Breaking down barriers to bariatric care: a qualitative study on how telemedicine could transform patient experiences in a Swiss monocentric setting.

OBJECTIVE: Telemedicine is becoming an increasingly feasible option for patients with chronic diseases due to its convenience, cost-effectiveness and ease of access. While there are certain limitations, the benefits can be appreciated by those seeking repetitive care. The perception of telemedicine as an alternative to recurrent, in-person appointments for patients with obesity in structured bariatric programmes is still unclear. This content analysis' primary endpoint was to explore how patients within our bariatric programme perceived telemedicine and virtual consultations as a new way of communication during COVID-19. DESIGN: A qualitative study using semistructured interviews and qualitative content analysis method by Elo and Kyngäs following four steps: data familiarisation, coding and categorising with Quirkos software and final interpretation guided by developed categories. SETTING: University Hospital, Switzerland. PARTICIPANTS: We conducted 33 interviews with 19 patients from a structured bariatric programme. RESULTS: Most patients shared positive experiences, acknowledging the convenience and accessibility of virtual appointments. Others voiced concerns, especially regarding telemedicine's limitations. These reservations centred around the lack of physical examinations, difficulties in fostering connections with healthcare providers, as well as barriers stemming from language and technology. The research identified a spectrum of patient preferences in relation to telemedicine versus in-person visits, shaped by the immediacy of their concerns and their availability. CONCLUSION: While telemedicine is increasingly accepted by the public and provides accessible and cost-effective options for routine follow-up appointments, there are still obstacles to overcome, such as a lack of physical examination and technological limitations. However, integrating virtual alternatives, like phone or video consultations, into routine bariatric follow-ups could improve continuity and revolutionise bariatric care.

Weight loss and treatment patterns in a real-world population of adults receiving liraglutide 3.0 mg for weight management in routine clinical practice in Switzerland (ADDRESS study).

AIM: To assess weight loss associated with liraglutide 3.0 mg treatment in individuals with obesity (body mass index [BMI] ≥30 kg/m2 ) or overweight (BMI > 27 to <30 kg/m2 ) in a reimbursed, real-world setting in Switzerland. MATERIALS AND METHODS: ADDRESS was a non-comparative, multicentre, retrospective exposure cohort study in Switzerland, examining weight loss in individuals with obesity or overweight whose treatment was reimbursed (divided into BMI subgroups) or non-reimbursed. The primary outcomes were proportions of participants in the reimbursed cohort achieving predefined weight loss targets with liraglutide 3.0 mg at Week 16 (≥5% and ≥7% for the lower BMI [28 to <35 kg/m2 with weight-related comorbidities] and higher BMI [≥35 kg/m2 ] subgroups, respectively) and Month 10 (additional ≥5% from Week 16; per Swiss reimbursement criteria). RESULTS: The full analysis set comprised 258 individuals (195 reimbursed; 63 non-reimbursed). In the reimbursed cohort, 139 individuals (71.3%) achieved their weight loss targets at Week 16. Of individuals who met the Week-16 criteria, 43.2% attained an additional 5% weight loss at Month 10. In 162 individuals for whom data were recorded at Month 10, the mean (standard deviation) relative weight loss from baseline to Month 10 was -12.4% (6.4%). CONCLUSIONS: Although reimbursement criteria may be difficult to achieve, particularly the additional weight loss of 5% from Week 16 to Month 10, a clinically relevant overall weight loss from baseline to Month 10 was shown in most individuals with obesity or overweight who received liraglutide 3.0 mg.

Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet.

Low-carbohydrates diets are increasingly used to treat obesity and metabolic disorders. A very low-carbohydrate, ketogenic diet is hard to follow and, due to the very high fat content, linked to severe side effects, like hyperlipidemia and atherogenesis. Therefore, a less restrictive, unsaturated fat-based low-carbohydrate diet appears as a promising alternative. Since neither sex differences, nor their effect on specific metabolic hormones and adipose tissue compartments have been investigated thoroughly in these diets, we aimed to analyze their dynamics and metabolic factors in mice. We found a significant sexual dimorphism with decreased body weight and subcutaneous fat only in males on ketogenic diet, while diminished insulin, elevated ghrelin and FGF-21 were present with a differential time course in both sexes. The non-ketogenic moderate low-carbohydrate diet increased body weight and perigonadal fat in females, but induced leptin elevation in males. Both diets enhanced transiently TNFɑ only in males and had no impact on behavior. Altogether, these results reveal complex sex-dependent effect of dietary interventions, indicating unexpectedly females as more prone to unfavorable metabolic effects of low-carbohydrate diets.

The Role of the Olfactory System in Obesity and Metabolism in Humans: A Systematic Review and Meta-Analysis.

