Circadian influences on feeding behavior.

Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master clock is located in the hypothalamic suprachiasmatic nucleus (SCN). Other brain areas and tissues throughout the body also display rhythmic functions and contain the molecular clock mechanism known as peripheral oscillators. To generate the daily feeding rhythm, the SCN signals to different hypothalamic areas with the lateral hypothalamus, paraventricular nucleus and arcuate nucleus being the most prominent. With respect to the rewarding aspects of feeding behavior, the dopaminergic system is also under circadian influence. However the SCN projects only indirectly to the different reward regions, such as the ventral tegmental area where dopamine neurons are located. In addition, high palatable, high caloric diets have the potential to disturb the normal daily rhythms of physiology and have been shown to alter for example meal patterns. Around a meal several hormones and peptides are released that are also under circadian influence. For example, the release of postprandial insulin and glucagon-like peptide following a meal depend on the time of the day. Finally, we review the effect of deletion of different clock genes on feeding behavior. The most prominent effect on feeding behavior has been observed in Clock mutants, whereas deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Data presented here focus on the rodent literature as only limited data are available on the mechanisms underlying daily rhythms in human eating behavior.

Mutant Tbl1x male mice have a short life span and do not breed: unexpected findings.

Humans with the mutation Y509C in transducin beta like 1 X-linked (TBL1X HGNC ID HGNC:11585) have been reported to present with the combination of central congenital hypothyroidism and impaired hearing. TBL1X belongs to the WD40 repeat-containing protein family, is part of NCoR and SMRT corepressor complexes, and thereby involved in thyroid hormone signaling. In order to investigate the effects of the Y509C mutation in TBL1X on cellular thyroid hormone action, we aimed to generate a hemizygous male mouse cohort carrying the Tbl1x Y459C mutation which is equivalent to the human TBL1X Y509C mutation using CRISPR/Cas9 technology. Hemizygous male mice were small at birth and inactive. Their life span (median life span 93 days) was very short compared with heterozygous female mice (survived to >200 days with no welfare issues). About 52% of mice did not survive to weaning (133 mice). Of the remaining 118 mice, only 8 were hemizygous males who were unable to mate whereby it was impossible to generate homozygous female mice. In conclusion, the Tbl1x Y459C mutation in male mice has a marked negative effect on birth weight, survival, and fertility of male mice. The present findings are unexpected as they are in contrast to the mild phenotype in human males carrying the equivalent TBL1X Y509C mutation.

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents.

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.

Stress, rhythm, choice and the munchies - tribute to Mary F. Dallman.

In December 2021, we lost a pioneer in the field of stress research who inspired generations of scientists. Mary Dallman was an expert on the hypothalamic-pituitary-adrenal (HPA) axis, its interactions with a wide variety of other physiological systems and the impact of chronic changes of HPA function on energy metabolism and adiposity. She was not only an excellent scientist, she was a great role model and mentor for young scientists, especially women. She encouraged and supported many of her trainees even long after they left the lab. Her outside-the-box thinking, the fun and crazy discussions we had in the lab proved to be a beautiful basis for my own future research.

Free-choice high-fat diet consumption reduces lateral hypothalamic GABAergic activity, without disturbing neural response to sucrose drinking in mice.

Nutrition can influence the brain and affect its regulation of food intake, especially that of high-palatable foods. We hypothesize that fat and sugar have interacting effects on the brain, and the lateral hypothalamus (LH) is a prime candidate to be involved in this interaction. The LH is a heterogeneous area, crucial for regulating consummatory behaviors, and integrating homeostatic and hedonic needs. GABAergic LH neurons stimulate feeding when activated, and are responsive to consummatory behavior while encoding sucrose palatability. Previously, we have shown that glutamatergic LH neurons reduce their activity in response to sugar drinking and that this response is disturbed by a free-choice high-fat diet (fcHFD). Whether GABAergic LH neurons, and their response to sugar, is affected by a fcHFD is yet unknown. Using head-fixed two-photon microscopy, we analyzed activity changes in LHVgat neuronal activity in chow or fcHFD-fed mice in response to water or sucrose drinking. A fcHFD decreased overall LHVgat neuronal activity, without disrupting the sucrose-induced increase. When focusing on the response per unique neuron, a vast majority of neurons respond inconsistently over time. Thus, a fcHFD dampens overall LH GABAergic activity, while it does not disturb the response to sucrose. The inconsistent responding over time suggests that it is not one specific subpopulation of LH GABAergic neurons that is driving these behaviors, but rather a result of the integrative properties of a complex neural network. Further research should focus on determining how this dampening of LH GABAergic activity contributes to hyperphagia and the development of obesity.

Investigating Habenula Functional Connectivity and Reward-Related Activity in Obesity Using Human Connectome Project Data.

Introduction: The habenula, a brain region involved in aversion, might negatively modulate caloric intake. Functional magnetic resonance imaging (fMRI) studies reported associations between weight loss and habenula functional connectivity. However, whether habenula resting-state functional connectivity (rsFC) and reward-related activity are altered in obesity is yet unknown. Methods: Using data from the Human Connectome Project, we included 300 subjects with various body mass indexes (BMIs) and a healthy long-term blood glucose (hemoglobin A1c [HbA1c]). In addition, we investigated a potential BMI × HbA1c interaction in a separate cohort including subjects with prediabetes (n = 72). Habenula rsFC was assessed using a region of interest (ROI)-to-ROI analysis. Furthermore, a separate analysis using gambling task fMRI data focused on reward-related habenula activity. Results: We did not find an association between BMI and habenula rsFC for any of the ROIs. For the exploratory analysis of the BMI × HbA1c effect, a significant interaction effect was found for the habenula-ventral tegmental area (VTA) connection, but this did not survive multiple comparisons correction. Monetary punishment compared with reward activated the bilateral habenula in the BMI sample, but this activity was not associated with BMI. Discussion: In conclusion, we did not find evidence for an association between BMI and habenula rsFC or reward-related activity. However, there might be an interaction between BMI and HbA1c for the habenula-VTA rsFC, suggestive of a role of the habenula in glucose regulation. Future studies should focus on metabolic parameters in their experimental design to confirm our findings and explore the precise role of the habenula in metabolism.

Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study.

Post-ingestive nutrient signals to the brain regulate eating behaviour in rodents, and impaired responses to these signals have been associated with pathological feeding behaviour and obesity. To study this in humans, we performed a single-blinded, randomized, controlled, crossover study in 30 humans with a healthy body weight (females N = 12, males N = 18) and 30 humans with obesity (females N = 18, males N = 12). We assessed the effect of intragastric glucose, lipid and water (noncaloric isovolumetric control) infusions on the primary endpoints cerebral neuronal activity and striatal dopamine release, as well as on the secondary endpoints plasma hormones and glucose, hunger scores and caloric intake. To study whether impaired responses in participants with obesity would be partially reversible with diet-induced weight loss, imaging was repeated after 10% diet-induced weight loss. We show that intragastric glucose and lipid infusions induce orosensory-independent and preference-independent, nutrient-specific cerebral neuronal activity and striatal dopamine release in lean participants. In contrast, participants with obesity have severely impaired brain responses to post-ingestive nutrients. Importantly, the impaired neuronal responses are not restored after diet-induced weight loss. Impaired neuronal responses to nutritional signals may contribute to overeating and obesity, and ongoing resistance to post-ingestive nutrient signals after significant weight loss may in part explain the high rate of weight regain after successful weight loss.

Voluntary physical activity modulates self-selection of a high-caloric choice diet in male Wistar rats.

Physical exercise training has been positioned as a behavioral strategy to prevent or alleviate obesity via promotion of energy expenditure as well as modulation of energy intake resulting from changes in dietary preference. Brain adaptations underlying the latter process are incompletely understood. Voluntary wheel running (VWR) is a self-reinforcing rodent paradigm that mimics aspects of human physical exercise training. Behavioral and mechanistic insight from such fundamental studies can help optimize therapies that improve body weight and metabolic health based on physical exercise training in humans. To assess the effects of VWR on dietary self-selection, male Wistar rats were given access to a two-component "no-choice" control diet (CD; consisting of prefabricated nutritionally complete pellets and a bottle with tap water) or a four-component free-choice high-fat high-sucrose diet (fc-HFHSD; consisting of a container with prefabricated nutritionally complete pellets, a dish with beef tallow, a bottle with tap water, and a bottle with 30% sucrose solution). Metabolic parameters and baseline dietary self-selection behavior during sedentary (SED) housing were measured for 21 days, after which half of the animals were allowed to run on a vertical running wheel (VWR) for another 30 days. This resulted in four experimental groups (SEDCD, SEDfc-HFHSD, VWRCD, and VWRfc-HFHSD). Gene expression of opioid and dopamine neurotransmission components, which are associated with dietary self-selection, was assessed in the lateral hypothalamus (LH) and nucleus accumbens (NAc), two brain regions involved in reward-related behavior, following 51 and 30 days of diet consumption and VWR, respectively. Compared to CD controls, consumption of fc-HFHSD before and during VWR did not alter total running distances. VWR and fc-HFHSD had opposite effects on body weight gain and terminal fat mass. VWR transiently lowered caloric intake and increased and decreased terminal adrenal and thymus mass, respectively, independent of diet. VWR during fc-HFHSD consumption consistently increased CD self-selection, had an acute negative effect on fat self-selection, and a delayed negative effect on sucrose solution self-selection compared to SED controls. Gene expression of opioid and dopamine neurotransmission components in LH and NAc were unaltered by fc-HFHSD or VWR. We conclude that VWR modulates fc-HFHSD component self-selection in a time-dependent manner in male Wistar rats.

