The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review.

Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.

Gut-brain mechanisms underlying changes in disordered eating behaviour after bariatric surgery: a review.

Bariatric surgery results in long-term weight loss and an improved metabolic phenotype due to changes in the gut-brain axis regulating appetite and glycaemia. Neuroendocrine alterations associated with bariatric surgery may also influence hedonic aspects of eating by inducing changes in taste preferences and central reward reactivity towards palatable food. However, the impact of bariatric surgery on disordered eating behaviours (e.g.: binge eating, loss-of-control eating, emotional eating and 'addictive eating'), which are commonly present in people with obesity are not well understood. Increasing evidence suggests gut-derived signals, such as appetitive hormones, bile acid profiles, microbiota concentrations and associated neuromodulatory metabolites, can influence pathways in the brain implicated in food intake, including brain areas involved in sensorimotor, reward-motivational, emotional-arousal and executive control components of food intake. As disordered eating prevalence is a key mediator of weight-loss success and patient well-being after bariatric surgery, understanding how changes in the gut-brain axis contribute to disordered eating incidence and severity after bariatric surgery is crucial to better improve treatment outcomes in people with obesity.

Compulsive-like eating of high-fat high-sugar food is associated with 'addiction-like' glutamatergic dysfunction in obesity prone rats.

Chronic overeating is a core feature of diet-induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive-like eating using a rat model of diet-induced obesity. A conditioned suppression task demonstrated that diet-induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet-induced obese animals. Lastly, both a computed 'addiction score' (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet-induced obesity is associated with compulsive-like eating of highly palatable food and is accompanied by 'addiction-like' glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction-like pathology in this model of obesity.

Orexins (hypocretins): The intersection between homeostatic and hedonic feeding.

Orexins are hypothalamic neuropeptides originally discovered to play a role in the regulation of feeding behaviour. The broad connections of orexin neurons to mesocorticolimbic circuitry suggest they may play a role in mediating reward-related behaviour beyond homeostatic feeding. Here, we review the role of orexin in a variety of eating-related behaviour, with a focus on reward and motivation, and the neural circuits driving these effects. One emerging finding is the involvement of orexins in hedonic and appetitive behaviour towards palatable food, in addition to their role in homeostatic feeding. This review discusses the brain circuitry and possible mechanisms underlying the role of orexins in these behaviours. Overall, there is a marked bias in the literature towards studies involving male subjects. As such, future work needs to be done to involve female subjects. In summary, orexins play an important role in driving motivation for high salient rewards such as highly palatable food and may serve as the intersection between homeostatic and hedonic feeding.

N-acetylcysteine reduces addiction-like behaviour towards high-fat high-sugar food in diet-induced obese rats.

Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug-taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for 8 weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared with DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100 mg/kg, i.p.) for 14 days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.

Adenosine 2A receptors modulate reward behaviours for methamphetamine.

Addiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2 A ) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2 A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates; yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2 A knockout (KO) mice to assess the role of A2 A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2 A KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A2 A KO mice in a dose-related manner. METH intravenous self-administration was intact in A2 A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A2 A KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A2 A KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A2 A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2 A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.

Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaine seeking in mice.

Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.

α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse.

Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy.

Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor.

We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.

Optogenetic evidence that pallidal projections, not nigral projections, from the nucleus accumbens core are necessary for reinstating cocaine seeking.

The core subcompartment of the nucleus accumbens (NAcore) contributes significantly to behavioral responses following motivationally relevant stimuli, including drug-induced, stress-induced, and cue-induced reinstatement of cocaine seeking. Projections from NAcore that could carry information necessary to initiate reinstated cocaine seeking include outputs via the indirect pathway to the dorsolateral subcompartment of the ventral pallidum (dlVP) and through the direct pathway to the medial substantia nigra (SN). Here we used an optogenetic strategy to determine whether the dlVP or nigral projections from the NAcore are necessary for cocaine seeking initiated by a cocaine and conditioned cue combination in rats extinguished from cocaine self-administration. Rats were pretreated in the NAcore with an adeno-associated virus expressing the inhibitory opsin archaerhodopsin, and fiber-optic cannulae were implanted above the indirect pathway axon terminal field in the dlVP, or the direct pathway terminal field in the SN. Inhibiting the indirect pathway to the dlVP, but not the direct pathway to the SN, prevented cocaine-plus-cue-induced reinstatement. We also examined projections back to the NAcore from the ventral tegmental area (VTA) and dlVP. Inhibiting the dlVP to NAcore projection did not alter, while inhibiting VTA afferents abolished reinstated cocaine seeking. Localization of green fluorescent protein reporter expression and whole-cell patch electrophysiology were used to verify opsin expression. These data reveal a circuit involving activation of VTA inputs to the NAcore and NAcore projections through the indirect pathway to the dlVP as critical for cocaine-plus-cue-induced reinstatement of cocaine seeking.

