Hedonic Feeding Research Articles

Neuroscience: Hedonic worms gorge on high-energy foods

Cannabinoids can enhance the preference for calorific foods through hedonic feeding behaviors. A new study identifies and characterizes these indulgent behaviors in the nematode Caenorhabditis elegans, providing insights into the mechanisms of their regulation.

The conserved endocannabinoid anandamide modulates olfactory sensitivity to induce hedonic feeding in C. elegans

The ability of cannabis to increase food consumption has been known for centuries. In addition to producing hyperphagia, cannabinoids can amplify existing preferences for calorically dense, palatable food sources, a phenomenon called hedonic amplification of feeding. These effects result from the action of plant-derived cannabinoids that mimic endogenous ligands called endocannabinoids. The high degree of conservation of cannabinoid signaling at the molecular level across the animal kingdom suggests hedonic feeding may also be widely conserved. Here, we show that exposure of Caenorhabditis elegans to anandamide, an endocannabinoid common to nematodes and mammals, shifts both appetitive and consummatory responses toward nutritionally superior food, an effect analogous to hedonic feeding. We find that anandamide's effect on feeding requires the C.elegans cannabinoid receptor NPR-19 but can also be mediated by the human CB1 cannabinoid receptor, indicating functional conservation between the nematode and mammalian endocannabinoid systems for the regulation of food preferences. Furthermore, anandamide has reciprocal effects on appetitive and consummatory responses to food, increasing and decreasing responses to inferior and superior foods, respectively. Anandamide's behavioral effects require the AWC chemosensory neurons, and anandamide renders these neurons more sensitive to superior foods and less sensitive to inferior foods, mirroring the reciprocal effects seen at the behavioral level. Our findings reveal a surprising degree of functional conservation in the effects of endocannabinoids on hedonic feeding across species and establish a new system to investigate the cellular and molecular basis of endocannabinoid system function in the regulation of food choice.

Dimensions of sleep quality are related to objectively measured eating behaviors among children at high familial risk for obesity.

The aim of this study was to evaluate whether dimensions of sleep quality were associated with homeostatic and hedonic eating behaviors among children with healthy weight (BMI-for-age < 90%) but varying maternal weight status. A total of 77 children (mean [SD], age: 7.4 [0.6] years; BMI z score: -0.10 [0.7]) with healthy weight and high (n= 32) or low (n= 45) familial obesity risk based on maternal weight status were served an ad libitum meal (homeostatic eating) followed by palatable snacks to assess eating in the absence of hunger (EAH; hedonic eating). Habitual sleep quality was quantified from seven nights of wrist actigraphy. Partial correlations, adjusted for child energy needs, pre-meal hunger, food liking, and socioeconomic status, evaluated associations of sleep with meal intake and EAH. Additionally, sleep-by-obesity risk interactions were assessed. Greater sleep fragmentation was associated with higher homeostatic meal energy intake, but only among children at high familial obesity risk (p value for interaction=0.001; β high risk=48.6, p= 0.001). Sleep fragmentation was not associated with total EAH but was related to higher and lower intake of carbohydrates (r= 0.33, p= 0.003) and fat (r= -0.33, p= 0.003), respectively. Adverse associations of poor sleep with energy intake may be amplified among children already predisposed to obesity. Furthermore, that fragmented sleep relates to preferential intake of carbohydrates over fat during EAH may suggest alterations in taste preferences with poor sleep.

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

RationaleThe endocannabinoid system makes critical contributions to reward processing, motivation, and behavioral control. Repeated exposure to THC or other cannabinoid drugs can cause persistent adaptions in the endocannabinoid system and associated neural circuitry. It remains unclear how such treatments affect the way rewards are processed and pursued.Objective and methodsWe examined if repeated THC exposure (5 mg/kg/day for 14 days) during adolescence or adulthood led to long-term changes in rats’ capacity to flexibly encode and use action-outcome associations for goal-directed decision making. Effects on hedonic feeding and progressive ratio responding were also assessed.ResultsTHC exposure had no effect on rats’ ability to flexibly select actions following reward devaluation. However, instrumental contingency degradation learning, which involves avoiding an action that is unnecessary for reward delivery, was augmented in rats with a history of adult but not adolescent THC exposure. THC-exposed rats also displayed more vigorous instrumental behavior in this study, suggesting a motivational enhancement. A separate experiment found that while THC exposure had no effect on hedonic feeding behavior, it increased rats’ willingness to work for food on a progressive ratio schedule, an effect that was more pronounced when THC was administered to adults. Adolescent and adult THC exposure had opposing effects on the CB1 receptor dependence of progressive ratio performance, decreasing and increasing sensitivity to rimonabant-induced behavioral suppression, respectively.ConclusionsOur findings reveal that exposure to a translationally relevant THC exposure regimen induces long-lasting, age-dependent alterations in cognitive and motivational processes that regulate the pursuit of rewards.

