The subfornical organ (SFO), vascular organ of the lamina terminalis (OVLT), area postrema (AP), pineal gland, subcommissural organ, median eminence–neurohypophysis (ME–NH), pineal gland and choroid plexus comprise the circumventricular organs (CVOs) of the rat brain. Located at strategic points along the walls of the lateral, third and fourth ventricles, these highly vascularized structures lack a blood–brain barrier (excepting the subcommissural organ), due to the presence of fenestrated endothelial cells lining their capillary walls. Only the SFO, OVLT and AP contain neuronal cell bodies. They are designated sensory CVOs; the others are termed secretory CVOs. Lack of a blood–brain barrier in sensory CVOs permits circulating humoral agents to interact directly with neurons located within them. Not surprisingly, these brain regions are rich in receptors for many peptides, monoamines and other signaling molecules. The SFO and OVLT located, respectively, at the dorsal and ventral ends of the midline anterior wall of the third ventricle have important roles in osmoreception and autonomic function that are mediated by direct afferent and efferent neural connections with regions of the hypothalamus, midbrain and hindbrain influencing thirst, vasopressin secretion, and cardiovascular regulation. The AP in the hindbrain has neural connections mainly with neurons of the adjacent medulla oblongata and midbrain that affect the baroreceptor reflex function and vomiting. The neurovascular arrangements in ME–NH (in the third ventricle floor) are crucial for secretion of pituitary hormones. Secretory products of the subcommissural organ influence brain development; while the choroid plexus elaborates cerebrospinal fluid.

The Asia-Pacific (APAC) region includes a significant proportion of the global population currently living with overweight and obesity. This modelling analysis was conducted to quantify the incidence of obesity-related comorbidities and change in obesity-related costs over 10 years with a hypothetical 10

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors ( Htr2a and Htr1a , respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine.

To identify perceptions and attitudes among people with obesity (PwO) and healthcare professionals (HCPs) toward obesity and its management in nine Asia-Pacific (APAC) countries, a cross-sectional online survey was conducted among adult PwO with self-reported body mass index of ≥25 kg/m2 (≥27 kg/m2, Singapore), and HCPs involved in direct patient care. In total, 10 429 PwO and 1901 HCPs completed the survey. Most PwO (68%) and HCPs (84%) agreed that obesity is a disease; however, a significant proportion of PwO (63%) and HCPs (41%) believed weight loss was the complete responsibility of PwO and only 43% of PwO discussed weight with an HCP in the prior 5 years. Most respondents acknowledged that weight loss would be extremely beneficial to PwO's overall health (PwO 76%, HCPs 85%), although nearly half (45%) of PwO misperceived themselves as overweight or of normal weight. Obesity was perceived by PwO (58%) and HCPs (53%) to negatively impact PwO forming romantic relationships. HCPs cited PwOs' lack of interest (41%) and poor motivation (37%) to lose weight as top reasons for not discussing weight. Most PwO (65%) preferred lifestyle changes over medications to lose weight. PwO and HCPs agreed that lack of exercise and unhealthy eating habits were the major barriers to weight loss. Our data highlights a discordance between the understanding of obesity as a disease and the actual behaviour and preferred approaches to manage it among PwO and HCPs. The study addresses a need to align these gaps to deliver optimal care for PwO.

ChatGPT/GPT-4 is a conversational large language model (LLM) based on artificial intelligence (AI). The potential application of LLM as a virtual assistant for bariatric healthcare professionals in education and practice may be promising if relevant and valid issues are actively examined and addressed. In general medical terms, it is possible that AI models like ChatGPT/GPT-4 will be deeply integrated into medical scenarios, improving medical efficiency and quality, and allowing doctors more time to communicate with patients and implement personalized health management. Chatbots based on AI have great potential in bariatric healthcare and may play an important role in predicting and intervening in weight loss and obesity-related complications. However, given its potential limitations, we should carefully consider the medical, legal, ethical, data security, privacy, and liability issues arising from medical errors caused by ChatGPT/GPT-4. This concern also extends to ChatGPT/GPT -4's ability to justify wrong decisions, and there is an urgent need for appropriate guidelines and regulations to ensure the safe and responsible use of ChatGPT/GPT-4.

Background and aims Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study is to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. Methods Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pairfed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of lean rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 2 deoxy-D-glucose (2DG)-14C, administered intraperitoneally. Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. Results Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity ( Ucp1, Dio2, Cpt1b, Cox8b, Ppargc ) and markers of increased browning of white fat ( Ucp1, Dio2, Cited1, Tbx1, Tnfrs9 ). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in lean animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlight a patent neural link between the gut and BAT that include groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. Conclusion Collectively, these data support a role for BAT in mediating the metabolic sequelae, particularly the improvement in glucose regulation following VSG surgery and highlight the need to better understand the contribution from this tissue in human patients.

PDF file - 175K, Effects of tumor C26 inoculation and food restriction on energy expenditure of mice

PDF file - 178K, Expression of genes involved in lipolysis and thermogenesis in animals bearing the non-cachectic C26 tumor

PDF file - 229K, Expression of nuclear transcription factor genes and target genes involved in lipid metabolism

Anorexia nervosa (AN) has high rates of mortality and low rates of recovery, with outcomes that worsen with illness duration. Improved early intervention strategies are required and identifying risk factors that contribute to the development of AN is critical to their implementation. The development of AN often follows a pre-existing diagnosis of anxiety disorders and obsessive-compulsive disorder and substantial genetic overlap between these conditions suggest common underlying features may predict vulnerability to AN. Moreover, patients with AN have increased levels of circulating proinflammatory cytokines, which may be involved in susceptibility to pathological weight loss considering that children with immune dysfunction have a higher risk of subsequent AN diagnoses. Here, we used the activity-based anorexia (ABA) model to examine whether baseline levels of locomotion, anxiety-like behaviour, compulsive behaviour, and circulating immune markers predict the subsequent development of pathological weight loss in adolescent female rats. While none of these primary features were shown to differentiate rats that went on to be susceptible or resistant to weight loss in ABA, increased locomotion and anxiety-like behaviour were both associated with the extent of weight loss in susceptible but not resistant animals. Intriguingly, behaviour related to poor decision-making in a situation of conflict was shown to predict vulnerability to ABA. Future research using the ABA model to uncover early predictors of AN should focus on translationally relevant assays of decision-making and cognitive behaviour, dysfunction of which may not only predispose animals to ABA but may also represent an endophenotype linking anorectic, anxiety-like and compulsive behaviour.

Obesity is a chronic disease in which the abnormal or excessive accumulation of body fat leads to impaired health and increased risk of mortality and chronic health complications. Prevalence of obesity is rising rapidly in South and Southeast Asia, with potentially serious consequences for local economies, healthcare systems, and quality of life. Our group of obesity specialists from Bangladesh, Brunei Darussalam, India, Indonesia, Malaysia, Philippines, Singapore, Sri Lanka, Thailand, and Viet Nam undertook to develop consensus recommendations for management and care of adults and children with obesity in South and Southeast Asia. To this end, we identified and researched 12 clinical questions related to obesity. These questions address the optimal approaches for identifying and staging obesity, treatment (lifestyle, behavioral, pharmacologic, and surgical options) and maintenance of reduced weight, as well as issues related to weight stigma and patient engagement in the clinical setting. We achieved consensus on 42 clinical recommendations that address these questions. An algorithm describing obesity care is presented, keyed to the various consensus recommendations.

Brain-derived neurotrophic factor (BDNF) is abundantly expressed in brain regions involved in both homeostatic and hedonic feeding, and it circulates at reduced levels in patients with anorexia nervosa (AN). A single nucleotide polymorphism in the gene encoding for BDNF (Val66Met) has been associated with worse outcomes in patients with AN, and it is shown to promote anorectic behaviour in a mouse model of caloric restriction paired with social isolation stress. Previous animal models of the Val66Met polymorphism have been in mice because of the greater ease in modification of the mouse genome, however, the most widely-accepted animal model of AN, known as activity-based anorexia (ABA), is most commonly conducted in rats. Here, we examine ABA outcomes in a novel rat model of the BDNF Val66Met allelic variation (Val68Met), and we investigate the role of this polymorphism in feeding, food choice and sucrose preference, and energy expenditure. We demonstrate that the BDNF Val68Met polymorphism does not influence susceptibility to ABA or any aspect of feeding behaviour. The discrepancy between these results and previous reports in mice may relate to species–specific differences in stress reactivity.

Efforts to prevent and treat obesity need to be grounded in science. A historical focus on individual responsibility has been ineffective in halting the rise in obesity prevalence. There needs to be a better understanding of environmental and biological drivers of weight gain to help reduce weight bias and stigma and identify more effective policies for action.

Higher-order executive functions such as decision-making, cognitive flexibility and behavioural control are critical to adaptive success in all aspects of life, including the maintenance of a healthy body weight by regulating food intake. Performance on tasks designed to assess these aspects of cognition is impaired in individuals with obesity and anorexia nervosa (AN); conditions at either end of a spectrum of body weight disturbance. While the conceptualisation of obesity and AN as mirror images of each other makes some sense from a metabolic point of view, whether or not these conditions also reflect opposing states of executive function is less clear. Here, we review evidence from neurocognitive and neuroimaging studies to compare the direction and extent of executive dysfunction in subjects with obesity and AN and how these are underpinned by changes in structure and function of subregions of the prefrontal cortex (PFC). Both conditions of extreme body weight disturbance are associated with impaired decision-making and cognitive inflexibility, however, impulsive behaviour presents in opposing directions; obesity being associated with reduced behavioural control and AN being associated with elevated control over behaviour with respect to food and feeding. Accordingly, the subregions of the PFC that guide inhibitory control and valuation of action outcomes (dorsolateral prefrontal cortex and orbitofrontal cortex) show opposite patterns of activation in subjects with obesity compared to those with AN, whereas the subregions implicated in cognitive and behavioural flexibility (ventromedial prefrontal cortex and anterior cingulate cortex) show alterations in the same direction in both conditions but with differential extent of dysfunction. We synthesise these findings in the context of the utility of animal models of obesity and AN to interrogate the detail of the neurobiological contributions to cognition in patient populations and the utility of such detail to inform future treatment strategies that specifically target executive dysfunction.

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.

BACKGROUND:The ability to adapt behavior to changing environmental circumstances, or cognitive flexibility, is impaired in multiple psychiatric conditions, including anorexia nervosa (AN). Exaggerated prefrontal cortical activity likely underpins the inflexible thinking and rigid behaviors exhibited by patients with AN. A better understanding of the neural basis of cognitive flexibility is necessary to enable treatment approaches that may target impaired executive control.METHODS:Utilizing the activity-based anorexia (ABA) model and touchscreen operant learning paradigms, we investigated the neurobiological link between pathological weight loss and cognitive flexibility. We used pathway-specific chemogenetics to selectively modulate activity in neurons of the medial prefrontal cortex (mPFC) projecting to the nucleus accumbens shell (AcbSh) in female Sprague Dawley rats.RESULTS:DREADD (designer receptor exclusively activated by designer drugs)-based inhibition of the mPFC-AcbSh pathway prevented weight loss in ABA and improved flexibility during early reversal learning by reducing perseverative responding. Modulation of activity within the mPFC-AcbSh pathway had no effect on running, locomotor activity, or feeding under ad libitum conditions, indicating the specific involvement of this circuit in conditions of dysregulated reward.CONCLUSIONS:Parallel attenuation of weight loss in ABA and improvement of cognitive flexibility following suppression of mPFC-AcbSh activity align with the relationship between disrupted prefrontal function and cognitive rigidity in AN patients. The identification of a neurobiological correlate between cognitive flexibility and pathological weight loss provides a unique insight into the executive control of feeding behavior. It also highlights the utility of the ABA model for understanding the biological bases of cognitive deficits in AN and provides context for new treatment strategies.

Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood‐brain barrier such that neurones within them are exposed to blood‐borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst‐related neural pathways, whereas circulating amylin, leptin and possibly glucagon‐like peptide‐1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst‐related neurones in the subfornical organ and OVLT, with hunger‐related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites subserving either thirst or hunger.