rats, the expression of 47 genes was altered; in the OF250 rats, the expression of 37 genes was altered, and in the FF250 rats, the expression of 21 genes was altered compared with FF25 rats. In both OF25 and OF250 rats, a series of target genes of the peroxisome proliferator-activated receptor α (PPARα) was upregulated. Determination of gene expression of acyl CoA oxidase and activity of catalase confirmed that oxidized fats caused peroxisome proliferation in the liver. In OF25 and OF250 rats, there was also upregulation of 12 and 5 genes involved in xenobiotic metabolism and stress response, of 7 and 7 genes involved in protein metabolism, of 5 and 2 genes encoding intracellular effectors or modulators and of 5 and 6 genes, respectively, encoding activators or repressors of transcription or translation. In conclusion, this study provides indirect evidence that dietary oxidized fats cause an activation of the PPARα irrespective of the dietary vitamin E concentration. Identification of several other differentially regulated genes may be helpful to understand the effects of oxidized fats on animal metabolism. [ABSTRACT FROM AUTHOR]

Investigates the importance of molecular and cellular aspects of copper transport in developing mammals. Classification of copper as an essential trace element that requires tightly regulated homeostatic mechanisms; Ensurance of adequate copper supplies without any toxic effects; Ability of the metal ion to catalyze the formation of free radicals.

The Menkes protein (MNK) and Wilson protein (WND) are transmembrane, CPX-type Cu-ATPases with six metal binding sites (MBSs) in the N-terminal region containing the motif GMXCXXC. In cells cultured in low copper concentration MNK and WND localize to the transGolgi network but in high copper relocalize either to the plasma membrane (MNK) or a vesicular compartment (WND). In this paper we investigate the role of the MBSs in Cu-transport and trafficking. The copper transport activity of MBS mutants of MNK was determined by their ability to complement a strain of Saccharomyces cerevisiae deficient in CCC2 (Δccc2), the yeast MNK/WND homologue. Mutants (CXXC to SXXS) of MBS1, MBS6, and MBSs1-3 were able to complement Δccc2 while mutants of MBS4-6, MBS5-6 and all six MBS inactivated the protein. Each of the inactive mutants also failed to display Cu-induced trafficking suggesting a correlation between trafficking and transport activity. A similar correlation was found with mutants of MNK in which various MBSs were deleted, but two constructs with deletion of MBS5-6 were unable to traffic despite retaining 25% of copper transport activity. Chimeras in which the N-terminal MBSs of MNK were replaced with the corresponding MBSs of WND were used to investigate the region of the molecules that is responsible for the difference in Cu-trafficking of MNK and WND. The chimera which included the complete WND N-terminus localized to a vesicular compartment, similar to WND in elevated copper. Deletions of various MBSs of the WND N-terminus in the chimera indicate that a targeting signal in the region of MBS6 directs either WND/MNK or WND to a vesicular compartment of the cell. [ABSTRACT FROM AUTHOR]

Investigates the role of hypothalmic melanocortin system in the regulation of food intake in the Siberian hamster. Evidence of profound seasonal decrease in food intake and body weight in short photoperiod; Potency of the melanocortin in short-term regulation of food; Absence of differential response or sensitivity to melanotan treatment.