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Energy homeostasis and metabolism in mammals are strongly influenced by seasonal changes. Variations in photoperiod patterns drive adaptations in body weight and adiposity, reflecting changes in the regulation of food intake and energy expenditure. Humans also show distinct patterns of energy balance depending on the season, being more susceptible to gaining weight during a specific time of the year. Changes in body weight are mainly reflected by the adipose tissue, which is a key metabolic tissue and is highly affected by circannual rhythms. Mostly, in summer-like (long-active) photoperiod, adipocytes adopt a rather anabolic profile, more predisposed to store energy, while food intake increases and energy expenditure is reduced. These metabolic adaptations involve molecular modifications, some of which have been studied during the last years and are summarized in this review. In addition, there is a bidirectional relation between obesity and the seasonal responses, with obesity disrupting some of the seasonal responses observed in healthy mammals, and altered seasonality being highly associated with increased risk of developing obesity. This suggests that changes in photoperiod produce important metabolic alterations in healthy organisms. Biological rhythms impact the regulation of metabolism to different extents, some of which are already known, but further research is needed to fully understand the relationship between energy balance and seasonality.

Neuroglobin (Ngb) is found in the neurones of several different brain areas and is known to bind oxygen and other gaseous molecules and reactive oxygen species (ROS) in vitro, but it does not seem to act as a respiratory molecule for neurones. Using male and female Ngb-knockout (KO) mice, we addressed the role of Ngb in neuronal brain activity using behavioral tests but found no differences in general behaviors, memory processes, and anxiety-/depression-like behaviors. Oxidative stress and ROS play key roles in epileptogenesis, and oxidative injury produced by an excessive production of free radicals is involved in the initiation and progression of epilepsy. The ROS binding properties led us to hypothesize that lack of Ngb could affect central coping with excitatory stimuli. We consequently explored whether exposure to the excitatory molecule kainate (KA) would increase severity of seizures in mice lacking Ngb. We found that the duration and severity of seizures were increased, while the latency time to develop seizures was shortened in Ngb-KO compared to wildtype adult female mice. Consistently, c-fos expression after KA was significantly increased in Ngb-KO mice in the amygdala and piriform cortex, regions rich in Ngb and known to be centrally involved in seizure generation. Moreover, the measured c-fos expression levels were correlated with seizure susceptibility. With these new findings combined with previous studies we propose that Ngb could constitute an intrinsic defense mechanism against neuronal hyperexcitability and oxidative stress by buffering of ROS in amygdala and other Ngb-containing brain regions.

Neuroglobin (Ngb) is found in the neurones of several different brain areas and is known to bind oxygen and other gaseous molecules and reactive oxygen species (ROS) in vitro, but it does not seem to act as a respiratory molecule for neurones. Using male and female Ngb-knockout (KO) mice, we addressed the role of Ngb in neuronal brain activity using behavioral tests but found no differences in general behaviors, memory processes, and anxiety-/depression-like behaviors. Oxidative stress and ROS play key roles in epileptogenesis, and oxidative injury produced by an excessive production of free radicals is involved in the initiation and progression of epilepsy. The ROS binding properties led us to hypothesize that lack of Ngb could affect central coping with excitatory stimuli. We consequently explored whether exposure to the excitatory molecule kainate (KA) would increase severity of seizures in mice lacking Ngb. We found that the duration and severity of seizures were increased, while the latency time to develop seizures was shortened in Ngb-KO compared to wildtype adult female mice. Consistently, c-fos expression after KA was significantly increased in Ngb-KO mice in the amygdala and piriform cortex, regions rich in Ngb and known to be centrally involved in seizure generation. Moreover, the measured c-fos expression levels were correlated with seizure susceptibility. With these new findings combined with previous studies we propose that Ngb could constitute an intrinsic defense mechanism against neuronal hyperexcitability and oxidative stress by buffering of ROS in amygdala and other Ngb-containing brain regions.

BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity.SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health.RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner.CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose ti

BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity.SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health.RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner.CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose ti

Background: Recently, intra-articular botulinum toxin A (IA BoNT A) has been shown to reduce joint pain in osteoarthritic dogs. Similar results have been reported in human patients with arthritis. However, the mechanism of the antinociceptive action of IA BoNT A is currently not known. The aim of this study was to explore this mechanism of action by investigating the effect of IA BoNT A on synovial fluid (SF) and serum substance P (SP), prostaglandin E-2 (PGE(2)), and tumor necrosis factor alpha (TNF-alpha) in osteoarthritic dogs. Additionally, the aim was to compare SF SP and PGE(2) between osteoarthritic and non-osteoarthritic joints, and investigate associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs. Thirty-five dogs with chronic naturally occurring osteoarthritis and 13 non-osteoarthritic control dogs were included in the study. Osteoarthritic dogs received either IA BoNT A (n = 19) or IA placebo (n = 16). Serum and SF samples were collected and osteoarthritic pain was evaluated before (baseline) and 2 and 8 weeks after treatment. Osteoarthritic pain was assessed with force platform, Helsinki Chronic Pain Index, and joint palpation. Synovial fluid samples were obtained from control dogs after euthanasia. The change from baseline in SP and PGE(2) concentration was compared between the IA BoNT A and placebo groups. The synovial fluid SP and PGE(2) concentration was compared between osteoarthritic and control joints. Associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs were evaluated. Results: There was no significant change from baseline in SP or PGE(2) after IA BoNT A. Synovial fluid PGE(2) was significantly higher in osteoarthritic compared to control joints. Synovial fluid PGE(2) correlated with osteoarthritic pain. No associations were found between SP or PGE2 and the signalment of dogs. The concentration of TNF-alpha remained under the detection limit of the assay in all samples. Conclusions: The resul

Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.

High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.

Animal and clinical studies of gene-environment interactions have helped elucidate the mechanisms involved in the pathophysiology of several mental illnesses including anxiety, depression, and schizophrenia; and have led to the discovery of improved treatments. The study of neuropeptides and their receptors is a parallel frontier of neuropsychopharmacology research and has revealed the involvement of several peptide systems in mental illnesses and identified novel targets for their treatment. Relaxin-3 is a newly discovered neuropeptide that binds, and activates the G-protein coupled receptor, RXFP3. Existing anatomical and functional evidence suggests relaxin-3 is an arousal transmitter which is highly responsive to environmental stimuli, particularly neurogenic stressors, and in turn modulates behavioral responses to these stressors and alters key neural processes, including hippocampal theta rhythm and associated learning and memory. Here, we review published experimental data on relaxin-3/RXFP3 systems in rodents, and attempt to highlight aspects that are relevant and/or potentially translatable to the etiology and treatment of major depression and anxiety. Evidence pertinent to autism spectrum and metabolism/eating disorders, or related psychiatric conditions, is also discussed. We also nominate some key experimental studies required to better establish the therapeutic potential of this intriguing neuromodulatory signaling system, including an examination of the impact of RXFP3 agonists and antagonists on the overall activity of distinct or common neural substrates and circuitry that are identified as dysfunctional in these debilitating brain diseases.

Huntington's Disease is a neurodegenerative condition caused by a polyglutamine expansion in the huntingtin (Htt) protein, which aggregates and also causes neuronal dysfunction. Pathogenic N-terminal htt fragments perturb axonal transport in vitro. To determine whether this occurs in vivo and to elucidate how transport is affected, we expressed htt exon 1 with either pathogenic (HttEx1Q93) or non-pathogenic (HttEx1Q20) polyglutamine tracts in Drosophila. We found that HttEx1Q93 expression causes axonal accumulation of GFP-tagged fast axonal transport vesicles in vivo and leads to aggregates within larval motor neuron axons. Time-lapse video microscopy, shows that vesicle velocity is unchanged in HttEx1Q93-axons compared to HttEx1Q20-axons, but vesicle stalling occurs to a greater extent. Whilst HttEx1Q93 expression did not affect locomotor behaviour, external heat stress unveiled a locomotion deficit in HttEx1Q93 larvae. Therefore vesicle transport abnormalities amidst axonal htt aggregation places a cumulative burden upon normal neuronal function under stressful conditions.

Huntington's Disease is a neurodegenerative condition caused by a polyglutamine expansion in the huntingtin (Htt) protein, which aggregates and also causes neuronal dysfunction. Pathogenic N-terminal htt fragments perturb axonal transport in vitro. To determine whether this occurs in vivo and to elucidate how transport is affected, we expressed htt exon 1 with either pathogenic (HttEx1Q93) or non-pathogenic (HttEx1Q20) polyglutamine tracts in Drosophila. We found that HttEx1Q93 expression causes axonal accumulation of GFP-tagged fast axonal transport vesicles in vivo and leads to aggregates within larval motor neuron axons. Time-lapse video microscopy, shows that vesicle velocity is unchanged in HttEx1Q93-axons compared to HttEx1Q20-axons, but vesicle stalling occurs to a greater extent. Whilst HttEx1Q93 expression did not affect locomotor behaviour, external heat stress unveiled a locomotion deficit in HttEx1Q93 larvae. Therefore vesicle transport abnormalities amidst axonal htt aggregation places a cumulative burden upon normal neuronal function under stressful conditions.

The chemical synthesis of moderate-sized proteins has benefited enormously from the development of chemoselective methods for the ligation of peptide fragments. In this regard, the reaction of peptide thioesters with peptides containing an N-terminal cysteine has proved particularly powerful. The thiol side chain of cysteine attacks the thioester and subsequent acyl transfer from sulfur to the amine yields a native peptide bond. Homocysteine, sulfur-containing auxiliary groups, and selenocysteine have also been exploited to mediate ligations to thioesters, thus broadening the scope of the method. Herein we show that selenohomocysteine can also facilitate efficient peptide ligation. Subsequent methylation of the resulting selenol affords selenomethionine at the ligation site, which is a useful probe for NMR spectroscopic and X-ray crystallographic investigations of biomolecules.

Whilst there have been many studies in various species examining the effects of leptin on food intake, there is a paucity of data comparing responsiveness in the two sexes. We have, therefore, addressed this issue in sheep. Because this species shows seasonal variation in voluntary food intake (VFI), we also considered the possibility that there might be seasonal variation in the responsivity to leptin. Centrally administered leptin was relatively ineffective as a satiety factor in either sex during AUTUMN: In Spring, leptin had a profound inhibitory effect on VFI in the females, but only a slight effect in males. These data indicate that responsiveness to leptin depends on sex and also on season in animals that are substantially affected by photoperiod.

Whilst there have been many studies in various species examining the effects of leptin on food intake, there is a paucity of data comparing responsiveness in the two sexes. We have, therefore, addressed this issue in sheep. Because this species shows seasonal variation in voluntary food intake (VFI), we also considered the possibility that there might be seasonal variation in the responsivity to leptin. Centrally administered leptin was relatively ineffective as a satiety factor in either sex during AUTUMN: In Spring, leptin had a profound inhibitory effect on VFI in the females, but only a slight effect in males. These data indicate that responsiveness to leptin depends on sex and also on season in animals that are substantially affected by photoperiod.

There is increasing clinical and experimental evidence that neuropeptide-Y (NPY), a 26-amino-acid sequence reported to be one of the most prevalent neuropeptides in the brain, plays an important role in modulation of memory. Clinically, the finding of reduced NPY immunoreactivity in the cortex and hippocampus of patients with Alzheimer's disease as well as the presence of NPY-like immunoreactivity in neuronal plaques has implicated has implicated NPY in the pathogenesis of senile dementia of the Alzheimer's type. Experimentally, posttraining administration of NPY has been shown to enhance retention for both active and passive avoidance in mice. Administration of NPY prior to a retention test improves recall in mice, and NPY reverses amnesia induced by scopolamine or anisomysin. NPY administered directly into the forebrain hippocampal formation selectively enhances or impairs retention, depending upon the location of injection within rostral or caudal portions of the hippocampus., Pub. in Pharmacology Biochemistry & Behavior, v40 p417-422 1991.