Binge eating, overeating and food addiction: Approaches for examining food overconsumption in laboratory rodents.

Overeating ranges in severity from casual overindulgence to an overwhelming drive to consume certain foods. At its most extreme, overeating can manifest as clinical diagnoses such as binge eating disorder or bulimia nervosa, yet subclinical forms of overeating such as emotional eating or uncontrolled eating can still have a profoundly negative impact on health and wellbeing. Although rodent models cannot possibly capture the full spectrum of disordered overeating, studies in laboratory rodents have substantially progressed our understanding of the neurobiology of overconsumption. These experimental approaches range from simple food-exposure protocols that promote binge-like eating and the development of obesity, to more complex operant procedures designed to examine distinct 'addiction-like' endophenotypes for food. This review provides an overview of these experimental approaches, with the view to providing a comprehensive resource for preclinical investigators seeking to utilize behavioural models for studying the neural systems involved in food overconsumption.

Incidence of adverse mental health outcomes after sleeve gastrectomy compared with gastric bypass and restrictive bariatric procedures: a retrospective cohort study.

OBJECTIVE: This study examined rates of suicide and hospitalization with psychiatric diagnoses after sleeve gastrectomy compared with gastric bypass and restrictive procedures (gastric banding/gastroplasty). METHODS: This was a longitudinal retrospective cohort study comprising all patients who underwent primary bariatric surgery in New South Wales or Queensland, Australia, between July 2001 and December 2020. Hospital admission records, death registration, and cause of death records (if applicable) within these dates were extracted and linked. Primary outcome was death by suicide. Secondary outcomes were admissions with self-harm; substance-use disorder, schizophrenia, mood, anxiety, behavioral, and personality disorders; any of these; and psychiatric inpatient admission. RESULTS: A total of 121,203 patients were included, with median follow-up of 4.5 years per patient. There were 77 suicides, with no evidence of difference in rates by surgery type (rates [95% CI] per 100,000 person years: 9.6 [5.0-18.4] restrictive, 10.8 [8.4-13.9] sleeve gastrectomy, 20.4 [9.7-42.8] gastric bypass; p = 0.18). Rates of admission with self-harm declined after restrictive and sleeve procedures. Admission with anxiety disorders, any psychiatric diagnosis, and as a psychiatric inpatient increased after sleeve gastrectomy and gastric bypass, but not restrictive procedures. Admissions with substance-use disorder increased after all surgery types. CONCLUSIONS: Variable associations between bariatric surgeries and hospitalization with psychiatric diagnoses might indicate distinct vulnerabilities among patient cohorts or that differing anatomical and/or functional changes may contribute to effects on mental health.

Addiction-like behaviour towards high-fat high-sugar food predicts relapse propensity in both obesity prone and obesity resistant C57BL/6 J mice.

Compulsive overeating of palatable food is thought to underlie some forms of obesity. Similarities are often observed in the behavioural symptomology and the neuropathophysiology underlying substance use disorder and compulsive overeating. As such, preclinical animal models which assess addiction-like behaviour towards food may assist the understanding of the neurobiology underlying overeating behaviour. Further, the relationship between these behaviours and the propensity for diet-induced obesity warrants examination. In this study we investigated the relationship between the propensity for diet-induced obesity (DIO) and addiction-like behaviour towards highly palatable food in C57BL/6 J mice as measured by a 3-criteria model. We also examined the extent to which performance on this 3-criteria model predicted two key hallmark features of addiction - resistance to extinction and relapse propensity (as measured by reinstatement of lever pressing). C57BL/6 J mice were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions whereby addiction-like behaviour towards a high-fat high-sugar food reward was assessed using a 3-criteria model similar to that used to assess addiction-like behaviour towards drugs of abuse. In contrast to findings in rats, no difference in addiction-like behaviour towards food was observed between obesity prone (OP) and obesity resistant (OR) mice. Similarly, principal components analysis found no distinct patterns in the relationship between addiction-like behaviours across treatment groups. This suggests that the strain and species of rodent may be critical for studying the mechanisms underlying pathological overconsumption. Further analysis revealed that the extent of performance on the 3-criteria model correlated with the propensity for C57BL/6 J mice to both extinguish food seeking behaviour and "relapse" after a period of withdrawal. This finding was evident across all groups, regardless of DIO. Collectively, these data validate the 3-criteria model as a robust model to comprehensively assess food addiction-like behaviour in mice, regardless of prior food intake history.

A paraventricular thalamus to insular cortex glutamatergic projection gates "emotional" stress-induced binge eating in females.

