ACTION APAC: Understanding perceptions, attitudes and behaviours in obesity and its management across south and Southeast Asia.

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.

The BDNF Val66Met Polymorphism Does Not Increase Susceptibility to Activity-Based Anorexia in Rats.

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.

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.

Executive function in obesity and anorexia nervosa: Opposite ends of a spectrum of disordered feeding behaviour?

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.

Suppression of Corticostriatal Circuit Activity Improves Cognitive Flexibility and Prevents Body Weight Loss in Activity-Based Anorexia in Rats.

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.

Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models.

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.

From sensory circumventricular organs to cerebral cortex: Neural pathways controlling thirst and hunger.

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.

Adolescent Inhalant Abuse Results in Adrenal Dysfunction and a Hypermetabolic Phenotype with Persistent Growth Impairments.

BACKGROUND/AIMS: Abuse of toluene products (e.g., glue-sniffing) primarily occurs during adolescence and has been associated with appetite suppression and weight impairments. However, the metabolic phenotype arising from adolescent inhalant abuse has never been fully characterised, and its persistence during abstinence and underlying mechanisms remain unknown. METHODS: Adolescent male Wistar rats (post-natal day 27) were exposed to inhaled toluene (10,000 ppm) (n = 32) or air (n = 48) for 1 h/day, 3 days/week for 4 weeks, followed by 4 weeks of abstinence. Twenty air rats were pair-fed to the toluene group, to differentiate the direct effects of toluene from under-nutrition. Food intake, weight, and growth were monitored. Metabolic hormones were measured after exposure and abstinence periods. Energy expenditure was measured using indirect calorimetry. Adrenal function was assessed using adrenal histology and hormone testing. RESULTS: Inhalant abuse suppressed appetite and increased energy expenditure. Reduced weight gain and growth were observed in both the toluene and pair-fed groups. Compared to the pair-fed group, and despite normalisation of food intake, the suppression of weight and growth for toluene-exposed rats persisted during abstinence. After exposure, toluene-exposed rats had low fasting blood glucose and insulin compared to the air and pair-fed groups. Consistent with adrenal insufficiency, adrenal hypertrophy and increased basal adrenocorticotropic hormone were observed in the toluene-exposed rats, despite normal basal corticosterone levels. CONCLUSIONS: Inhalant abuse results in negative energy balance, persistent growth impairment, and endocrine changes suggestive of adrenal insufficiency. We conclude that adrenal insufficiency contributes to the negative energy balance phenotype, potentially presenting a significant additional health risk for inhalant users.

Evaluating anhedonia in the activity-based anorexia (ABA) rat model.

Patients suffering anorexia nervosa (AN) become anhedonic, in other words, unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The neurobiological underpinnings of anhedonia are likely to involve mesolimbic reward circuitry. We propose here that this circuitry and its involvement in AN can be investigated using the activity-based anorexia (ABA) rodent model that recapitulates many of the characteristics of the human condition, most notably rapid weight loss. Preference for sweetened water was used to assay hedonic processing in female Sprague-Dawley rats exposed to the ABA protocol, which involves free access to running wheels paired with time-limited access to food. This protocol uncovered a transient anhedonia in only one quarter of cases; however, exposure to running wheels alone was associated with a rapid aversion to sweetened water (F1.833, 20.17 = 78.29, p < .0001), and time-limited food access alone did not impact preference (F2.205, 24.25 = 0.305, p = .761). High levels of running wheel activity prior to the onset of food restriction increased susceptibility to body weight loss in ABA (F10,196.129 = 2.069, p = .029) and food anticipatory activity predicted subsequent food intake only for rats that were resistant to body weight loss (r = 0.44, p = .001). These data are inconsistent with the hypothesis that anhedonia underscores the precipitous weight loss in ABA, however, they highlight the predictive nature of hyperactivity in susceptibility to the ABA paradigm. These results will help inform the neurobiological framework of ABA and provide insight into the mechanisms of reward relevant to feeding and weight loss.

Insights into the neurochemical signature of the Innervation of Beige Fat.

