The melanocortin-4 receptor pathway and the emergence of precision medicine in obesity management.

Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation. The best characterized pathway, thus far, is the leptin-melanocortin pathway, from which disruptions are responsible for the majority of monogenic obesity disorders. The effectiveness of conservative lifestyle interventions in addressing monogenic obesity has been limited. Therefore, it is crucial to complement the management strategy with pharmacological and surgical options. Emphasis has been placed on developing drugs aimed at replacing the absent signals, with the goal of restoring the pathway. In both monogenic and polygenic forms of obesity, outcomes differ across various interventions, likely due to the multifaceted nature of the disease. This underscores the need to explore alternative therapeutic strategies that can mitigate this heterogeneity. Precision medicine can be regarded as a powerful tool that can address this concern, as it values the understanding of the underlying abnormality triggering the disease and provides a tailored treatment accordingly. This would assist in optimizing outcomes of the current therapeutic approaches and even aid in the development of novel treatments capable of more effectively managing the global obesity epidemic.

Ultra-processed foods cause weight gain and increased energy intake associated with reduced chewing frequency: A randomized, open-label, crossover study.

AIM: To elucidate the effects of ultra-processed foods (UPFs) on body weight and ad libitum energy intake compared with non-UPFs. MATERIALS AND METHODS: In this randomized, open-label crossover study conducted at the University of Tokyo Hospital, overweight/obese Japanese male participants were randomly assigned (1:1) to start the study with consumption of either UPFs or non-UPFs for 1 week, followed by a 2-week washout period, before crossing over to the alternate food diet for 1 week. Individuals with diabetes, hypertension or any other medical conditions who visited a hospital regularly were excluded. The meals were designed to be matched for the total energy and macronutrient levels. The primary outcome was the difference in the body weight change between the UPF and non-UPF periods. The differences in the average daily energy intake and chewing frequency were assessed as one of the prespecified secondary outcomes. RESULTS: Nine eligible participants were randomly assigned to start the study with either UPFs or non-UPFs. All participants completed the study. During the UPF period, participants gained 1.1 kg more weight (95% confidence interval 0.2 to 2.0; P = .021) and consumed 813.5 kcal more per day (342.4 to 1284.7; P = .0041) compared with during the non-UPF period. Regarding the chewing frequency, the number of chews per calorie was significantly lower during the UPF period (P = .016). CONCLUSIONS: Consumption of UPFs causes significant weight gain. Medical nutritional therapy focused on reducing the consumption of UPFs could be an effective strategy for preventing obesity.

TAAR1 agonist ulotaront delays gastric emptying of solids in patients with schizophrenia and concurrent metabolic syndrome with prediabetes.

BACKGROUND: Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. METHODS: Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a 99mTc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T1/2) and percentage gastric retention at 1, 2 and 4 h. RESULTS: Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal. CONCLUSION: Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.

Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management.

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management.

Bardet-Biedl syndrome: A focus on genetics, mechanisms and metabolic dysfunction.

Bardet-Biedl syndrome (BBS) is a rare, monogenic, multisystem disorder characterized by retinal dystrophy, renal abnormalities, polydactyly, learning disabilities, as well as metabolic dysfunction, including obesity and an increased risk of type 2 diabetes. It is a primary ciliopathy, and causative mutations in more than 25 different genes have been described. Multiple cellular mechanisms contribute to the development of the metabolic phenotype associated with BBS, including hyperphagia as a consequence of altered hypothalamic appetite signalling as well as alterations in adipocyte biology promoting adipocyte proliferation and adipogenesis. Within this review, we describe in detail the metabolic phenotype associated with BBS and discuss the mechanisms that drive its evolution. In addition, we review current approaches to the metabolic management of patients with BBS, including the use of weight loss medications and bariatric surgery. Finally, we evaluate the potential of targeting hypothalamic appetite signalling to limit hyperphagia and induce clinically significant weight loss.

Hypothalamic control of body fat mass by food intake: The key to understanding why obesity should be treated as a disease.