It is well-established that stress and negative affect trigger eating disorder symptoms and that the brains of men and women respond to stress in different ways. Indeed, women suffer disproportionately from emotional or stress-related eating, as well as associated eating disorders such as binge eating disorder. Nevertheless, our understanding of the precise neural circuits driving this maladaptive eating behavior, particularly in women, remains limited. We recently established a clinically relevant model of 'emotional' stress-induced binge eating whereby only female mice display binge eating in response to an acute "emotional" stressor. Here, we combined neuroanatomic, transgenic, immunohistochemical and pathway-specific chemogenetic approaches to investigate whole brain functional architecture associated with stress-induced binge eating in females, focusing on the role of Vglut2 projections from the paraventricular thalamus (PVTVglut2+) to the medial insular cortex in this behavior. Whole brain activation mapping and hierarchical clustering of Euclidean distances revealed distinct patterns of coactivation unique to stress-induced binge eating. At a pathway-specific level, PVTVglut2+ cells projecting to the medial insular cortex were specifically activated in response to stress-induced binge eating. Subsequent chemogenetic inhibition of this pathway suppressed stress-induced binge eating. We have identified a distinct PVTVglut2+ to insular cortex projection as a key driver of "emotional" stress-induced binge eating in female mice, highlighting a novel circuit underpinning this sex-specific behavior.

Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice.

Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse-like behaviour can be investigated using animal models of drug seeking. As yet there have been no comprehensive brain mapping studies that have specifically examined the neuroanatomical substrates of cue-induced opiate seeking following abstinence in a mouse operant paradigm. The aim of this study was to compare the brain regions involved in sucrose vs. morphine seeking following protracted abstinence in mice. Male CD1 mice were trained to respond for either sucrose (10% w/v) or intravenous morphine (0.1 mg kg(-1) per infusion) in an operant paradigm in the presence of a discrete cue. Once stable responding was established, mice were subjected to abstinence in their home cages for 3 weeks and then perfused for tissue collection, or returned to the operant chambers to assess cue-induced reward seeking before being perfused for tissue collection. Brain tissue was processed for Fos immunohistochemistry and Fos expression was quantified in a range of brain nuclei. We identified unique patterns of neuronal activation for sucrose and morphine seeking mice as well as some overlap. Structures activated in both 'relapse' groups included the anterior cingulate and orbitofrontal cortex, nucleus accumbens shell, bed nucleus of the stria terminalis, substantia nigra pars compacta, ventral tegmental area, hippocampus, periaqueductal grey, locus coeruleus and lateral habenula. Structures that were more activated in morphine seeking mice included the nucleus accumbens core, basolateral amygdala, substantia nigra pars reticulata, and the central nucleus of the amygdala. The dorsal raphe was the only structure examined that was specifically activated in sucrose seeking mice. Overall our findings support a cortico-striatal limbic circuit driving opiate seeking, and we have identified some additional circuitry potentially relevant to reward seeking following abstinence.

mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine.

Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug-seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor-activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP.

A Comparison of Emotional Triggers for Eating in Men and Women with Obesity.

OBJECTIVE: Emotional eating (EE) is prevalent in people seeking obesity treatment and is a contributor to poor weight loss outcomes. We aimed to delineate the emotions most associated with this type of eating, and whether they differ by sex in people undergoing obesity treatment. METHODS: A cross-sectional study recruiting 387 adults from a hospital obesity management service. Emotional eating was measured using the Emotional Eating Scale (EES). Separate analyses included all participants, and those undergoing lifestyle interventions alone or in combination with obesity medication and/or bariatric surgery. RESULTS: A total of 387 people (71% women) participated in the study (n = 187 receiving lifestyle modification alone; n = 200 in combination with additional treatments). Feeling 'bored' was most commonly and most strongly associated with the urge to eat, regardless of sex or treatment. Women had higher scores for total EES, for subscales of depression and anger, and individual feelings of 'blue', 'sad' and 'upset' compared to men. CONCLUSIONS: Understanding why certain emotions differentially trigger an urge to eat in men and women, and finding strategies to break the link between boredom and eating may enable better personalisation of lifestyle interventions for people with obesity.

New directions in modelling dysregulated reward seeking for food and drugs.

Behavioral models are central to behavioral neuroscience. To study the neural mechanisms of maladaptive behaviors (including binge eating and drug addiction), it is essential to develop and utilize appropriate animal models that specifically focus on dysregulated reward seeking. Both food and cocaine are typically consumed in a regulated manner by rodents, motivated by reward and homeostatic mechanisms. However, both food and cocaine seeking can become dysregulated, resulting in binge-like consumption and compulsive patterns of intake. The speakers in this symposium for the 2021 International Behavioral Neuroscience Meeting utilize behavioral models of dysregulated reward-seeking to investigate the neural mechanisms of binge-like consumption, enhanced cue-driven reward seeking, excessive motivation, and continued use despite negative consequences. In this review, we outline examples of maladaptive patterns of intake and explore recent animal models that drive behavior to become dysregulated, including stress exposure and intermittent access to rewards. Lastly, we explore select behavioral and neural mechanisms underlying dysregulated reward-seeking for both food and drugs.

The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review.

Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250).