OBJECTIVE: The potential for brown adipose tissue (BAT) to be targeted as a therapeutic option to combat obesity has been heightened by the discovery of a brown-like form of inducible "beige" adipose tissue in white fat which has overlapping structural and functional properties to "classical" BAT. The likelihood that both beige and brown fat are recruited functionally by neural mechanisms, taken together with the lack of a detailed understanding of the nature of changes in the nervous system when white adipose tissue (WAT) is transformed to brown, provides the impetus for this study. Here, we aim to identify whether there is a shift in the gene expression profile in neurons directly innervating inguinal white adipose tissue (iWAT) that has undergone "beiging" to a signature that is more similar to neurons projecting to BAT. METHODS: Two groups of rats, one housed at thermoneutrality (27 °C) and the other exposed to cold (8 °C) for 7 days, were killed, and their T13/L1 ganglia, stellate ganglion (T1/T2), or superior cervical ganglion (SCG, C2/3) removed. This approach yielded ganglia containing neurons that innervate either beiged white fat (8 °C for 7 days), inguinal WAT (27 °C for 7 days), BAT (both 27 °C and 8 °C for 7 days) or non-WAT (8 °C for 7 days), the latter included to isolate changes in gene expression that were more aligned with a response to cold exposure than the transformation of white to beige adipocytes. Bioinformatics analyses of RNA sequencing data was performed followed by Ingenuity Pathway Analysis (IPA) to determine differential gene expression and recruitment of biosynthetic pathways. RESULTS: When iWAT is "beiged" there is a significant shift in the gene expression profile of neurons in sympathetic ganglia (T13/L1) innervating this depot toward a gene neurochemical signature that is similar to the stellate ganglion projecting to BAT. Bioinformatics analyses of "beiging" related genes revealed upregulation of genes encoding neuropeptides proopiomelanocortin (POMC) and calcitonin-gene related peptide (CGRP) within ganglionic neurons. Treatment of differentiated 3T3L1 adipocytes with αMSH, one of the products cleaved from POMC, results in an elevation in lipolysis and the beiging of these cells as indicated by changes in gene expression markers of browning (Ucp1 and Ppargc1a). CONCLUSION: These data indicate that, coincident with beiging, there is a shift toward a "brown-like" neurochemical signature of postganglionic neurons projecting to inguinal white fat, an increased expression of POMC, and, consistent with a causative role for this prohormone in beiging, an αMSH-mediated increase in beige gene markers in isolated adipocytes.

AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning.

AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding.

Characterization of the central neural projections to brown, white, and beige adipose tissue.

The functional recruitment of classic brown adipose tissue (BAT) and inducible brown-like or beige fat is, to a large extent, dependent on intact sympathetic neural input. Whereas the central neural circuits directed specifically to BAT or white adipose tissue (WAT) are well established, there is only a developing insight into the nature of neural inputs common to both fat types. Moreover, there is no clear view of the specific central and peripheral innervation of the browned component of WAT: beige fat. The objective of the present study is to examine the neural input to both BAT and WAT in the same animal and, by exposing different cohorts of rats to either thermoneutral or cold conditions, define changes in central neural organization that will ensure that beige fat is appropriately recruited and modulated after browning of inguinal WAT (iWAT). At thermoneutrality, injection of the neurotropic (pseudorabies) viruses into BAT and WAT demonstrates that there are dedicated axonal projections, as well as collateral axonal branches of command neurons projecting to both types of fat. After cold exposure, central neural circuits directed to iWAT showed evidence of reorganization with a greater representation of command neurons projecting to both brown and beiged WAT in hypothalamic (paraventricular nucleus and lateral hypothalamus) and brainstem (raphe pallidus and locus coeruleus) sites. This shift was driven by a greater number of supraspinal neurons projecting to iWAT under cold conditions. These data provide evidence for a reorganization of the nervous system at the level of neural connectivity following browning of WAT.-Wiedmann, N. M., Stefanidis, A., Oldfield, B. J. Characterization of the central neural projections to brown, white, and beige adipose tissue.

Prevention of the adverse effects of olanzapine on lipid metabolism with the antiepileptic zonisamide.

BACKGROUND: Atypical antipsychotic drugs, particularly olanzapine, represent a mainstay in the treatment of psychoses; however, their use is commonly associated with weight gain and diabetes. The aim of this study was to determine whether combined administration of olanzapine and zonisamide can be used to prevent olanzapine-induced metabolic disturbances. METHODS AND RESULTS: These experiments involved female Sprague Dawley rats (n = 6-8/group) that were administered olanzapine, either acutely (6 mg/kg, s. c) or via continuous osmotic minipump infusion (6 mg/kg/day for 6 or 14 days), in combination with zonisamide (26 mg/kg/day,i.p.). Continuous infusion of olanzapine induced accumulation of adipose tissue and an associated reduction in stimulated lipolysis and reduced protein expression of CGI-58, a critical co-activator of ATGL. Olanzapine treatment caused a preferential shift toward carbohydrate oxidation (or reduced fat oxidation), elevated blood triglycerides and a reduction in locomotor activity. Olanzapine had a direct effect on glucose regulation, causing rapid hyperglycemia, and a reduction in glucose tolerance and insulin sensitivity. Continuous administration of olanzapine caused significant hyperinsulinemia and a significant reduction in insulin sensitivity. Zonisamide did not affect the impact of olanzapine on glucose homeostasis. On the other hand, co-administration of olanzapine with zonisamide completely ameliorated olanzapine-mediated shifts in lipid metabolism resulting in a normalization of olanzapine-induced weight gain. CONCLUSION: These data collectively show an impact of olanzapine on body weight and lipid metabolism, which is ameliorated by co-administration with zonisamide. These findings suggest that a combined olanzapine and zonisamide approach might reduce weight gain, but will not provide protection against olanzapine-induced glucose intolerance.

The Role of Mesolimbic Reward Neurocircuitry in Prevention and Rescue of the Activity-Based Anorexia (ABA) Phenotype in Rats.

Patients suffering from anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the characteristics of the human condition, including anhedonia, and allows investigation of the underlying neurobiology of AN. The potential for increased neuronal activity in reward/hedonic circuits to prevent and rescue weight loss is investigated in this model. The mesolimbic pathway extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) was activated using a dual viral strategy, involving retrograde transport of Cre (CAV-2-Cre) to the VTA and coincident injection of DREADD receptors (AAV-hSyn-DIO-hM3D(Gq)-mCherry). Systemic clozapine-n-oxide (CNO; 0.3 mg/kg) successfully recruited a large proportion of the VTA-NAc dopaminergic projections, with activity evidenced by colocalization with elevated levels of Fos protein. The effects of reward circuit activation on energy balance and predicted survival was investigated in female Sprague-Dawley rats, where free access to running wheels was paired with time-limited (90 min) access to food, a paradigm (ABA) which will cause anorexia and death if unchecked. Excitation of the reward pathway substantially increased food intake and food anticipatory activity (FAA) to prevent ABA-associated weight loss, while overall locomotor activity was unchanged. Similar activation of reward circuitry, delayed until establishment of the ABA phenotype, rescued rats from their precipitous weight loss. Although these data are consistent with shifts primarily in food intake, the contribution of mechanisms including energy expenditure to survival remains to be determined. These results will inform the neurobiological underpinnings of AN, and provide insight into the mechanisms of reward circuitry relevant to feeding and weight loss.

Improving efficacy of the adjustable gastric band: studies of the use of adjuvant approaches in a rodent model.

BACKGROUND: The laparoscopic adjustable gastric band (AGB) has been effective in reducing excess weight by approximately 50% for at least 16 years. However, as with all weight loss approaches, reduction in weight resulting from bariatric surgery is associated with a compensatory reduction in energy expenditure, which may confound and limit weight loss. Adjuvant therapies that reduce food intake and increase energy expenditure may be used to improve weight loss outcomes by ameliorating, or even reversing, this reduction in energy expenditure. METHODS: Rats were either fitted with an AGB or were sham operated and received one of 2 adjunctive pharmacologic treatments, (1) thyroxine or (2) bupropion/naltrexone (Contrave), at a range of doses and matched with vehicle controls (n = 6-8/group) over a 4-week period of combined treatments. Metabolic parameters including food intake, weight, fat mass, and energy expenditure in brown adipose tissue (BAT), whole body calorimetry, and physical activity were assessed. RESULTS: Inflation of the AGB caused a reduction in weight gain that was further enhanced by cotreatment with either thyroxine or Contrave (P<.05). Thyroxine completely ameliorated the reduction in AGB-induced BAT thermogenesis and significantly improved weight loss, particularly in fat mass. Contrave also augmented the loss of weight and fat mass associated with the AGB and increased BAT thermogenesis in banded rats even at doses below that required to change food intake. CONCLUSION: Adjuvant therapies can improve the efficacy of the AGB, at least in part by negating the compensatory reduction in energy expenditure, but also via a combined effect on food intake.

An investigation of the neural mechanisms underlying the efficacy of the adjustable gastric band.

BACKGROUND: The mechanisms via which adjustable gastric band (AGB) surgery provides effective and durable weight loss remain unclear. OBJECTIVES: This study defines the role of sensory vagal fibers in the efficacy of the adjustable gastric banding using capsaicin to eliminate unmyelinated afferent fibers in the vagus nerve in a rodent model. SETTING: University. METHODS: A miniaturized AGB was fitted at the gastroesophageal junction of obese rats with either intact or sensory fiber depleted vagus nerves where deafferentation involved intraperitoneal (125 mg/kg) or topical (1% to the stomach) application of capsaicin. The extent of sensory fiber lesion was assessed using c-fiber-mediated reduction in cholecystokinin-induced feeding. Food intake, weight, and composition, as well as shifts in central neural activity (measured by elevation of Fos protein), were assessed after either control or AGB inflation with or without vagal deafferentation. RESULTS: AGB inflation caused a significant reduction in food intake, weight, and fat mass (P<.05) in obese rats. The effect of AGB on these parameters was prevented in capsaicin pretreated (vagal sensory lesioned) rats. Elevations in neural activity in the nucleus of the solitary tract and parabrachial nucleus after AGB inflation were ameliorated in capsaicin-treated rats. CONCLUSION: Vagal sensory fibers are integral to the efficacy of the AGB.