Microbes, oxytocin and stress: Converging players regulating eating behavior.

Oxytocin is a peptide-hormone extensively studied for its multifaceted biological functions and has recently gained attention for its role in eating behavior, through its action as an anorexigenic neuropeptide. Moreover, the gut microbiota is involved in oxytocinergic signaling through the brain-gut axis, specifically in the regulation of social behavior. The gut microbiota is also implicated in appetite regulation and is postulated to play a role in central regulation of hedonic eating. In this review, we provide an overview on oxytocin and its individual links with the microbiome, the homeostatic and non-homeostatic regulation of eating behavior as well as social behavior and stress.

Association Between Food Intake and Gastrointestinal Symptoms in Patients With Obesity.

Hunger, satiation, postprandial satiety, and hedonic eating constitute key food intake parameters. We aim to study whether these symptoms are associated with gastrointestinal symptoms (GIS) in patients with obesity. This is a cross-sectional study of patients with obesity. Patients completed the following validated biomarkers and questionnaires: hunger was measured via visual analog scale (100 mm) following a standard meal, satiation was measured via ad libitum meal (calories to fullness; kcal), postprandial satiety was measured via gastric emptying scintigraphy (T1/2; mins), and hedonic eating was measured via the Hospital Anxiety and Depression Scale questionnaire. Participants completed the abridged Bowel Disease Questionnaire to evaluate their GIS. We calculated the odds ratios (ORs) adjusted for sex, weight, and age between food intake parameters <25th or >75th percentile observed in a prior cohort of 450 participants with obesity and GIS. A total of 274 participants (41 ± 10 [SD] years, 75% females, body mass index 39 ± 8 kg/m2) were included in the analysis. Increased hunger was associated with a lower prevalence of lumpy stools (OR = 0.18, P = .02). Satiation was associated with abdominal pain/discomfort (relieved by defecation [OR = 2.4, P = .02] or associated with change in stool consistency [OR = 2.92, P < .01]), loose/watery stools (OR = 2.09, P = .02), and bloating (OR = 2.49, P < .01). Abnormal postprandial satiety was associated with bloating (OR = 2.26, P < .01) and loose/watery stools (OR = 1.84, P = .04). Hedonic eating was associated with abdominal pain/discomfort with stool frequency change (OR = 2.4, P = .02), >3 bowel movements per day (OR = 1.93, P = .048), bloating (OR = 2.49, P = .01), abdominal pain after meals >1 per month (OR = 4.24, P < .01), and nausea >1 per week (OR = 4.51, P < .01). Alterations in hunger, satiation, postprandial satiety, and hedonic eating are associated with GIS in patients with obesity.

Glucagon-like Peptide-1 Receptor in the Human Hypothalamus Is Associated with Body Mass Index and Colocalizes with the Anorexigenic Neuropeptide Nucleobindin-2/Nesfatin-1.

Data on animals emphasize the importance of the neuronal glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The present study aimed to explore GLP-1R protein expression in the human hypothalamus and its correlation with body mass index (BMI). Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 kg/m2) and 17 with non-normal weight (BMI ≥ 25 kg/m2), were examined using immunohistochemistry and double immunofluorescence labeling. Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei; the lateral hypothalamic area (LH); and basal forebrain nuclei. Interestingly, in the LH, GLP-1R was significantly decreased in individuals with BMI ≥ 25 kg/m2 compared with their normal weight counterparts (p = 0.03). Furthermore, GLP-1R was negatively correlated (τb = −0.347, p = 0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and antiobesogenic neuropeptide nucleobindin-2/nesfatin-1 but not with the astrocytic marker glial fibrillary acidic protein. These data suggest a potential role for GLP-1R in the regulation of energy balance in the human hypothalamus. In the LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to the dysregulation of homeostatic and/or hedonic feeding behavior. Possible effects of NUCB2/nesfatin-1 on central GLP-1R signaling require further investigation.

Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis.