Obesity, linked to chronic diseases, poses a global health challenge. While the role of the olfactory system in energy homeostasis is well-documented in rodents, its role in metabolism regulation and obesity in humans remains understudied. This review examines the interplay between olfactory function and metabolic alterations in human obesity and the effects of bariatric surgery on olfactory capabilities in humans. Adhering to PRISMA guidelines, a systematic review and meta-analysis was conducted, focusing exclusively on original human studies. From 51 articles, 14 were selected for the meta-analysis. It was found that variations in olfactory receptor genes influence the susceptibility to odors and predisposition to weight gain and poor eating habits. Bariatric surgery, particularly sleeve gastrectomy, shows significant improvements in olfactory function (SMD 2.37, 95% CI [0.96, 3.77], I = 92%, p = 0.001), especially regarding the olfactory threshold (SMD -1.65, 95% CI [-3.03, -0.27], I = 81%, p = 0.02). There is a bidirectional relationship between olfactory function and metabolism in humans. Bariatric surgery improves olfactory perception in obese patients, but it is still unclear if impacting the olfactory system directly affects eating behavior and the energy balance. However, these findings open novel avenues for future studies addressing the olfactory system as a novel target to alter systemic metabolism in humans.

The Impact of the COVID-19 Pandemic on Patients from a Bariatric Program: A Qualitative Analysis of Their Perceptions of Health and Well-Being.

INTRODUCTION: The study was conducted to explore the perceptions of patients from a bariatric program who have undergone or will undergo bariatric surgery during the ongoing COVID-19 pandemic, specifically as related to their struggles with health issues and their psychological well-being. MATERIALS AND METHODS: We conducted semi-structured, in-depth interviews with nineteen pre- or post-bariatric patients to generate data on their perceptions of COVID-19. Consistent with the methods of constructivist grounded theory, we collected and analyzed data iteratively through a constant comparative process for data coding and develop themes in the transcripts. RESULTS: We identified themes to summarize the pandemic-associated experiences of our cohort as follows: their life structure before COVID-19, the turning point with changes and adaptations, and the impact of isolation on psychological well-being. We identified grief due to loss of social contacts as well as physical and psychological health impairment as consequences of pandemic-related lifestyle changes. Most participants were not aware of overweight and obesity being major risk factors for worse outcomes of COVID-19. We developed a theme-based theory on patients' perceptions and fears regarding the pandemic as they live through phases of grief. DISCUSSION: Most participants shared critical perceptions about their own somatic and psychological health. These findings may inform recommendations and strategies for both patients and healthcare professionals to manage the challenges potentially presented by this vulnerable patient group in the context of the COVID-19 pandemic.

Regular intake of energy drinks and multivitamin supplements is associated with elevated plasma vitamin B6 levels in post-bariatric patients.

The aim of the present survey was to analyze plasma vitamin B6 levels in post-bariatric patients and to elucidate the causal factors associated with elevated plasma vitamin B6 levels. This is a retrospective analysis of electronic patient data of all post-bariatric patients evaluated at the endocrine outpatient clinic of the University Hospital Basel in 2017, for which plasma vitamin B6 values were assessed during regular follow-up visits. In total, 205 patients were included in the study, whereof a minority of 43% had vitamin B6 levels in the normal range. 50% of the patients had vitamin B6 levels up to fourfold higher than the upper normal limit and 7% had levels more than fourfold above the upper normal limit. Vitamin B6 deficiency was not observed in any patient. While multivitamin supplementation in general was associated with elevated plasma vitamin B6 levels, the highest vitamin B6 levels were found after biliopancreatic diversion (BPD) and in patients who reported daily energy drink intake. Elevated plasma vitamin B6 levels up to fourfold above the upper normal limit are common in postbariatric patients and are associated with regular multivitamin supplementation, while highly elevated plasma vitamin B6 levels were seen primarily upon regular energy drink intake. Thus, a regular follow-up of vitamin B6 plasma levels and critical evaluation of vitamin B6 supplementation, either as part of the multivitamin preparation or related to regular energy drink intake, is highly warranted and should be an integral part of the routine post-bariatric follow-up.

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (-2.7 ± 8.2% in the placebo vs. -20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function.

Astrocytes represent central regulators of brain glucose metabolism and neuronal function. They have recently been shown to adapt their function in response to alterations in nutritional state through responding to the energy state-sensing hormones leptin and insulin. Here, we demonstrate that glucagon-like peptide (GLP)-1 inhibits glucose uptake and promotes ß-oxidation in cultured astrocytes. Conversely, postnatal GLP-1 receptor (GLP-1R) deletion in glial fibrillary acidic protein (GFAP)-expressing astrocytes impairs astrocyte mitochondrial integrity and activates an integrated stress response with enhanced fibroblast growth factor (FGF)21 production and increased brain glucose uptake. Accordingly, central neutralization of FGF21 or astrocyte-specific FGF21 inactivation abrogates the improvements in glucose tolerance and learning in mice lacking GLP-1R expression in astrocytes. Collectively, these experiments reveal a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity, and lack of GLP-1R signaling mounts an adaptive stress response resulting in an improvement of systemic glucose homeostasis and memory formation.

GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study.

AIMS/HYPOTHESIS: IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. METHODS: In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration-time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. RESULTS: Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p = 0.261). CONCLUSIONS/INTERPRETATION: IL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade. TRIAL REGISTRATION: Clinicaltrials.gov NCT01073826. FUNDING: Danish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation.

