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The consumption of Western diets, high in sugar and saturated fat, is a crucial contributor to the alarming incidence of obesity and its associated morbidities. These diets have been reported to induce an inflammatory response in the hypothalamus, which promotes the development of central leptin resistance and obesity. This inflammatory signalling involves dynamic changes in the expression and activity of several mediators of the innate immune system, including toll-like receptor 4, IκB kinase- β/nuclear factor- κB, c- Jun N-terminal kinase, suppressor of cytokine signalling 3 and pro-inflammatory cytokines, as well as the induction of endoplasmic reticulum stress and autophagy defect. Although the exact cellular mechanisms remain incompletely understood, recent evidence suggests that the inflammatory response is at least mediated by interactions between neurons and non-neuronal cells such as microglia and astrocytes. Current evidence of the contribution of each inflammatory mediator to leptin resistance and diet-induced obesity ( DIO), including their reciprocal interactions and cell-type-specific effects, is reviewed and integrated in a conceptual model. Based upon this model and pharmacological intervention studies, several inflammatory mediators are proposed to be promising therapeutic targets for the treatment of DIO. [ABSTRACT FROM AUTHOR]

The neuropeptide Y (NPY) system in the brain regulates a wide variety of behavioral, metabolic and hormonal homeostatic processes required for energy balance control. During times of limited food availability, NPY promotes behavioral hyperactivity necessary to explore and prepare for novel food resources. As NPY can act via 5 different receptor subtypes, we investigated the path through which NPY affects different behavioral components relevant for adaptation to such conditions. We tested NPY Y1 and Y2 receptor knockout mice and their wild-type littermate controls in a daily scheduled limited food access paradigm with unlimited access to running wheel. Here we show that NPY Y1 receptor deficient mice lack the expression of appetitive behavior and that NPY Y2 receptors control the level of hyperactive behavior under these conditions. Thus, receptor specificity determines the differential expression of NPY-mediated behavioral adaptations to overcome a negative energy status. [ABSTRACT FROM AUTHOR]

Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor antagonist or with the inverse agonist AgRP results in increased food intake. This review addresses the role of the MC system in different aspects of feeding behaviour. MC4R activity affects meal size and meal choice, but not meal frequency, and the type of diet affects the efficacy of MC4R agonists to reduce food intake. The central sites involved in the different aspects of feeding behaviour that are affected by MC4R signalling are being unravelled. The paraventricular nucleus plays an important role in food intake per se, whereas MC signalling in the lateral hypothalamus is associated with the response to a high fat diet. MC4R signalling in the brainstem has been shown to affect meal size. Further genetic, behavioural and brain-region specific studies need to clarify how the MC4R agonists affect feeding behaviour in order to determine which obese individuals would benefit most from treatment with these drugs. Application of MCR agonists in humans has already revealed side effects, such as penile erections, which may complicate introduction of these drugs in the treatment of obesity.British Journal of Pharmacology (2006) 149, 815–827. doi:10.1038/sj.bjp.0706929; published online 16 October 2006 [ABSTRACT FROM AUTHOR]

Brainfood cluster The mission of EBRA brainfood is to increase awareness of the importance of research exploring the bidirectional links between brain health and nutrition, including the mediating systems, and to use this knowledge to identify novel nutritional, neuropsychological and neuropharmacological intervention strategies. The BRAINFOOD cluster builds new bridges across research disciplines and strengthens links to relevant stakeholders across Europe, including those involved in health and food policy. It gathers experts on brain health and nutrition that by combining and integrating strengths and complimentary expertise has the volume and capacity to develop novel intervention strategies that improve brain health of European citizens, working together with public health and the food industry. BRAINFOOD is built upon an existing network that includes: 1Discovery, with expertise in human genetics, metabolomics, nutrition, the microbiome and brain health that utilizes existing data from a variety of population and disease cohorts across the lifespan and aims to propose testable hypotheses; 2 Mechanism, with expertise in animal models, metabolomics, the microbiome and neuroscience that tests hypothesis of how the microbiome and nutrients impact on performance in different behavioral domains; 3 Experimental medicine, with expertise in psychiatry, neurology and nutrition with capacity to run randomized controlled trials; 4 Implementation, with expertise in dissemination and policy making and behavior change, to ensure that EU citizens benefit from novel insights gained in the project. [ABSTRACT FROM AUTHOR]

The adipocyte-derived hormone leptin is a peripheral signal that informs the brain about the metabolic status of an organism. Although traditionally viewed as an appetite-suppressing hormone, studies in the past decade have highlighted the role of leptin in energy expenditure. Leptin has been shown to increase energy expenditure in particular through its effects on the cardiovascular system and brown adipose tissue (BAT) thermogenesis via the hypothalamus. The current review summarizes the role of leptin signaling in various hypothalamic nuclei and its effects on the sympathetic nervous system to influence blood pressure, heart rate, and BAT thermogenesis. Specifically, the role of leptin signaling on three different hypothalamic nuclei, the dorsomedial hypothalamus, the ventromedial hypothalamus, and the arcuate nucleus, is reviewed. It is known that all of these brain regions influence the sympathetic nervous system activity and thereby regulate BAT thermogenesis and the cardiovascular system. Thus the current work focuses on how leptin signaling in specific neuronal populations within these hypothalamic nuclei influences certain aspects of energy expenditure. [ABSTRACT FROM AUTHOR]

Leptin exerts its effects on energy balance by inhibiting food intake and increasing energy expenditure via leptin receptors in the hypothalamus. While LepR neurons in the arcuate nucleus of the hypothalamus, the primary target of leptin, have been extensively studied, LepR neurons in other hypothalamic nuclei remain understudied. LepR neurons in the lateral hypothalamus contribute to leptin's effects on food intake and reward, but due to the low abundance of this population it has been difficult to study their molecular profile and responses to energy deficit. We here explore the transcriptome of LepR neurons in the LH and their response to energy deficit. Male LepR-Cre mice were injected in the LH with an AAV carrying Cre-dependent L10:GFP. Few weeks later the hypothalami from fed and food-restricted (24-h) mice were dissected and the TRAP protocol was performed, for the isolation of translating mRNAs from LepR cells in the LH, followed by RNA sequencing. After mapping and normalization, differential expression analysis was performed with DESeq2. We confirm that the isolated mRNA is enriched in LepR transcripts and other known neuropeptide markers of LepRLH neurons, of which we investigate the localization patterns in the LH. We identified novel markers of LepRLH neurons with association to energy balance and metabolic disease, such as Acvr1c, Npy1r, Itgb1, and genes that are differentially regulated by food deprivation, such as Fam46a and Rrad. Our dataset provides a reliable and extensive resource of the molecular makeup of LH LepR neurons and their response to food deprivation. [ABSTRACT FROM AUTHOR]

Eating disorders, such as anorexia nervosa ( AN), bulimia nervosa ( BN) and binge eating disorders ( BED), are described as abnormal eating habits that usually involve insufficient or excessive food intake. Animal models have been developed that provide insight into certain aspects of eating disorders. Several drugs have been found efficacious in these animal models and some of them have eventually proven useful in the treatment of eating disorders. This review will cover the role of monoaminergic neurotransmitters in eating disorders and their pharmacological manipulations in animal models and humans. Dopamine, 5- HT (serotonin) and noradrenaline in hypothalamic and striatal regions regulate food intake by affecting hunger and satiety and by affecting rewarding and motivational aspects of feeding. Reduced neurotransmission by dopamine, 5- HT and noradrenaline and compensatory changes, at least in dopamine D2 and 5- HT2C/2A receptors, have been related to the pathophysiology of AN in humans and animal models. Also, in disorders and animal models of BN and BED, monoaminergic neurotransmission is down-regulated but receptor level changes are different from those seen in AN. A hypofunctional dopamine system or overactive α2-adrenoceptors may contribute to an attenuated response to (palatable) food and result in hedonic binge eating. Evidence for the efficacy of monoaminergic treatments for AN is limited, while more support exists for the treatment of BN or BED with monoaminergic drugs. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between DNA polymorphisms in the NPY and AGRP genes and body fatness. Design and methods: The association between the AGRP Ala67Thr or the NPY Leu7Pro polymorphisms and indicators of body fatness (baseline leptin levels, body mass index (BMI) values and prevalence of overweight) are investigated in 582 participants of two large cohorts in The Netherlands (total 18 500 adult men and women), aged 20-40 years whose weight remained relatively constant or whose weight increased substantially (range 5.5-47 kg) during a mean follow-up of 7 years. Results: No consistent associations were found for the indicators of body fatness for men and women. Among women, BMI values, leptin levels and prevalence of overweight were not statistically different for carriers of the mutant alleles compared to that of the non-carriers. Among men, carriers of the Thr67-allele of the AGRP gene had similar leptin levels, but higher BMI values compared to those with the genotyping Ala67/Ala67: mean adjusted BMI 25.6 kg/m² (95% CI 24.3-27.0) vs 23.9 kg/m² (23.6-24.3). Also, the risk of being overweight at baseline tended to be higher for male carriers of the Thr67-allele of the AGRP gene (OR 2.52; 95% CI 0.86-7.4). Furthermore, male carriers of the Pro7-allele of the NPY gene had on average higher leptin levels and BMI values vs non-carriers of this allele: 4.7 μg/l (95% CI 3.7-6.0) and 25.7 kg/m² (95% CI 24.4-27.0) vs 3.1 μg/l (95% CI 2.9-3.4) and 23.9 kg/m² (95% CI 23.5-24.3), respectively. These male carriers had also a higher risk on being overweight at baseline (OR 3.3 (95% CI 1.2-8.9)) compared to non-carriers of the Pro7-allele. Conclusion: The consistent findings among men suggest that the NPY Leu7Pro polymorphism (or another linked marker) might be involved in the development of obesity at younger ages. The findings for the AGRP Ala67Thr were less consistent and need further investigation. Among women, these polymorphisms do not play an important role. [ABSTRACT FROM AUTHOR]

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

Anorexia nervosa (AN) is one of the most common chronic disorders in adolescencewith still highmortality rates. Knowledge on gutbrain interaction might help to develop new treatments, as severe starvation-induced changes of the microbiome in AN-patients have been demonstrated, which do not alleviate with weight gain. In our own pilot study alpha-diversity was increased in patients with AN after short-term weight recovery, while beta diversity showed clear group differences with healthy controls before and after weight gain. A reduction of taxa belonging to Enterobacteriaceae at admission and discharge and an increase in taxa belonging to Lachnospiraceae at discharge were typically found in patients with AN. The work plan of our European project comprises an observational study and two phase II RCTs with the application of omega-3-PUFA and a multistrain psychobiotic to both, humans and rodents. With the help of a well-established animal model for AN (activity-based anorexia, ABA), the effect of stool transplants from patients to rodents will be analysed. LongitudinalMRI will be conducted in rodents together with cellular and molecular brain analyses. In addition, immune response and circulating antibodies associated with the presence of certain bacterial strains and interaction with hunger and satiety hormones will be explored. We hope that by this translational research we may systematically investigate the role of an altered microbiome for the course of AN and to identify new therapeutic tools. [ABSTRACT FROM AUTHOR]

Summary: Western diets, with high consumption of simple sugars and saturated fats, contribute to the rise in the prevalence of obesity. It now seems clear that high‐fat diets cause obesity, at least in part, by modifying the composition and function of the microorganisms that colonize in the gastrointestinal tract, the microbiota. The exact pathways by which intestinal microbiota contribute to obesity remain largely unknown. High‐fat diet‐induced alterations in intestinal microbiota have been suggested to increase energy extraction, intestinal permeability and systemic inflammation while decreasing the capability to generate obesity‐suppressing short‐chain fatty acids. Moreover, by increasing systemic inflammation, microglial activation and affecting vagal nerve activity, ‘obese microbiota’ indirectly influence hypothalamic gene expression and promote overeating. Because the potential of intestinal microbiota to induce obesity has been recognized, multiple ways to modify its composition and function are being investigated to provide novel preventive and therapeutic strategies against diet‐induced obesity. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. [ABSTRACT FROM AUTHOR]

Rats on different free-choice (fc) diets for 1 week of either chow, saturated fat and liquid sugar (fc HFHS), chow and saturated fat (fc HF), or chow and liquid sugar (fc HS) have differential levels of neuropeptide Y ( NPY) m RNA in the arcuate nucleus. Because these differences were not explained by plasma leptin levels but did predict subsequent feeding behaviour, in the present study, we first examined whether leptin sensitivity could explain these differences. Second, we focused on the role of NPY on feeding behaviour, and measured NPY m RNA levels and sensitivity to NPY after 4 weeks on the different choice diets. To determine leptin sensitivity, we measured food intake after i.p. leptin or vehicle injections in male Wistar rats subjected to the fc HFHS, fc HS, fc HF or Chow diets for 7 days. Next, we measured levels of arcuate nucleus NPY m RNA with in situ hybridisation in rats subjected to the choice diets for 4 weeks. Finally, we studied NPY sensitivity in rats subjected to the fc HFHS, fc HS, fc HF or Chow diet for 4 weeks by measuring food intake after administration of NPY or vehicle in the lateral ventricle. Leptin decreased caloric intake in rats on Chow, fc HS and fc HF but not in rats on the fc HFHS diet. After 4 weeks, rats on the fc HFHS diet remained hyperphagic, whereas fc HS and fc HF rats decreased caloric intake to levels similar to rats on Chow. By contrast to 1 week, after 4 weeks, levels of NPY m RNA were not different between the diet groups. Lateral ventricle administration of NPY resulted in higher caloric intake in fc HFHS rats compared to rats on the other choice diets or rats on Chow. Our data show that consuming a combination of saturated fat and liquid sugar results in leptin resistance and increased NPY sensitivity that is associated with persistent hyperphagia. [ABSTRACT FROM AUTHOR]

Objectives:Rats subjected to a free-choice high-fat high-sugar (fcHFHS) diet persistently overeat, exhibit increased food-motivated behavior and become overtly obese. Conversely, several studies using a non-choice (nc) high-energy diet showed only an initial increase in food intake with unaltered or reduced food-motivated behavior. This raises the question of the importance of choice in the persistence of hyperphagia in rats on a fcHFHS diet.Subjects:Meal patterns, food intake and body weight gain were studied in male Wistar rats on free-choice diets with fat and/or sugar and in rats on nc diets with fat and sugar (custom made with ingredients similar to the fcHFHS diet).Results:Rats on a ncHFHS diet initially overconsumed, but reduced intake thereafter, whereas rats on a fcHFHS diet remained hyperphagic. Because half of the sugar intake in the fcHFHS group occurred during the inactive period, we next determined whether sugar intake during the light phase was a necessary requirement for hyperphagia, by restricting access to liquid sugar to either the light or dark period with unlimited access to fat and chow. Results showed that hyperphagia occurred irrespective of the timing of sugar intake. Meal pattern analysis revealed consumption of larger but fewer meals in the ncHFHS group, as well as the fcHF group. Interestingly, meal number was increased in all rats drinking liquid sugar (whether on a fcHFHS or a fcHS diet), whereas a compensatory decrease in meal size was only observed in the fcHS group, but not the fcHFHS group.Conclusion:We hereby show the importance of choice in the observation of fcHFHS diet-induced hyperphagia, which results in increases in meal number due to sugar drinking without any compensatory decrease in meal size. We thus provide a novel dietary model in rats that mimics important features of human overconsumption that have been ignored in rodent models of obesity. [ABSTRACT FROM AUTHOR]

Background:Rats that have restricted access to food at a fixed time point of the circadian phase display high levels of food anticipatory activity (FAA). The orexigenic hormone ghrelin has been implicated in the regulation of FAA. However, it is not known via which brain area ghrelin exerts this effect. Growth hormone secretagogue receptor 1a (GHS-R1a) is highly expressed in the hypothalamus, including the dorsomedial hypothalamus (DMH) and the ventromedial hypothalamus (VMH). These two hypothalamic areas have been reported to play a role in FAA.Aim of the study:To examine the role of GHS-R1a signaling in the DMH and VMH in FAA.Design:Adeno-associated virus expressing a shRNA directed against GHS-R1a was used to establish local knockdown of GHS-R1a in the DMH and VMH in rats. Rats were subsequently subjected to a restricted feeding schedule (RFS).Results:Under ad libitum conditions, knockdown of GHS-R1a in the VMH increased food intake and body weight gain. In addition, GHS-R1a knockdown in VMH and DMH reduced body temperature and running wheel activity (RWA). When rats were subjected to a RFS, the main effect of GHS-R1a knockdown in both DMH and VMH was a decrease in RWA and an attenuation of body weight loss. Rats with knockdown of GHS-R1a in DMH and VMH showed a delay in onset of FAA. In addition, GHS-R1a knockdown in DMH resulted in a reduction of FAA amplitude.Conclusion:This is the first study to investigate the effect of local hypothalamic knockdown of GHS-R1a on FAA. Our results implicate hypothalamic GHS-R1a signaling in the regulation of FAA. Nevertheless, some FAA remained, suggesting that a distributed network of brain areas and signaling pathways is involved in the development of FAA. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) is a powerful strategy for unraveling gene function and for drug target validation, but exogenous expression of short hairpin RNAs (shRNAs) has been associated with severe side effects. These may be caused by saturation of the microRNA pathway. This study shows degenerative changes in cell morphology and intrusion of blood vessels after transduction of the ventromedial hypothalamus (VMH) of rats with a shRNA expressing adeno-associated viral (AAV) vector. To investigate whether saturation of the microRNA pathway has a role in the observed side effects, expression of neuronal microRNA miR-124 was used as a marker. Neurons transduced with the AAV vector carrying the shRNA displayed a decrease in miR-124 expression. The decreased expression was unrelated to shRNA sequence or target and observed as early as 1 week after injection. In conclusion, this study shows that the tissue response after AAV-directed expression of a shRNA to the VMH is likely to be caused by shRNA-induced saturation of the microRNA pathway. We recommend controlling for miR-124 expression when using RNAi as a tool for studying (loss of) gene function in the brain as phenotypic effects caused by saturation of the RNAi pathway might mask true effects of specific downregulation of the shRNA target. [ABSTRACT FROM AUTHOR]

Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists. [ABSTRACT FROM AUTHOR]

Background:Cues that are associated with the availability of food are known to trigger food anticipatory activity (FAA). This activity is expressed as increased locomotor activity and enables an animal to prepare for maximal utilization of nutritional resources. Although the exact neural network that mediates FAA is still unknown, several studies have revealed that the medial hypothalamus is involved. Interestingly, this area is responsive to the anorexigenic hormone leptin and the orexigenic hormone ghrelin that have been shown to modulate FAA. However, how FAA is regulated by neuronal activity and how leptin and ghrelin modulate this activity is still poorly understood.Objective:We aimed to examine how the total neuronal population and individual neurons in the medial hypothalamus respond to cue-signaled food availability in awake, behaving rats. In addition, ghrelin and leptin were injected to investigate whether these hormones could have a modulatory role in the regulation of FAA.Design:Using in vivo electrophysiology, neuronal activity was recorded in the medial hypothalamus in freely moving rats kept on a random feeding schedule, in which a light cue signaled upcoming food delivery. Ghrelin and leptin were administered systemically following the behavioral paradigm.Results:The food-predictive cue induced FAA as well as a significant increase in neural activity on a population level. More importantly, a sub-population of medial hypothalamic neurons displayed highly correlated identical responses to both ghrelin and FAA, suggesting that these neurons are part of the network that regulates FAA.Conclusion:This study reveals a role for ghrelin, but not leptin, signaling within medial hypothalamus in FAA on both a population level and in single cells, identifying a subset of neurons onto which cue information and ghrelin signaling converge, possibly to drive FAA. [ABSTRACT FROM AUTHOR]

Objective:Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear.Methods and results:In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature.Conclusion:Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA. [ABSTRACT FROM AUTHOR]

Objective:Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood.Design:We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc).Results:Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters.Conclusions:Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance. [ABSTRACT FROM AUTHOR]

Objectives:In diet-induced obesity, it is not clear whether impaired glucose metabolism is caused directly by the diet, or indirectly via obesity. This study examined the effects of different free-choice, high-caloric, obesity-inducing diets on glucose metabolism. In these free-choice diets, saturated fat and/or a 30% sugar solution are provided in an addition to normal chow pellets.Method:In the first experiment, male rats received a free-choice high-fat high-sugar (HFHS), free-choice high-fat (HF) or a chow diet. In a second experiment, male rats received a free-choice high-sugar (HS) diet or chow diet. For both experiments, after weeks 1 and 4, an intravenous glucose tolerance test was performed.Results:Both the HFHS and HF diets resulted in obesity with comparable plasma concentrations of free fatty acids. Interestingly, the HF diet did not affect glucose metabolism, whereas the HFHS diet resulted in hyperglycemia, hyperinsulinemia and in glucose intolerance because of a diminished insulin response. Moreover, adiposity in rats on the HF diet correlated positively with the insulin response to the glucose load, whereas adiposity in rats on the HFHS diet showed a negative correlation. In addition, total caloric intake did not explain differences in glucose tolerance. To test whether sugar itself was crucial, we next performed a similar experiment in rats on the HS diet. Rats consumed three times as much sugar when compared with rats on the HFHS diet, which resulted in obesity with basal hyperinsulinemia. Glucose tolerance, however, was not affected.Conclusion:Together, these results suggest that not only obesity or total caloric intake, but the diet content also is crucial for the glucose intolerance that we observed in rats on the HFHS diet. [ABSTRACT FROM AUTHOR]

Many vertebrates express profound annual cycles of body fattening, although it is not clear whether these represent differential activity of the central pathways known to mediate homeostatic control of food intake and energy expenditure, or whether the recent discovery of a major role for pars tuberalis-ependymal signalling points towards novel mechanisms. We examined this in the Siberian hamster ( Phodopus sungorus) by using gene transfection to up-regulate a major orexigenic peptide, agouti-related peptide (AgRP), and then determined whether this increased anabolic drive could prevent the short-day induced winter catabolic state. Infusions of a recombinant adeno-associated virus encoding an AgRP construct into the hypothalamus of hamsters in the long-day obese phase of their seasonal cycle produced a 20% gain in body weight over 6 weeks compared to hamsters receiving a control reporter construct, reflecting a significant increase in food intake and a significant decrease in energy expenditure. However, all hamsters showed a significant, prolonged decrease in body weight when exposed to short photoperiods, despite the hamsters expressing the AgRP construct maintaining a higher food intake and lower energy expenditure relative to the control hamsters. Visualisation of the green fluorescent protein reporter and analysis of AgRP-immunoreactivity confirmed widespread expression of the construct in the hypothalamus, which was maintained for the 21-week duration of the study. In conclusion, the over-expression of AgRP in the hypothalamus produced a profoundly obese state but did not block the seasonal catabolic response, suggesting a separation of rheostatic mechanisms in seasonality from those maintaining homeostasis of energy metabolism. [ABSTRACT FROM AUTHOR]

Objectives:The mechanisms for how saturated fat and sugar-based beverages contribute to human obesity are poorly understood. This paper describes a series of experiments developed to examine the response of hypothalamic neuropeptides to diets rich in sugar and fat, using three different diets: a high-fat high-sugar (HFHS) choice diet with access to chow, saturated fat and a 30% sugar solution; a high-fat (HF) choice diet with access to chow and saturated fat; or to a high-sugar (HS) choice diet with access to chow and a sugar solution.Method:We first studied caloric intake, body weight gain, hormonal alterations and hypothalamic neuropeptide expression when male Wistar rats were subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week. Next, we studied caloric intake and body weight gain when rats were subjected to the choice diets for 5 weeks. Finally, we measured neuropeptide expression in hepatic vagotomized rats subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week.Results:In rats on an HF choice diet, plasma leptin concentrations and proopiomelanocortin (POMC) mRNA increased and neuropeptide Y (NPY) mRNA decreased. Rats on an HFHS choice diet showed identical plasma leptin concentrations as rats on an HF choice diet. However, NPY mRNA increased and POMC mRNA decreased. An HS choice diet for 1 week did not alter hypothalamic neuropeptide expression or plasma leptin concentrations. As hormonal changes did not explain the differences in hypothalamic neuropeptide expression between rats on the choice diets, we addressed whether neuronal feedback signals mediated the hypothalamic neuropeptide response. The POMC mRNA response to different diets depended on an intact innervation of liver and upper intestinal tract.Conclusion:Our data suggest that the specific combination of saturated fat and a 30% sugar solution results in hyperphagia-induced obesity and alters hypothalamic neuropeptide expression, and that the response of the melanocortin system is mediated by the hepatic vagus. [ABSTRACT FROM AUTHOR]

Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living. [ABSTRACT FROM AUTHOR]

Objectives:One of the main causes of obesity is overconsumption of diets high in fat and sugar. We studied the metabolic changes and food-motivated behavior when rats were subjected to a choice diet with chow, lard and a 30% sucrose solution (high fat high sugar (HFHS)-choice diet). Because rats showed considerable variations in the feeding response to HFHS-choice diet and in food-motivated behavior, we investigated whether the motivation to obtain a sucrose reward correlated with the development of obesity when rats were subsequently subjected to HFHS-choice diet.Method:We first studied feeding, locomotor activity and body temperature, fat weights and hormonal concentrations when male Wistar rats were subjected to HFHS-choice diet for 1 week. Second, we studied sucrose-motivated behavior, using a progressive ratio (PR) schedule of reinforcement in rats that were subjected to the HFHS-choice diet for at least 2 weeks, compared to control rats on a chow diet. Third, we measured motivation for sucrose under a PR schedule of reinforcement in rats that were subsequently subjected to HFHS-choice diet or a chow diet for 4 weeks. Fat weights were measured and correlated with the motivation to obtain sucrose pellets.Results:One week on the HFHS-choice diet increased plasma concentrations of glucose and leptin, increased fat stores, but did not alter body temperature or locomotor activity. Moreover, consuming the HFHS-choice diet for several weeks increased the motivation to work for sucrose pellets. Furthermore, the motivation to obtain sucrose pellets correlated positively with abdominal fat stores in rats subsequently subjected to the HFHS-choice diet, whereas this correlation was not found in rats fed on a chow diet.Conclusion:Our data suggest that the motivation to respond for palatable food correlates with obesity due to an obesogenic environment. Conversely, the HFHS-choice diet, which results in obesity, also increased the motivation to work for sucrose. Thus, being motivated to work for sucrose results in obesity, which, in turn, increases food-motivated behavior, resulting in a vicious circle of food motivation and obesity.International Journal of Obesity (2007) 31, 1286–1294; doi:10.1038/sj.ijo.0803570; published online 27 February 2007 [ABSTRACT FROM AUTHOR]

The hunger hormone ghrelin is secreted from the stomach and binds to the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin activates the ventral tegmental area (VTA) dopamine system to increases food reward-seeking behaviour [1],[2]. Although dopamine neuronal activity and licking behavior were proportional to the amount of sucrose reward, ghrelin did not modulate the licks and calcium signal during the reward consumption (FGCamp(1,12) = 0.01 p=0.91; Flicks F(1,9)=0.651, p=0.44). In summary, ghrelin enhances the activity of dopaminergic neurons in the VTA during a predictive cue but did not affect dopamine response to sucrose reward value. [Extracted from the article]

