In dit hoofdstuk wordt besproken hoe eet- en drinkgedrag gereguleerd worden. Op het moment dat er behoefte is aan energie, geeft het lichaam bepaalde signalen af aan de hersenen die een gevoel van eetlust geven. Deze signalen kunnen door de hersenen worden vertaald naar gedrag, wat uiteindelijk resulteert in de inname van voeding. Tijdens en na het eten worden er signalen van het lichaam afgegeven aan de hersenen die een gevoel van verzadiging geven. Ook deze signalen kunnen door de hersenen worden omgezet in gedrag, waardoor de maaltijd wordt beëindigd. Deze honger- en verzadigingssignalen zorgen voor een adequate dagelijkse voedingsinname. Het evenwicht tussen een adequaat energiegebruik en voedingsinname heet de energiebalans. Er wordt echter ook gegeten als er geen honger is. Voedingsinname wordt dus ook gereguleerd door gewoonte of omdat iets lekker is. Dit wordt aangeduid als hedonisch eten, en kan tot overeten leiden. Ook dit is onderwerp van dit hoofdstuk.

BACKGROUND:Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of type 2 diabetes. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism. METHODS:Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation. RESULTS:VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation. CONCLUSIONS:We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

Fibroblast growth factor 23 (FGF23) is a key regulator of systemic phosphate homeostasis, but also an interplay with glucose metabolism has been suggested. Several studies implicate a function of FGF23 in the brain, and indeed we have recently identified FGF23 protein in several brain areas in rats, such as the hypothalamus, third ventricle and choroid plexus. In the current study, we aimed to determine the effect of an intracerebroventricular (icv) injection of FGF23 in the third ventricle of rats on hypothalamic genes involved in glucose regulation. In addition, we assessed whether glycerol can be used safely for icv injections as glycerol is used as a stabilizing compound for FGF23 protein. Adult Wistar rats received an icv injection of recombinant rat FGF23 or vehicle. Dose dependent behavioral changes, suggestive of stress, were observed directly after infusion of FGF23. After 60 min animals were sacrificed and the arcuate nucleus, lateral hypothalamus and choroid plexus were isolated. In these brain regions gene expression was determined of the FGF23 receptor complex (FGFR1, αKlotho), NPY, POMC, phosphate transporters (SLC20 and SLC34 families) and markers of cellular ER stress (ATF4 and the ratio of spliced/unspliced XBP1). We showed that glycerol is well tolerated as stabilizer for icv injections. In FGF23-treated animals, cellular ER stress markers were increased in the arcuate nucleus. FGF23 injection did not affect expression of its receptor complex, NPY, POMC, or phosphate transporters. Future studies are warranted to investigate the effect of FGF23 in the brain on the protein level and on neuronal activation.

Opioids are known to affect blood glucose levels but their exact role in the physiological control of glucose metabolism remains unclear. Although there are numerous studies investigating the peripheral effects of opioid stimulation, little is known about how central opioids control blood glucose and which brain areas are involved. One brain area possibly involved is the nucleus accumbens because, as well as being a key site for opioid effects on food intake, it has also been implicated in the control of blood glucose levels. Within the nucleus accumbens, μ‐opioid receptors are most abundantly expressed. Therefore, in the present study, we investigated the role of μ‐opioid receptors in the nucleus accumbens in the control of glucose metabolism. We show that infusion of the μ‐opioid receptor agonist [ d ‐Ala 2 , N ‐MePhe 4 , Gly‐ol]‐enkephalin (DAMGO) in the nucleus accumbens by itself does not affect blood glucose levels, but it enhances the glycaemic response after both an insulin tolerance test, as well as a glucose tolerance test. These findings indicate that the nucleus accumbens plays a role in the central effects of opioids on glucose metabolism, and highlight the possibility of nucleus accumbens μ‐opioid receptors as a therapeutic target for enhancing the counter‐regulatory response.

Objectives: We have previously shown that the combined consumption of fat and a sucrose solution induces overeating, and there is evidence indicating that sucrose drinking directly stimulates fat intake. One neurochemical pathway by which sucrose may enhance fat intake is through the release of endogenous opioids in the nucleus accumbens (NAC). Methods: To test this hypothesis, we provided rats with a free-choice high-fat diet for two weeks. During the second week, rats had access to an additional bottle of water or a 30% sucrose solution for five minutes per day. After these two weeks, we infused vehicle or the mu-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAC 30 min after their daily access to the additional bottle of water or the sucrose solution. Results: Sucrose drinking had two effects, (1) it stimulated fat intake in the absence of DAMGO infusion, (2) it diminished sensitivity to DAMGO, as it prevented the rapid increase in fat intake typically seen upon DAMGO infusion in the nucleus accumbens. In a second experiment, we confirmed that these results are not due to the ingested calories of the sucrose solution. Lastly, we investigated which brain areas are involved in the observed effects on fat intake by assessing c-Fos-expression in brain areas previously linked to DAMGO's effects on food intake. Both intra-NAC DAMGO infusion and sucrose consumption in the absence of DAMGO infusion had no effect on c-Fos-expression in orexin neurons and the central amygdala but increased c-Fos-expression in the NAC as well as the basolateral amygdala. Discussion: In conclusion, we confirm that sucrose drinking stimulates fat intake, likely through the release of endogenous opioids. [GRAPHICS] .

Fibroblast growth factor 23 (FGF23) is an endocrine growth factor and known to play a pivotal role in phosphate homeostasis. Interestingly, several studies point towards a function of FGF23 in the hypothalamus. FGF23 classically activates the FGF receptor 1 in the presence of the co‐receptor αKlotho, of both gene expression in the brain was previously established. However, studies on gene and protein expression of FGF23 in the brain are scarce and have been inconsistent. Therefore, our aim was to localise FGF23 gene and protein expression in the rat brain with focus on the hypothalamus. Also, we investigated the protein expression of αKlotho. Adult rat brains were used to localise and visualise FGF23 and αKlotho protein in the hypothalamus by immunofluorescence labelling. Furthermore, western blots were used for assessing hypothalamic FGF23 protein expression. FGF23 gene expression was investigated by qPCR in punches of the arcuate nucleus, lateral hypothalamus, paraventricular nucleus, choroid plexus, ventrolateral thalamic nucleus and the ventromedial hypothalamus. Immunoreactivity for FGF23 and αKlotho protein was found in the hypothalamus, third ventricle lining and the choroid plexus. Western blot analysis of the hypothalamus confirmed the presence of FGF23. Gene expression of FGF23 was not detected, suggesting that the observed FGF23 protein is not brain‐derived. Several FGF receptors are known to be present in the brain. Therefore, we conclude that the machinery for FGF23 signal transduction is present in several brain areas, indeed suggesting a role for FGF23 in the brain.

Central dopamine signaling regulates reward-related aspects of feeding behavior, and during diet-induced obesity dopamine receptor signaling is altered. Yet, the influence of dopamine signaling on the consumption of specific dietary components remains to be elucidated. We have previously shown that 6-hydroxydopaminemediated lesions of dopamine neuron terminals in the lateral shell of the nucleus accumbens promotes fat intake in rats fed a multi-component free-choice high-fat high-sugar (fcHFHS) diet. It is however not yet determined which dopamine receptors are responsible for this shift towards fat preference. In this study, we assess the effects of D1-or D2 receptor acute inhibition in the lateral shell of the nucleus accumbens on fcHFHS diet consumption. We report that infusion of the D1 receptor antagonist SCH2 3390, but not the D2 receptor antagonist raclopride, promotes dietary fat consumption in male Sprague Dawley rats on a fcHFHS diet during 2 h after infusion. Furthermore, anatomical analysis of infusion sites revealed that the rostral region, but not the caudal region, of the lateral shell of the nucleus accumbens is sensitive to the D1 receptor inhibition effects on fat consumption. Our data highlight a role for D1 receptors in the rostral region of the lateral shell of the nucleus accumbens to control dietary fat consumption.

AIM:The tools that have been used to assess the function of the vagus nerve lack specificity. This could explain discrepancies about the role of vagal gut-brain signalling in long-term control of energy balance. Here we use a validated approach to selectively ablate sensory vagal neurones that innervate the gut to determine the role of vagal gut-brain signalling in the control of food intake, energy expenditure and glucose homoeostasis in response to different diets.METHODS:Rat nodose ganglia were injected bilaterally with either the neurotoxin saporin conjugated to the gastrointestinal hormone cholecystokinin (CCK), or unconjugated saporin as a control. Food intake, body weight, glucose tolerance and energy expenditure were measured in both groups in response to chow or high-fat high-sugar (HFHS) diet. Willingness to work for fat or sugar was assessed by progressive ratio for orally administered solutions, while post-ingestive feedback was tested by measuring food intake after an isocaloric lipid or sucrose pre-load.RESULTS:Vagal deafferentation of the gut increases meal number in lean chow-fed rats. Switching to a HFHS diet exacerbates overeating and body weight gain. The breakpoint for sugar or fat solution did not differ between groups, suggesting that increased palatability may not drive HFHS-induced hyperphagia. Instead, decreased satiation in response to intra-gastric infusion of fat, but not sugar, promotes hyperphagia in CCK-Saporin-treated rats fed with HFHS diet.CONCLUSIONS:We conclude that intact sensory vagal neurones prevent hyperphagia and exacerbation of weight gain in response to a HFHS diet by promoting lipid-mediated satiation.

The consumption of saturated fat and sucrose can have synergistic effects on the brain that do not occur when either nutrient is consumed by itself. In this study we hypothesize that saturated fat intake modulates glucose handling in the hypothalamus and nucleus accumbens, both brain areas highly involved in the control of food intake. To study this, male Wistar rats were given a free-choice high fat diet (fcHFD) or a control diet for two weeks. During the last seven days rats were given a daily bolus of either a 30% sucrose solution or water. Rats were sacrificed on day eight, 30 minutes after the onset of drinking. mRNA and protein levels of genes involved in glucose handling were assessed in the hypothalamus and nucleus accumbens. We found increased Glut3 and Glut4 mRNA in the hypothalamus of fcHFD-fed rats without an additional effect of the sucrose bolus. In the nucleus accumbens, the sucrose bolus increased Glut3 mRNA and decreased Glut4 mRNA independent of prior diet exposure. The ATP-sensitive potassium channel subunit Kir6.1 in the nucleus accumbens tended to be affected by the synergistic effects of a fcHFD and a sucrose bolus. These data suggest that acute glucose handling in the hypothalamus and nucleus accumbens may be affected by prior high fat exposure.

Humans have engineered a dietary environment that has driven the global prevalence of obesity and several other chronic metabolic diseases to pandemic levels. To prevent or treat obesity and associated comorbidities, it is crucial that we understand how our dietary environment, especially in combination with a sedentary lifestyle and/or daily‐life stress, can dysregulate energy balance and promote the development of an obese state. Substantial mechanistic insight into the maladaptive adaptations underlying caloric overconsumption and excessive weight gain has been gained by analysing brains from rodents that were eating prefabricated nutritionally‐complete pellets of high‐fat diet (HFD). Although long‐term consumption of HFDs induces chronic metabolic diseases, including obesity, they do not model several important characteristics of the modern‐day human diet. For example, prefabricated HFDs ignore the (effects of) caloric consumption from a fluid source, do not appear to model the complex interplay in humans between stress and preference for palatable foods, and, importantly, lack any aspect of choice. Therefore, our laboratory uses an obesogenic free‐choice high‐fat high‐sucrose (fc‐HFHS) diet paradigm that provides rodents with the opportunity to choose from several diet components, varying in palatability, fluidity, texture, form and nutritive content. Here, we review recent advances in our understanding how the fc‐HFHS diet disrupts peripheral metabolic processes and produces adaptations in brain circuitries that govern homeostatic and hedonic components of energy balance. Current insight suggests that the fc‐HFHS diet has good construct and face validity to model human diet‐induced chronic metabolic diseases, including obesity, because it combines the effects of food palatability and energy density with the stimulating effects of variety and choice. We also highlight how behavioural, physiological and molecular adaptations might differ from those induced by prefabricated HFDs that lack an element of choice. Finally, the advantages and disadvantages of using the fc‐HFHS diet for preclinical studies are discussed.

We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic-euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity.

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There is a lack of tools that selectively target vagal afferent neurons (VAN) innervating the gut. We use saporin (SAP), a potent neurotoxin, conjugated to the gastronintestinal (GI) hormone cholecystokinin (CCK-SAP) injected into the nodose ganglia (NG) of male Wistar rats to specifically ablate GI-VAN. We report that CCK-SAP ablates a subpopulation of VAN in culture. In vivo, CCK-SAP injection into the NG reduces VAN innervating the mucosal and muscular layers of the stomach and small intestine but not the colon, while leaving vagal efferent neurons intact. CCK-SAP abolishes feeding-induced c-Fos in the NTS, as well as satiation by CCK or glucagon like peptide-1 (GLP-1). CCK-SAP in the NG of mice also abolishes CCK-induced satiation. Therefore, we provide multiple lines of evidence that injection of CCK-SAP in NG is a novel selective vagal deafferentation technique of the upper GI tract that works in multiple vertebrate models. This method provides improved tissue specificity and superior separation of afferent and efferent signaling compared with vagotomy, capsaicin, and subdiaphragmatic deafferentation.NEW & NOTEWORTHY We develop a new method that allows targeted lesioning of vagal afferent neurons that innervate the upper GI tract while sparing vagal efferent neurons. This reliable approach provides superior tissue specificity and selectivity for vagal afferent over efferent targeting than traditional approaches. It can be used to address questions about the role of gut to brain signaling in physiological and pathophysiological conditions.

Vagal afferent neurons (VANs) play an important role in the control of food intake by signaling nutrient type and quantity to the brain. Recent findings are broadening our view of how VANs impact not only food intake but also energy homeostasis. This review focuses exclusively on studies of the vagus nerve from the past 2 years that highlight major new advancements in the field. We firstly discuss evidence that VANs can directly sense nutrients, and we consider new insights into mechanisms affecting sensing of gastric distension and signaling by gastrointestinal hormones ghrelin and GLP1. We discuss evidence that disrupting vagal afferent signaling increases long-term control of food intake and body weight management, and the importance of this gut-brain pathway in mediating beneficial effects of bariatric surgery. We conclude by highlighting novel roles for vagal afferent neurons in circadian rhythm, thermogenesis, and reward that may provide insight into mechanisms by which VAN nutrient sensing controls long-term control of energy homeostasis.

The brain is well known to regulate blood glucose, and the hypothalamus and hindbrain, in particular, have been studied extensively to understand the underlying mechanisms. Nuclei in these regions respond to alterations in blood glucose concentrations and can alter glucose liver output or glucose tissue uptake to maintain blood glucose concentrations within strict boundaries. Interestingly, several cortico-limbic regions also respond to alterations in glucose concentrations and have been shown to project to hypothalamic nuclei and glucoregulatory organs. For instance, electrical stimulation of the shell of the nucleus accumbens (sNAc) results in increased circulating concentrations of glucose and glucagon and activation of the lateral hypothalamus (LH). Whether this is caused by the simultaneous increase in serotonin release in the sNAc remains to be determined. To study the effect of sNAc serotonin on systemic glucose metabolism, we implanted bilateral microdialysis probes in the sNAc of male Wistar rats and infused fluoxetine, a serotonin reuptake inhibitor, or vehicle after which blood glucose, endogenous glucose production (EGP) and glucoregulatory hormones were measured. Fluoxetine in the sNAc for 1h significantly increased blood glucose concentrations without an effect on glucoregulatory hormones. This increase was accompanied by a higher EGP in the fluoxetine infused rats compared to the controls. These data provide further evidence for a role of sNAc-serotonin in the regulation of glucose metabolism.

Glucose is the most important source of fuel for the brain and its concentration must be kept within strict boundaries to ensure the organism's optimal fitness. To maintain glucose homeostasis, an optimal balance between glucose uptake and glucose output is required. Besides managing acute changes in plasma glucose concentrations, the brain controls a daily rhythm in glucose concentrations. The various nuclei within the hypothalamus that are involved in the control of both these processes are well known. However, novel studies indicate an additional role for brain areas that are originally appreciated in other processes than glucose metabolism. Therefore, besides the classic hypothalamic pathways, we will review cortico‐limbic brain areas and their role in glucose metabolism. © 2013 BioFactors 39(5):505–513, 2013

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients.

Recently, we showed that deep brain stimulation (DBS) of the nucleus accumbens shell (sNAc) in rats rapidly increases blood glucose and plasma glucagon concentrations in a region- and intensity dependent manner.