Exercise upregulates copeptin levels which is not regulated by interleukin-1.

OBJECTIVE: Studies have suggested that arginine vasopressin (AVP) and its surrogate marker copeptin increase during exercise, independently of serum sodium and/or osmolality. In extreme cases, this can lead to runners-induced hyponatremia. Interleukin-1 (IL-1) increases during exercise and induces AVP in animal models. We here therefore investigate whether copeptin (a surrogate marker for AVP) increases upon exercise in young and healthy males, and whether this increase is regulated by IL-1. DESIGN: In a randomized, placebo-controlled, double-blind, crossover trial in 17 healthy male volunteers, the effect of the IL-1 receptor antagonist anakinra on exercise-induced copeptin was compared with placebo. METHODS: Participants exercised for one hour at 75% of VO2max and were not allowed to drink/eat 6 hours before and during the study. Participants received either 100 mg of anakinra or placebo 1h before exercise. Blood was drawn at certain time intervals. RESULTS: In both groups, copeptin levels were induced by 2.5-fold upon exercise (p<0.001), from 4.5-10.6 pmol/l in the placebo, and 4.3-11.3 pmol/l in the anakinra group, (p = 0.38). One hour after exercise, copeptin levels dropped to 7.7 and 7.9 pmol/l in the placebo and anakinra group, respectively (p = 0.58). The increase of copeptin levels was not explained by sodium concentrations. CONCLUSIONS: Exercise induces a continuous rise of plasma copeptin levels in healthy male volunteers independently of sodium levels and fluid intake. This increase is not regulated by the IL-1 pathway.

CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance.

Skeletal muscle accumulates ceramides in obesity, which contribute to the development of obesity-associated insulin resistance. However, it remained unclear which distinct ceramide species in this organ contributes to instatement of systemic insulin resistance. Here, ceramide profiling of high-fat diet (HFD)-fed animals revealed increased skeletal muscle C18:0 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Mice lacking CerS1, either globally or specifically in skeletal muscle (CerS1ΔSkM), exhibit reduced muscle C18:0 ceramide content and significant improvements in systemic glucose homeostasis. CerS1ΔSkM mice exhibit improved insulin-stimulated suppression of hepatic glucose production, and lack of CerS1 in skeletal muscle improves systemic glucose homeostasis via increased release of Fgf21 from skeletal muscle. In contrast, muscle-specific deficiency of C16:0 ceramide-producing CerS5 and CerS6 failed to protect mice from obesity-induced insulin resistance. Collectively, these results reveal the tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance.

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity.

Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity.

The role of IL-1 in postprandial fatigue.

OBJECTIVES: Cytokines such as IL-1 seems to play a role in the pathogenesis of fatigue associated with some chronic diseases and anti-inflammatory treatment has been shown to reduce these symptoms. Ingestion of a calorie rich meal leads to postprandial fatigue, and is associated with increased systemic concentrations of cytokines, which is more pronounced in obese than lean subjects. We investigated whether postprandial fatigue is regulated by IL-1, and therefore reduced by IL-1 antagonism, in lean and obese subjects. METHODS: In a double-blind, crossover study in 8 lean and 8 obese male subjects, randomized to receive either saline (placebo) or the IL-1 receptor antagonist anakinra, we investigated whether postprandial fatigue was regulated by IL-1. To promote postprandial fatigue, subjects ran 30 min prior to a high-fat, high-carbohydrate meal. Fatigue was determined using the Stanford Sleepiness Scale and blood samples were drawn at baseline and after the intervention. RESULTS: IL-1 antagonism led to a reduction in postprandial fatigue and this effect was more pronounced in obese than lean individuals. CONCLUSIONS: We conclude that IL-1 is involved in the regulation of postprandial fatigue under physiologic conditions in lean and obese individuals. It remains to be shown whether this effect translates into clinical relevant effects.

IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis.

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance. We demonstrate that in mice obesity promotes expansion of a distinct, interleukin-6 receptor (IL6R)a-expressing NK subpopulation, which also expresses a number of other myeloid lineage genes such as the colony-stimulating factor 1 receptor (Csf1r). Selective ablation of this Csf1r-expressing NK cell population prevents obesity and insulin resistance. Moreover, conditional inactivation of IL6Ra or Stat3 in NK cells limits obesity-associated formation of these myeloid signature NK cells, protecting from obesity, insulin resistance, and obesity-associated inflammation. Also in humans IL6Ra+ NK cells increase in obesity and correlate with markers of systemic low-grade inflammation, and their gene expression profile overlaps with characteristic gene sets of NK cells in obese mice. Collectively, we demonstrate that obesity-associated inflammation and metabolic disturbances depend on interleukin-6/Stat3-dependent formation of a distinct NK population, which may provide a target for the treatment of obesity, metaflammation-associated pathologies, and diabetes.

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity.

The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.

IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling.

Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study.

BACKGROUND: In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting. METHODS: Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview. RESULTS: Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression. CONCLUSIONS: Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department. TRIAL REGISTRATION: Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov.

Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity.

Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity.