Lipid signaling and fat storage in the dark-eyed junco.

Seasonal hyperphagia and fattening promote survivorship in migratory and wintering birds, but reduced adiposity may be more advantageous during the breeding season. Factors such as photoperiod, temperature, and food predictability are known environmental determinants of fat storage, but the underlying neuroendocrine mechanisms are less clear. Endocannabinoids and other lipid signaling molecules regulate multiple aspects of energy balance including appetite and lipid metabolism. However, these functions have been established primarily in mammals; thus the role of lipid signals in avian fat storage remains largely undefined. Here we examined relationships between endocannabinoid signaling and individual variation in fat storage in captive white-winged juncos (Junco hyemalis aikeni) following a transition to long-day photoperiods. We report that levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide (AEA), in furcular and abdominal fat depots correlate negatively with fat mass. Hindbrain mRNA expression of CB1 endocannabinoid receptors also correlates negatively with levels of fat, demonstrating that fatter animals experience less central and peripheral endocannabinoid signaling when in breeding condition. Concentrations of the anorexigenic lipid, oleoylethanolamide (OEA), also inversely relate to adiposity. These findings demonstrate unique and significant relationships between adiposity and lipid signaling molecules in the brain and periphery, thereby suggesting a potential role for lipid signals in mediating adaptive levels of fat storage.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization.

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity.

Role of oxytocin signaling in the regulation of body weight.

Obesity and its associated metabolic disorders are growing health concerns in the US and worldwide. In the US alone, more than two-thirds of the adult population is classified as either overweight or obese [1], highlighting the need to develop new, effective treatments for these conditions. Whereas the hormone oxytocin is well known for its peripheral effects on uterine contraction during parturition and milk ejection during lactation, release of oxytocin from somatodendrites and axonal terminals within the central nervous system (CNS) is implicated in both the formation of prosocial behaviors and in the control of energy balance. Recent findings demonstrate that chronic administration of oxytocin reduces food intake and body weight in diet-induced obese (DIO) and genetically obese rodents with impaired or defective leptin signaling. Importantly, chronic systemic administration of oxytocin out to 6 weeks recapitulates the effects of central administration on body weight loss in DIO rodents at doses that do not result in the development of tolerance. Furthermore, these effects are coupled with induction of Fos (a marker of neuronal activation) in hindbrain areas (e.g. dorsal vagal complex (DVC)) linked to the control of meal size and forebrain areas (e.g. hypothalamus, amygdala) linked to the regulation of food intake and body weight. This review assesses the potential central and peripheral targets by which oxytocin may inhibit body weight gain, its regulation by anorexigenic and orexigenic signals, and its potential use as a therapy that can circumvent leptin resistance and reverse the behavioral and metabolic abnormalities associated with DIO and genetically obese models.

Habitat type influences endocrine stress response in the degu (Octodon degus).

While many studies have examined whether the stress response differs between habitats, few studies have examined this within a single population. This study tested whether habitat differences, both within-populations and between-populations, relate to differences in the endocrine stress response in wild, free-living degus (Octodon degus). Baseline cortisol (CORT), stress-induced CORT, and negative feedback efficacy were measured in male and female degus from two sites and three habitats within one site during the mating/early gestation period. Higher quality cover and lower ectoparasite loads were associated with lower baseline CORT concentrations. In contrast, higher stress-induced CORT but stronger negative feedback efficacy were associated with areas containing higher quality forage. Stress-induced CORT and body mass were positively correlated in female but not male degus across all habitats. Female degus had significantly higher stress-induced CORT levels compared to males. Baseline CORT was not correlated with temperature at time of capture and only weakly correlated with rainfall. Results suggest that degus in habitats with good cover quality, low ectoparasite loads, and increased food availability have decreased endocrine stress responses.

Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene.

CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r(-/-) rats. Both Cck1r(+/+) and Cck1r(-/-) rats became diet-induced obese (DIO) when maintained on a high-fat diet relative to chow-fed controls. Cck1r(-/-) rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity, and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient during the light cycle. To assess whether enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype, we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r(-/-) rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure.

Parental Stress as the Mediator Between Symptom Burden and the Quality of Life of Chinese Children With Cancer.

BACKGROUND: Because of their cancer and treatment adverse effects, most pediatric oncology patients will experience 1 or more symptoms at one time that can seriously affect their quality of life. Because these children are attached to parents, their symptom burden directly influences the parental stress level and parental interpretations of their children's quality of life. OBJECTIVE: The aim of this study was to examine the association between child-reported symptom burden and the pediatric quality of life reported by children with cancer and their parents, and whether parental perceived stress mediates these relationships. METHODS: In a cross-sectional design, convenience sampling was used to recruit 80 parent-child dyads. Advanced statistical methods were adopted to analyze the mediating effects of parental stress between children's symptom burden and their quality of life. RESULTS: The results revealed that parental stress was the mediator in the relationship between child-reported symptom burden and children's quality of life reported by parents. The results also showed that parental stress was not a mediator in the relationship between child-reported symptom burden and their quality of life. This underscored the differences in interpretations of quality of life reported by children and their parents. CONCLUSION: Children's symptom burden is an important factor in predicting parental stress level and the quality of life reported by the children. Children's voice should be incorporated whenever possible. IMPLICATIONS FOR PRACTICE: The knowledge gained from this study will facilitate intervention development to enhance parents' abilities in stress management and symptom management for their children with the support of the nursing profession.

Symptom Burden of Children with Cancer and Parental Quality of Life: The Mediating Role of Parental Stress.

BACKGROUND: The aim of this study was to investigate the association between children's reported symptom burden and their parents' quality of life, and whether parents' perceived stress mediates this relationship. METHOD: this was a cross-sectional quantitative research study. Convenience sampling was used to recruit 80 pairs of parents and their children with cancer. Advanced statistical methods were used to analyse the mediating effects of parental stress between children's symptom burden and parents' quality of life. RESULTS: The results showed that parental stress was the mediator in the relationship between children's reported symptom burden and their parents' quality of life. CONCLUSIONS: Symptom burden was prevalent in Chinese children with cancer living in the community. Children's symptom burden is an important factor in predicting parental stress level, which simultaneously and directly lower parents' quality of life. The evidence in this study enlarges the knowledge base about the mediating effect of parental stress on the association between the symptom burden of children with cancer and their parents' quality of life. This evidence is crucial in paving the way for the development of interventions that improve the parental quality of life through stress-reduction programs.

Hindbrain Administration of Oxytocin Reduces Food Intake, Weight Gain and Activates Catecholamine Neurons in the Hindbrain Nucleus of the Solitary Tract in Rats.

Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third (3V; forebrain) and fourth (4V; hindbrain) ventricles to assess sensitivity to OT in forebrain and hindbrain sites, (2) the extent to which chronic 4V administration of OT reduces weight gain associated with the progression of diet-induced obesity, and (3) whether nucleus tractus solitarius (NTS) catecholamine neurons are downstream targets of 4V OT. Initially, we examined the dose-response effects of 3V and 4V OT (0.04, 0.2, 1, or 5 µg). 3V and 4V OT (5 µg) suppressed 0.5-h food intake by 71.7 ± 6.0% and 60 ± 12.9%, respectively. 4V OT (0.04, 0.2, 1 µg) reduced food intake by 30.9 ± 12.9, 42.1 ± 9.4, and 56.4 ± 9.0%, respectively, whereas 3V administration of OT (1 µg) was only effective at reducing 0.5-h food intake by 38.3 ± 10.9%. We subsequently found that chronic 4V OT infusion, as with chronic 3V infusion, reduced body weight gain (specific to fat mass) and tended to reduce plasma leptin in high-fat diet (HFD)-fed rats, in part, through a reduction in energy intake. Lastly, we determined that 4V OT increased the number of hindbrain caudal NTS Fos (+) neurons (156 ± 25) relative to vehicle (12 ± 3). The 4V OT also induced Fos in tyrosine hydroxylase (TH; marker of catecholamine neurons) (+) neurons (25 ± 7%) relative to vehicle (0.8 ± 0.3%). Collectively, these findings support the hypothesis that OT within the hindbrain is effective at reducing food intake, weight gain, and adiposity and that NTS catecholamine neurons in addition to non-catecholaminergic neurons are downstream targets of CNS OT.

Vasopressin cell groups exhibit strongly divergent responses to copulation and male-male interactions in mice.

Arginine vasopressin (AVP) and its nonmammalian homolog arginine vasotocin influence social behaviors ranging from affiliation to resident-intruder aggression. Although numerous sites of action have been established for these behavioral effects, the involvement of specific AVP cell groups in the brain is poorly understood, and socially elicited Fos responses have not been quantified for many of the AVP cell groups found in rodents. Surprisingly, this includes the AVP population in the posterior part of the medial bed nucleus of the stria terminalis (BSTMP), which has been extensively implicated, albeit indirectly, in various aspects of affiliation and other social behaviors. We examined the Fos responses of eight hypothalamic and three extra-hypothalamic AVP-immunoreactive (-ir) cell groups to copulation, nonaggressive male-male interaction, and aggressive male-male interaction in both dominant and subordinate C57BL/6J mice. The BSTMP cells exhibited a response profile that was unlike all other cell groups: from a control baseline of approximately 5% of AVP-ir neurons colocalizing with Fos, colocalization increased significantly to approximately 12% following nonaggressive male-male interaction, and to approximately 70% following copulation. Aggressive interactions did not increase colocalization beyond the level observed in nonaggressive male mice. These results suggest that BSTMP neurons in mice may increase AVP-Fos colocalization selectively in response to affiliation-related stimuli, similar to findings in finches. In contrast, virtually all other cell groups were responsive to negative aspects of interaction, either through elevated AVP-Fos colocalization in subordinate animals, positive correlations of AVP-Fos colocalization with bites received, and/or negative correlations of AVP-Fos colocalization with dominance. These findings greatly expand what is known of the contributions of specific brain AVP cell groups to social behavior.

Acceptability and tolerability of alcohol-based hand hygiene products for elderly residents in long-term care: a crossover study.

Background: Hand hygiene is a critical component of infection control. Much of the focus on improving hand hygiene in healthcare settings has been directed towards healthcare worker compliance but its importance for patients, including those in long-term care facilities (LTCFs), is increasingly being recognised. Alcohol-based hand rub (ABHR) can lead to improved compliance. We aimed to determine acceptability and tolerability of two ABHRs for hand hygiene of elderly LTCF residents using a modified version of the WHO protocol. Methods: Thirty six elderly LTCF residents participated in this crossover study. A modified and translated (Chinese) version of the WHO protocol for evaluation of two or more ABHRs was used to determine product acceptability and tolerability for one gel (bottle with reclosable cap) and one foam (pump). During the 3-day testing period, participants were provided with their own portable bottle of ABHR. A research nurse objectively assessed the skin integrity of the hands at baseline and throughout the study. Skin moisture content was determined using a Scalar Moisture Checker Probe (Science Technology Resources, Ca, USA). Participants rated ABHR tolerability and acceptability using the WHO checklist at the end of each test period. Results: Both products passed the WHO criteria for acceptability and tolerability. The foam (86%) scored higher than the gel (51%) for ease of use possibly because some participants found the cap of the gel bottle difficult to open due to finger stiffness. No evidence of damage to skin integrity was observed. Overall, skin moisture content had improved by the end of the study. Residents preferred either of the test products to the liquid formulation currently in use by the LTCF. Conclusions: Overall, the elderly were willing to use ABHR for hand hygiene. Both products were well tolerated and preferred over the usual product provided by the LTCF. However, forgetfulness and difficulty rubbing the product over the hands due to finger stiffness posed a challenge for some residents. This could be overcome by using healthcare worker-assisted hand hygiene at specified times each day and prompts to serve as reminders to perform hand hygiene.

Acute sleep disruption- and high-fat diet-induced hypothalamic inflammation are not related to glucose tolerance in mice.

Chronic insufficient sleep is a major societal problem and is associated with increased risk of metabolic disease. Hypothalamic inflammation contributes to hyperphagia and weight gain in diet-induced obesity, but insufficient sleep-induced neuroinflammation has yet to be examined in relation to metabolic function. We therefore fragmented sleep of adult male C57BL/6J mice for 18 h daily for 9 days to determine whether sleep disruption elicits inflammatory responses in brain regions that regulate energy balance and whether this relates to glycemic control. To additionally test the hypothesis that exposure to multiple inflammatory factors exacerbates metabolic outcomes, responses were compared in mice exposed to sleep fragmentation (SF), high-fat diet (HFD), both SF and HFD, or control conditions. Three or 9 days of high-fat feeding reduced glucose tolerance but SF alone did not. Transient loss of body mass in SF mice may have affected outcomes. Comparisons of pro-inflammatory cytokine concentrations among central and peripheral metabolic tissues indicate that patterns of liver interleukin-1ß concentrations best reflects observed changes in glucose tolerance. However, we demonstrate that SF rapidly and potently increases Iba1 immunoreactivity (-ir), a marker of microglia. After 9 days of manipulations, Iba1-ir remains elevated only in mice exposed to both SF and HFD, indicating a novel interaction between sleep and diet on microglial activation that warrants further investigation.

Effects of sleep disruption and high fat intake on glucose metabolism in mice.

Poor sleep quality or quantity impairs glycemic control and increases risk of disease under chronic conditions. Recovery sleep may offset adverse metabolic outcomes of accumulated sleep debt, but the extent to which this occurs is unclear. We examined whether recovery sleep improves glucose metabolism in mice subjected to prolonged sleep disruption, and whether high fat intake during sleep disruption exacerbates glycemic control. Adult male C57BL/6J mice were subjected to 18-h sleep fragmentation daily for 9 days, followed by 1 day of recovery. During sleep disruption, one group of mice was fed a high-fat diet (HFD) while another group was fed standard laboratory chow. Insulin sensitivity and glucose tolerance were assessed by insulin and glucose tolerance testing at baseline, after 3 and 7 days of sleep disruption, and at the end of the protocol after 24h of undisturbed sleep opportunity (recovery). To characterize changes in sleep architecture that are associated with sleep debt and recovery, we quantified electroencephalogram (EEG) recordings during sleep fragmentation and recovery periods from an additional group of mice. We now report that 9 days of 18-h daily sleep fragmentation significantly reduces rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Mice respond with increases in REMS, but not NREMS, during the daily 6-h undisturbed sleep opportunity. However, both REMS and NREMS increase significantly during the 24-h recovery period. Although sleep disruption alone has no effect in this protocol, high fat feeding in combination with sleep disruption impairs glucose tolerance, effects that are reversed by recovery sleep. Insulin sensitivity modestly improves after 3 days of sleep fragmentation and after 24h of recovery, with significantly greater improvements in mice exposed to HFD during sleep disruption. Improvements in both glucose tolerance and insulin sensitivity are associated with NREMS rebound, raising the possibility that this sleep phase contributes to restorative effects of recovery sleep on glycemic control.

Hindbrain oxytocin receptors contribute to the effects of circulating oxytocin on food intake in male rats.

Oxytocin (OT)-elicited hypophagia has been linked to neural activity in the nucleus of the solitary tract (NTS). Because plasma OT levels increase after a meal, we hypothesized that circulating OT acts at both peripheral and hindbrain OT receptors (OTRs) to limit food intake. To initially determine whether circulating OT inhibits food intake by acting at hindbrain OTRs, we pretreated rats with an OTR antagonist administered into the fourth ventricle (4V) followed by either central or systemic OT administration. Administration of the OTR antagonist into the 4V blocked anorexia induced by either 4V or i.p. injection of OT. However, blockade of peripheral OTRs also weakened the anorectic response to ip OT. Our data suggest a predominant role for hindbrain OTRs in the hypophagic response to peripheral OT administration. To elucidate central mechanisms of OT hypophagia, we tested whether OT activates NTS catecholaminergic neurons. OT (ip) increased the number of NTS cells expressing c-Fos, of which 10%-15% were catecholaminergic. Furthermore, electrophysiological studies in mice revealed that OT stimulated 47% (8 of 17) of NTS catecholamine neurons through a presynaptic mechanism. However, OT-elicited hypophagia did not appear to require activation of α1-adrenoceptors, and blockade of glucagon-like peptide-1 receptors similarly did not attenuate anorexia induced by OT. These findings demonstrate that OT elicits satiety through both central and peripheral OTRs and that although catecholamine neurons are a downstream target of OT signaling in the NTS, the hypophagic effect is mediated independently of α1-adrenoceptor signaling.

Coming full circle: contributions of central and peripheral oxytocin actions to energy balance.

The neuropeptide oxytocin has emerged as an important anorexigen in the regulation of energy balance. Its effects on food intake have largely been attributed to limiting meal size through interactions in key regulatory brain regions such as the hypothalamus and hindbrain. Pharmacologic and pair-feeding studies indicate that its ability to reduce body mass extends beyond that of food intake, affecting multiple factors that determine energy balance such as energy expenditure, lipolysis, and glucose regulation. Systemic administration of oxytocin recapitulates many of its effects when administered centrally, raising the questions of whether and to what extent circulating oxytocin contributes to energy regulation. Its therapeutic potential to treat metabolic conditions remains to be determined, but data from diet-induced and genetically obese rodent models as well as application of oxytocin in humans in other areas of research have revealed promising results thus far.

Intravenous angiotensin and salt appetite in rats.

Circulating angiotensin II is crucial for the activation of salt appetite after sodium depletion. We tested if angiotensin (ANG) II infused intravenously at 50 ng/kg/min overnight (chronic) can mimic the rapid salt appetite similar to furosemide and overnight sodium depletion. In experiment 1, rats received chronic ANG II or vehicle infusions all night with access to water and chow but no saline solution. In the morning, the infusions continued, but half of the vehicle-infused group was switched to ANG II (acute). Thirty minutes after the switch, all rats received 10 mg/kg furosemide SC. One hour later they were provided water and 0.3 M NaCl to drink. Rats infused with vehicle or acute ANG drank little, but the chronic ANG group drank 11+/-1 ml of saline in 90 min. In experiment 2, the furosemide was omitted, and a group receiving a chronic infusion of phenylephrine at 6.25 microg/kg/min was included. The chronic ANG group drank 10+/-1 ml saline in 90 min, but the phenylephrine group, which also incurred a significant negative sodium balance overnight, drank little. Thus, an overnight infusion of ANG II is sufficient to mimic the robust expression of salt appetite as observed after furosemide and overnight sodium depletion.

Differential effects of intravenous hyperosmotic solutes on drinking latency and c-Fos expression in the circumventricular organs and hypothalamus of the rat.

Hyperosmotic intravenous infusions of NaCl are more potent for inducing drinking and vasopressin (AVP) secretion than equally osmotic solutions of glucose or urea. The fact that all three solutes increased cerebrospinal fluid osmolality and sodium concentration led the investigators to conclude that critical sodium receptors or osmoreceptors for stimulating drinking and AVP secretion were outside the blood-brain barrier (BBB) in the circumventricular organs (CVOs). We tested an obvious prediction of this hypothesis: that all three solutes should increase c-Fos-like immunoreactivity (Fos-ir) inside the BBB, but that only NaCl should increase Fos-ir in the CVOs. We gave intravenous infusions of 3.0 Osm/l NaCl, glucose, or urea to rats for 11 or 22 min at 0.14 ml/min and perfused the rats for assay of Fos-ir at 90 min. Controls received isotonic NaCl at the same volume. Drinking latency was measured, but water was then removed. Drinking consistently occurred with short latency during hyperosmotic NaCl infusions only. Fos-ir in the forebrain CVOs, the subfornical organ, and organum vasculosum laminae terminalis was consistently elevated only by hyperosmotic NaCl. However, all three hyperosmotic solutes potently stimulated Fos-ir in the supraoptic and paraventricular nuclei of the hypothalamus inside the BBB. Hyperosmotic NaCl greatly elevated Fos-ir in the area postrema, but even glucose and urea caused moderate elevations that may be related to volume expansion rather than osmolality. The data provide strong support for the conclusion that the osmoreceptors controlling drinking are located in the CVOs.