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNts neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNts neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNts neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

Sex differences in activation of extra-hypothalamic forebrain areas during hedonic eating.

Palatable foods can stimulate appetite without hunger, and unconstrained overeating underlies obesity and binge eating disorder. Women are more prone to obesity and binge eating than men but the neural causes of individual differences are unknown. In an animal model of hedonic eating, a prior study found that females were more susceptible than males to eat palatable food when sated and that the neuropeptide orexin/hypocretin (ORX) was crucial in both sexes. The current study examined potential extra-hypothalamic forebrain targets of ORX signaling during hedonic eating. We measured Fos induction in the cortical, thalamic, striatal, and amygdalar areas that receive substantial ORX inputs and contain their receptors in hungry and sated male and female rats during palatable (high-sucrose) food consumption. During the test, hungry rats of both sexes ate substantial amounts, and while sated males ate much less than hungry rats, sated females ate as much as hungry rats. The Fos induction analysis identified sex differences in recruitment of specific areas of the medial prefrontal cortex, paraventricular nucleus of the thalamus (PVT), nucleus accumbens (ACB), and central nucleus of the amygdala (CEA), and similar patterns across sexes in the insular cortex. There was a striking activation of the infralimbic cortex in sated males, who consumed the least amount food and unique correlations between the insular cortex, PVT, and CEA, as well as the prelimbic cortex, ACB, and CEA in sated females but not sated males. The study identified key functional circuits that may drive hedonic eating in a sex-specific manner.

Pharmacological modulation of ventral tegmental area neurons elicits changes in trigeminovascular sensory processing and is accompanied by glycemic changes: Implications for migraine.

Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.

Investigating a role of orexin and ‘cocaine- and amphetamine-regulated transcript’ in the nucleus accumbens shell in binge eating of male rats and the relationship with impulsivity

Binge eating disorder (BED) is the most prevalent eating disorder in the adult population. It is characterized by recurrent episodes of uncontrollable overconsumption of palatable food (PF). BED is connected to several comorbidities such as obesity, major depression, and substance use disorder, and was linked to heightened levels of impulsivity. The neurobiological basis of BED is however still vaguely known. Binge eating (BE) occurs without homeostatic needs, and therefore, relates to hedonic consumption of PF. A major brain structure in the control of hedonic feeding, and part of the network regulating impulsive action, is the nucleus accumbens shell (NAcSh). The present study in rats assessed the influence of trait impulsivity on the development of BE-like feeding and the role of the orexigenic neuropeptide orexin (OX) and the anorexigenic neuropeptide cocaine- and amphetamine-regulated transcript (CART) within the NAcSh in a BE-model. The rats were initially ranked for their trait impulsivity based on a screening in the 5-choice serial reaction time task. They were subsequently introduced into a limited access-model to establish BE-like feeding with pure vegetable fat to examine a correlation between trait impulsivity and the development of BE-like feeding. The effect of bilateral infusions of the OX 1-receptor (OX1R) antagonist SB-334867 (SB) and CART-antibodies (CART-ABs) into the NAcSh was examined in relation to trait impulsivity. Further, accumbal OX1R density was evaluated by immunohistochemical staining in rats with normal and BE-like feeding behavior. We found that all animals developed stable BE-like PF intake, independent of trait impulsivity and without differences in the dynamics. The blockade of accumbal OX1Rs effectively reduced PF intake only in the control group that had daily access to PF, with impulsivity trait as a decisive factor, pointing towards alterations in orexinergic transmission in the NAcSh of rats bingeing on pure fat. This was corroborated by a lower density of OX1Rs in the NAcSh of rats with BE-like feeding behavior, precisely, in low-impulsive bingeing rats. Regardless of impulsivity trait, antagonizing CART in the NAcSh did not affect PF intake of control or bingeing animals. This suggests that endogenous accumbal CART does not influence consummatory behavior in ad libitum-fed rats with access to fat, under both normal and BE-like feeding patterns.

Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice

ObjectiveInsulin-like peptide 5 (INSL5) signalling, through its cognate receptor relaxin/insulin-like family peptide receptor 4 (RXFP4), has been reported to be orexigenic, and the high fat diet (HFD) preference observed in wildtype mice is altered in Rxfp4 knock-out mice. In this study, we used a new Rxfp4-Cre mouse model to investigate the mechanisms underlying these observations. MethodsWe generated transgenic Rxfp4-Cre mice and investigated central expression of Rxfp4 by RT-qPCR, RNAscope and intraparenchymal infusion of INSL5. Rxfp4-expressing cells were chemogenetically manipulated in global Cre-reporter mice using designer receptors exclusively activated by designer drugs (DREADDs) or after stereotactic injection of a Cre-dependent AAV-DIO-Dq-DREADD targeting a population located in the ventromedial hypothalamus (RXFP4VMH). Food intake and feeding motivation were assessed in the presence and absence of a DREADD agonist. Rxfp4-expressing cells in the hypothalamus were characterised by single-cell RNA-sequencing (scRNAseq) and the connectivity of RXFP4VMH cells was investigated using viral tracing. ResultsRxfp4-Cre mice displayed Cre-reporter expression in the hypothalamus. Active expression of Rxfp4 in the adult mouse brain was confirmed by RT-qPCR and RNAscope. Functional receptor expression was supported by cyclic AMP-responses to INSL5 application in ex vivo brain slices and increased HFD and highly palatable liquid meal (HPM), but not chow, intake after intra-VMH INSL5 infusion. scRNAseq of hypothalamic RXFP4 neurons defined a cluster expressing VMH markers, alongside known appetite-modulating neuropeptide receptors (Mc4r, Cckar and Nmur2). Viral tracing demonstrated RXFP4VMH neural projections to nuclei implicated in hedonic feeding behaviour. Whole body chemogenetic inhibition (Di-DREADD) of Rxfp4-expressing cells, mimicking physiological INSL5-RXFP4 Gi-signalling, increased intake of the HFD and HPM, but not chow, whilst activation (Dq-DREADD), either at whole body level or specifically within the VMH, reduced HFD and HPM intake and motivation to work for the HPM. ConclusionThese findings identify RXFP4VMH neurons as regulators of food intake and preference, and hypothalamic RXFP4 signalling as a target for feeding behaviour manipulation.

Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters.

Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain. How this relates to effective weight management is unclear, especially in older people, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, 50 overweight, non-diabetic older adults participated in a double-blind, placebo-controlled, pharmacological functional magnetic resonance imaging study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and peripheral insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.

Consumers’ Intention to Purchase Functional Non-Dairy Milk and Gender-Based Market Segmentation

The increasing awareness of the benefits of functional non-dairy milk has been growing significantly due to the increasing recognition of the benefits of functional foods. Functional non-dairy milk provides a valuable alternative for lactose-intolerant people with other dietary restrictions preventing them from consuming dairy milk. However, some evidence suggests that not all consumers benefit equally from food. Previous research indicated that women more often purchase foods that are perceived to be healthy, while men are more likely to purchase foods that are perceived to be hedonistic. Thus, this study aimed to examine the significant relationships among factors influencing functional non-dairy milk purchase intention based on the theory of planned behavior (TPB) and to identify behavioral differences between men and women. We conducted a quantitative study using structured questionnaires and with 413 valid respondents that consume functional non-dairy milk in six regions of Thailand. Further, we used a multi-group structural equation modeling approach to explore and compare consumers’ intentions across genders. The results showed that trust and health consciousness positively influence an individual’s perceived behavioral control and then directly affect their attitude and purchase intention of functional non-dairy milk products. Additionally, the multi-group analysis proposed that men and women consumers significantly differ in their requirements for enjoyable experiences while consuming functional non-dairy milk. More specifically, hedonic eating value has a greater impact on men’s attitudes than women’s attitudes. This study deepens our understanding of the functional non-dairy milk industry in Thailand in terms of market segments based on gender.

Corticotropin-releasing factor system in the lateral septum: Implications in the pathophysiology of obesity.

Obesity is a pandemic associated with lifestyles changes. These include excess intake of obesogenic foods and decreased physical activity. Brain areas, like the lateral hypothalamus (LH), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been linked in both homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. Interestingly, these control systems are regulated by the lateral septum (LS), a relay of γ-aminobutyric (GABA) acid neurons (GABAergic neurons) that inhibit the LH and GABAergic interneurons of the VTA. Furthermore, the LS has a diverse receptor population for neurotransmitters and neuropeptides such as dopamine, glutamate, GABA and corticotropin-releasing factor (CRF), among others. Particularly, CRF a key player in the stress response, has been related to the development of overweight and obesity. Moreover, evidence shows that LS neurons neurophysiologically regulate reward and stress, although there is little evidence of LS taking part in homeostatic and hedonic feeding. In this review, we discuss the evidence that supports the role of LS and CRF on feeding, and how alterations in this system contribute to weight gain obesity.