Central Administration of the Ciliary Neurotrophic Factor Analogue, Axokine, Does Not Play a Role in Long-Term Energy Homeostasis in Adult Mice.

BACKGROUND/AIMS: Ciliary neurotrophic factor (CNTF) exerts powerful anorectic effects and has been suggested to regulate long-term energy balance by inducing adult neurogenesis in the arcuate nucleus of the hypothalamus. METHODS: The CNTF analogue, Axokine, was infused into the lateral ventricle of high-fat-fed mice for 1 week. Food intake, energy expenditure, body mass, glucose metabolism, and neurogenesis in the arcuate nucleus (ARC) of the hypothalamus were assessed 3 weeks after cessation of Axokine treatment. RESULTS: Short-term administration of Axokine induced an anorexic response but did not promote sustained weight loss. Instead, a rapid rebound in food intake and body mass occurred immediately after cessation of Axokine treatment, and this tended to reduce insulin sensitivity. Immunolabeling of 5-bromo-2'-deoxyuridine revealed limited neurogenesis in the ARC 3 weeks after Axokine treatment. CONCLUSION: These findings suggest that Axokine/CNTF does not induce substantial or sustained ARC neurogenesis or contribute to the long-term regulation of energy balance in mice.

Combination cannabinoid and opioid receptor antagonists improves metabolic outcomes in obese mice.

The CB1 receptor antagonist, rimonabant, causes weight loss but also produces undesirable psychiatric side effects. We investigated using a combination of rimonabant with the opioid receptor antagonists naloxone and norBNI to treat the metabolic sequelae of long-term high fat diet feeding in mice. This combination has previously been shown to have positive effects on both weight loss and mood related behaviour. Diet-induced obese mice were treated chronically with either low dose rimonabant (1 mg/kg) or the combination of rimonabant, naloxone and norBNI (rim nal BNI). After 6 days of treatment, glucose and insulin tolerance tests were performed and body composition analysed using DEXA. Changes in BAT thermogenesis were assessed using implantable radio telemetry probes. Behavioural responses to acute rimonabant or rim nal BNI were examined in the forced swim test and elevated plus maze. Separately, we assessed shifts in Fos immunoreactivity in response to rimonabant or rim nal BNI. Rim nal BNI was significantly better than rimonabant treatment alone at reducing body weight and food intake. In addition, it improved fasting blood glucose and fat mass. Acute low dose rimonabant did not alter behaviour in either the forced swim test or elevated plus maze. Combination rim nal BNI reversed the behavioural effects of high dose (10 mg/kg) rimonabant in obese mice. Rim nal BNI altered Rimonabant-induced Fos in a number of nuclei, with particular shifts in expression in the central and basolateral amygdala, and insular cortex. This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes. These results indicate that CB1-targeted drugs for weight loss may still be feasible.

Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.

The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.

Hypothalamic neurogenesis is not required for the improved insulin sensitivity following exercise training.

Neurons within the hypothalamic arcuate nucleus (ARC) are important regulators of energy balance. Recent studies suggest that neurogenesis in the ARC is an important regulator of body mass in response to pharmacological stressors. Regular exercise training improves insulin action, and is a primary treatment modality for obesity and type 2 diabetes. We examined whether exercise training causes hypothalamic neurogenesis and whether this contributes to exercise-induced improvements in insulin action. Short-term exercise in adult mice induced a proneurogenic transcriptional program involving growth factors, cell proliferation, and neurogenic regulators in the hypothalamus. Daily exercise training for 7 days increased hypothalamic cell proliferation 3.5-fold above that of sedentary mice, and exercise-induced cell proliferation was maintained in diet-induced obese mice. Colocalization studies indicated negligible neurogenesis in the ARC of sedentary or exercise-trained mice. Blocking cell proliferation via administration of the mitotic blocker arabinosylcytosine (AraC) did not affect food intake or body mass in obese mice. While 4 weeks of exercise training improved whole-body insulin sensitivity compared with sedentary mice, insulin action was not affected by AraC administration. These data suggest that regular exercise training induces significant non-neuronal cell proliferation in the hypothalamus of obese mice, but this proliferation is not required for enhanced insulin action.