The Clash of Two Epidemics: the Relationship Between Opioids and Glucose Metabolism.

PURPOSE OF REVIEW: We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels. RECENT FINDINGS: This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid ß-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma ß-endorphin levels. Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use.

Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.

Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.

Effects of Neuropeptide Y administration into the lateral hypothalamus on intake of free-choice high-fat high-sucrose diet components of the male Wistar rat.

Introduction: Neuropeptide Y (NPY) signaling in the brain plays an important role in energy regulation, and is altered during diet-induced obesity. Yet, NPY function during the consumption of specific diet components remains to be fully determined. We have previously demonstrated that consumption of a saturated fat component (free-choice high-fat; fcHF), a sucrose solution (high-sugar; fcHS), or both (fcHFHS) combined with a standard diet (chow and water) has diverse effects on Npy expression in the arcuate nucleus and the sensitivity to intraventricular NPY administration. Arcuate NPY neurons project to the lateral hypothalamus (LHA), and NPY administration in the LHA potently promotes chow intake in rats on a standard diet. However, it is currently unclear if short-term consumption of a palatable free-choice diet alters NPY function in the LHA. Therefore, we assessed the effects of intra-LHA NPY administration on intake in rats following one-week consumption of a fcHF, fcHS, or fcHFHS diet.Methods: Male Wistar rats consumed a fcHF, fcHS, fcHFHS, or control (CHOW) diet for one week before NPY (0.3 µg / 0.3 µL) or phosphate-buffered saline (0.3 µL) was administered into the LHA. Intake was measured 2h later. fcHFHS-fed rats were divided into high-fat (fcHFHS-hf) and low-fat (fcHFHS-lf) groups based on differences in basal fat intake.Results: Intra-LHA NPY administration increased chow intake in fcHFHS- (irrespective of basal fat intake), fcHF- and CHOW-fed rats. Intra-LHA NPY infusion increased fat intake in fcHF-, fcHFHS-hf, but not fcHFHS-lf, rats. Intra-LHA NPY infusion did not increase caloric intake in fcHS-fed rats.Discussion: Our data demonstrate that the effects of intra-LHA NPY on caloric intake differ depending on the consumption of a fat or sugar component, or both, in a free-choice diet. Our data also indicate that baseline preference for the fat diet component modulates the effects of intra-LHA NPY in fcHFHS-fed rats.

How exposure to chronic stress contributes to the development of type 2 diabetes: A complexity science approach.

Chronic stress contributes to the onset of type 2 diabetes (T2D), yet the underlying etiological mechanisms are not fully understood. Responses to stress are influenced by earlier experiences, sex, emotions and cognition, and involve a complex network of neurotransmitters and hormones, that affect multiple biological systems. In addition, the systems activated by stress can be altered by behavioral, metabolic and environmental factors. The impact of stress on metabolic health can thus be considered an emergent process, involving different types of interactions between multiple variables, that are driven by non-linear dynamics at different spatiotemporal scales. To obtain a more comprehensive picture of the links between chronic stress and T2D, we followed a complexity science approach to build a causal loop diagram (CLD) connecting the various mediators and processes involved in stress responses relevant for T2D pathogenesis. This CLD could help develop novel computational models and formulate new hypotheses regarding disease etiology.

Striatal Dopamine Transporter Availability Is Not Associated with Food Craving in Lean and Obese Humans; a Molecular Imaging Study.

Brain dopamine signaling is essential for the motivation to eat, and obesity is associated with altered dopaminergic signaling and increased food craving. We used molecular neuroimaging to explore whether striatal dopamine transporter (DAT) availability is associated with craving as measured with the General Food Craving Questionnaire-Trait (G-FCQ-T). We here show that humans with obesity (n = 34) experienced significantly more craving for food compared with lean subjects (n = 32), but food craving did not correlate significantly with striatal DAT availability as assessed with 123I-FP-CIT single-photon emission computed tomography. We conclude that food craving is increased in obesity, but the scores for food craving are not related to changes in striatal DAT availability.

Activation of nucleus accumbens µ-opioid receptors enhances the response to a glycaemic challenge.

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-Ala2 , N-MePhe4 , 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.

Disruption of lateral hypothalamic calorie detection by a free choice high fat diet.

During the last few decades, the consumption of low-calorie sweeteners, as a substitute for caloric sweeteners, has sharply increased. Although research shows that caloric versus low-calorie sweeteners can have differential effects on the brain, it is unknown which neuronal populations are responsible for detecting the difference between the two types of sweeteners. Using in vivo two-photon calcium imaging, we investigated how drinking sucrose or sucralose (a low-calorie sweetener) affects the activity of glutamatergic neurons in the lateral hypothalamus. Furthermore, we explored the consequences of consuming a free-choice high fat diet on the calorie detection abilities of these glutamatergic neurons. We found that glutamatergic neurons indeed can discriminate sucrose from water and sucralose, and that consumption of a free-choice high fat diet shifts the glutamatergic neuronal response from sucrose-specific to sucralose-specific, thereby disrupting calorie detection. These results highlight the disruptive effects of a diet high in saturated fat on calorie detection in the lateral hypothalamus.

Dopamine D1 receptor signalling in the lateral shell of the nucleus accumbens controls dietary fat intake in male rats.

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-hydroxydopamine-mediated 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.

Connections of the mouse subfornical region of the lateral hypothalamus (LHsf).

The lateral hypothalamus is a major integrative hub with a complex architecture characterized by intricate and overlapping cellular populations expressing a large variety of neuro-mediators. In rats, the subfornical lateral hypothalamus (LHsf) was identified as a discrete area with very specific outputs, receiving a strong input from the nucleus incertus, and involved in defensive and foraging behaviors. We identified in the mouse lateral hypothalamus a discrete subfornical region where a conspicuous cluster of neurons express the mu opioid receptor. We thus examined the inputs and outputs of this LHsf region in mice using retrograde tracing with the cholera toxin B subunit and anterograde tracing with biotin dextran amine, respectively. We identified a connectivity profile largely similar, although not identical, to what has been described in rats. Indeed, the mouse LHsf has strong reciprocal connections with the lateral septum, the ventromedial hypothalamic nucleus and the dorsal pre-mammillary nucleus, in addition to a dense output to the lateral habenula. However, the light input from the nucleus incertus and the moderate bidirectional connectivity with nucleus accumbens are specific to the mouse LHsf. A preliminary neurochemical study showed that LHsf neurons expressing mu opioid receptors also co-express calcitonin gene-related peptide or somatostatin and that the reciprocal connection between the LHsf and the lateral septum may be functionally modulated by enkephalins acting on mu opioid receptors. These results suggest that the mouse LHsf may be hodologically and functionally comparable to its rat counterpart, but more atypical connections also suggest a role in consummatory behaviors.

The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.

BACKGROUND AND AIMS: Serotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. METHODS: In this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. RESULTS: As compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. CONCLUSION: Lean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.

Localization of fibroblast growth factor 23 protein in the rat hypothalamus.

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.

The Role of the Gut Microbiota in the Gut-Brain Axis in Obesity: Mechanisms and Future Implications.

Interaction between the gut and the brain is essential for energy homeostasis. In obesity, this homeostasis is disrupted, leading to a positive energy balance and weight gain. Obesity is a global epidemic that affects individual health and strains the socioeconomic system. Microbial dysbiosis has long been reported in obesity and obesity-related disorders. More recent literature has focused on the interaction of the gut microbiota and its metabolites on human brain and behavior. Developing strategies that target the gut microbiota could be a future approach for the treatment of obesity. Here, we review the microbiota-gut-brain axis and possible therapeutic options.