Food restriction leads to a paradoxical increase in physical activity and further suppression of food intake such as observed in anorexia nervosa. To understand this pathophysiological process, we induced physical hyperactivity and self-starvation in rats by restricting food in the presence of running wheels. Normally, decreased melanocortin receptor activity will prevent starvation. However, we found that self-starvation increased melanocortin receptors in the ventral medial hypothalamus, a brain region involved in eating behavior. Suppression of melanocortin receptor activity, via central infusion of Agouti-related protein (AgRP), increased survival rate in these rats by counteracting physical hyperactivity, food intake suppression as well as deregulated body temperature. We conclude that self-starvation may result from insufficient suppression of central melanocortin receptor activity. [ABSTRACT FROM AUTHOR]

Targeting specific neuronal cell types is a major challenge for unraveling their function and utilizing specific cells for gene therapy strategies. Viral vector tools are widely used to target specific cells or circuits for these purposes. Here, we use viral vectors with short promoters of neuropeptide genes to target distinct neuronal populations in the hypothalamus of rats and mice. We show that lowering the amount of genomic copies is effective in increasing specificity of a melanin-concentrating hormone promoter. However, since too low titers reduce transduction efficacy, there is an optimal titer for achieving high specificity and sufficient efficacy. Other previously identified neuropeptide promoters as those for oxytocin and orexin require further sequence optimization to increase target specificity. We conclude that promoter-driven viral vectors should be used with caution in order to target cells specifically. [ABSTRACT FROM AUTHOR]

Substance addiction is a chronic relapsing brain disorder, characterised by loss of control over substance intake. Despite a high prevalence and enormous costs to society, treatment options for addiction are limited in number and efficacy. The neural underpinnings of loss of control are poorly understood, while restoring control over substance intake is a promising treatment strategy for addictive disorders. Loss of control over substance intake has been operationalised as resistance to adversity in rodent models, since people suffering from addiction continue substance use despite their awareness of its negative consequences [1,2]. Importantly, the negative consequences of continued substance use are often unpredictable in humans. Therefore, the primary aim of this study was to develop a novel paradigm to study loss of control over substance use in rats that captures these aspects. This novel model allows us to measure reward seeking under threat of adversity in a within-subjects design. Outbred Lister-Hooded rats were trained to lever press for a reward (i.e. alcohol or sucrose). Subsequently, they were confronted with a tone cue during reward-seeking that functions as a warning sign since lever pressing during tone presentation results in a probabilistic footshock. We observed reduced responding in sessions during which the tone was presented compared to baseline sessions without a tone. This was observed when rats were lever pressing for either alcohol or sucrose. Also, the amount of responding in sessions in which the tone was presented was stable over time, allowing for repeated testing and within-subject comparisons. By increasing the shock intensity over sessions, we found that the optimal shock intensity at which most rats showed suppression of seeking was 0.25 mA. In ongoing experiments, we are applying this novel paradigm to study the neural underpinnings of loss of control. Previous studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control promotes compulsive substance use [3-5]. More specifically, dysfunction of the prelimbic prefrontal cortex (PrL) is thought to contribute to control over substance intake. Therefore, the secondary aim of this study was to test the hypothesis that PrL activity is necessary to maintain control over reward seeking behaviour under threat of adversity. We used chemogenetic inactivation of the PrL using designer receptors exclusively activated by designer drugs (DREADD) by bilaterally infusing an adeno-associated DREADD expressing virus (AAV5-CamKII-hM4D-mCherry) in the PrL. In initial experiments, we observed no significant effect of DREADD ligand clozapine-N-oxide (CNO) on sucrose seeking under threat of adversity. Taken together, we successfully implemented a novel paradigm that captures behavioural control over substance seeking in the face of adversity. It allows for within-subject comparisons and repetitive examination, which is essential for chemogenetic and pharmacological studies. Therefore, this model enables us to unravel the neurobiological mechanisms involved in loss of control over substance use. In ongoing experiments, we apply this model to determine the involvement of the PrL on alcohol seeking behaviour in this task. [ABSTRACT FROM AUTHOR]