Progress of neural circuits mechanism underlying metabolic and hedonic feeding

Feeding behavior is imperative for the survival and reproduction of animals. Depending on the motivation, feeding is induced by metabolic need or hedonic reason, which is associated with energy demand or pleasurable food intake respectively. Although substantial differences exist, neural circuits for metabolic and hedonic feeding are largely intertwined. Here, we review the distinctions and overlaps between metabolic and hedonic feeding to provide insights into the central regulation of feeding.

A circuit from lateral septum neurotensin neurons to tuberal nucleus controls hedonic feeding

Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding. LSNts neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LSNts→the supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LSNts neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LSNts or LSNts→TU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LSNts→TU is a key pathway in regulating hedonic feeding.

Gut microbes and food reward: From the gut to the brain.

Inappropriate food intake behavior is one of the main drivers for fat mass development leading to obesity. Importantly the gut microbiota-mediated signals have emerged as key actors regulating food intake acting mainly on the hypothalamus, and thereby controlling hunger or satiety/satiation feelings. However, food intake is also controlled by the hedonic and reward systems leading to food intake based on pleasure (i.e., non-homeostatic control of food intake). This review focus on both the homeostatic and the non-homeostatic controls of food intake and the implication of the gut microbiota on the control of these systems. The gut-brain axis is involved in the communications between the gut microbes and the brain to modulate host food intake behaviors through systemic and nervous pathways. Therefore, here we describe several mediators of the gut-brain axis including gastrointestinal hormones, neurotransmitters, bioactive lipids as well as bacterial metabolites and compounds. The modulation of gut-brain axis by gut microbes is deeply addressed in the context of host food intake with a specific focus on hedonic feeding. Finally, we also discuss possible gut microbiota-based therapeutic approaches that could lead to potential clinical applications to restore food reward alterations. Therapeutic applications to tackle these dysregulations is of utmost importance since most of the available solutions to treat obesity present low success rate.

The PACAP Paradox: Dynamic and Surprisingly Pleiotropic Actions in the Central Regulation of Energy Homeostasis.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) – suggesting that PACAP is capable of regulating energy homeostasis via both the homeostatic and hedonic energy balance circuitries. The evidence gathered over the years has increased our appreciation for its function in controlling energy balance. Therefore, this review aims to further probe how the pleiotropic actions of PACAP in regulating energy homeostasis is influenced by sex and dynamic changes in energy status. We start with a general overview of energy homeostasis, and then introduce the integral components of the homeostatic and hedonic energy balance circuitries. Next, we discuss sex differences inherent to the regulation of energy homeostasis via these two circuitries, as well as the activational effects of sex steroid hormones that bring about these intrinsic disparities between males and females. Finally, we explore the multifaceted role of PACAP in regulating homeostatic and hedonic feeding through its actions in regions like the NAc, BNST, and in particular the ARC, VMN and VTA that occur in sex- and energy status-dependent ways.

Deep Brain Stimulation for Morbid Obesity: An Underutilized Neuromodulatory Treatment for Severely Obese Patients?

Morbid obesity (MO) has been steadily increasing in the last few years. Pharmacotherapy and bariatric surgeries remain the main treatment modalities for MO, although in the long-term they may lose their effectiveness. Other treatment approaches are urgently needed and deep brain stimulation (DBS) is a promising therapy. Disturbed energy homeostasis caused by intake of highly palatable and caloric foods may induce hedonic eating. The brain nuclei responsible for energy homeostasis and hedonia are the hypothalamic nuclei and nucleus accumbens. These brain structures constitute the stereotactic targets approached with DBS to treat MO. We have performed a literature search of all available clinical applications of DBS for MO in humans. We were able to identify three case series reports and additional six case reports involving 16 patients. The selected stereotactic targets included lateral hypothalamus in eight patients, ventromedial hypothalamus in two patients, and nucleus accumbens in six patients. In general, the safety profile of DBS in refractory MO patients was good. Clinical improvement regarding the mean body mass index could be observed in obese patients. MO is a demanding condition. Since in some cases standardized treatment is ineffective, new therapies should be implemented. DBS is a promising therapy that might be used in patients suffering from MO, however, more studies incorporating more individuals and with a longer follow-up are needed to obtain more reliable results concerning its effectiveness and safety profile.