BACKGROUND: Hypothalamic centres have been recognized to play a central role in body weight regulation for nearly 70 years. AIMS: In this review, we will explore the current undersanding of the role the hypothalamus plays in controlling food intake behaviours. MATERIALS AND METHODS: Review of relevant literature from PubMed searches and review article citations. RESULTS: Beginning with autopsy studies showing destructive hypothalamic lesions in patients manifesting hyperphagia and rapid weight gain, followed by animal lesioning studies pinpointing adjacent hypothalamic sites as the 'satiety' centre and the 'feeding' centre of the brain, the neurocircuitry that governs our body weight is now understood to consist of a complex, interconnected network, including the hypothalamus and extending to cortical sites, reward centres and brainstem. Neurons in these sites receive afferent signals from the gastrointestinal tract and adipose tissue indicating food availability, calorie content, as well as body fat mass. DISCUSSION: Integration of these complex signals leads to modulation of the two prime effector systems that defend a body fat mass set point: food intake and energy expenditure. CONCLUSION: Understanding the hypothalamic control of food intake forms the foundation for understanding and managing obesity as a chronic disease.

Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial.

AIM: To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying. METHODS: A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast. RESULTS: The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was -39.2% points (95% confidence interval -59.0%, -19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20. CONCLUSIONS: In participants with obesity, once-daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption.

A web-based and mobile randomised controlled trial providing complementary feeding guidelines to first-time parents in France to promote responsive parental feeding practices, healthy children's eating behaviour and optimal body mass index: the NutrienT trial study protocol.

BACKGROUND: Childhood obesity is a crucial public health issue. Early childhood is a critical time to foster the establishment of healthy eating behaviours and growth, which are partly shaped by parental feeding practices. To inform French parents of the recently updated national complementary feeding guidelines for 0-3 years (in terms of nutrition and responsive feeding as a mean to encourage infant appetite control skills and promote healthy growth), an official printed brochure was developed and nationally disseminated in 2021 by the French public health agency, Santé publique France. This randomised controlled trial aims to investigate whether the provision of guidelines through digital (smartphone application) and printed (brochure) tools (vs. the printed brochure alone, usual service) results in healthier parental feeding practices, infant eating behaviours and weight status. METHODS: This double-blinded monocentric 2-arm trial is currently conducted among first-time parents living in the area of Dijon (France) and recruited in a maternity ward. From child age 3 to 36 months (mo), an app provides a range of 106 age-adapted messages, including dietary recommendations, educational advice, recipes, and tips (intervention group only). Additionally, parents of both groups are provided with 48 messages related to child general development and the printed brochure at child age 2.7 mo. The primary outcome is the body mass index (BMI) z-score at child age 36 mo. Secondary outcome measures include a combination of online parents' reports and behavioural assessments (experimental meals) of parental feeding practices and infant eating behaviours from inclusion to 36 months of age. Analyses of covariance on these outcomes will assess the effect of the intervention, adjusted for relevant confounders. Complementary mediation and moderation analyses will be conducted. Sample size was determined to be n = 118 in each arm of the trial, plus 20% to compensate for potential attrition. DISCUSSION: This is the first public eHealth randomised control trial in France to assess the effect of a web-based and mobile intervention targeted to first-time parents to improve child feeding practices and child growth. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT05285761 (March 18, 2022).

The 'Behavioral Balance Model': A new perspective on the aetiology and therapy of obesity.

Obesity is a debilitating disease of global proportions that necessitates refined, concept-driven therapeutic approaches. Policy makers, the public and even health care professionals, but also individuals with obesity harbour many misconceptions regarding this disease, which leads to prejudice, negative attitudes, stigmatization, discrimination, self-blame, and failure to provide and finance adequate medical care. Decades of intensive, successful scientific research on obesity have only had a very limited effect on this predicament. We propose a science-based, easy-to-understand conceptual model that synthesizes the complex pathogenesis of obesity including biological, psychological, social, economic and environmental aspects with the aim to explain and communicate better the nature of obesity and currently available therapeutic modalities. According to our integrative 'Behavioral Balance Model', 'top-down cognitive control' strategies are implemented (often with limited success) to counterbalance the increased 'bottom-up drive' to gain weight, which is triggered by biological, psycho-social and environmental mechanisms in people with obesity. Besides offering a deeper understanding of obesity, the model also highlights why there is a strong need for multimodal therapeutic approaches that may not only increase top-down control but also reduce a pathologically increased bottom-up drive.

No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE).

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.

Perceptions, behaviours and potential barriers to effective obesity care. Results from the ACTION-DK study.

AIM: Weight bias, stigma and discrimination are pervasive in the health care system and society and may result in biased treatment of people living with obesity (PwO). We aimed to identify perceptions, attitudes and potential barriers that exist between people with obesity and health care professionals (HCPs) in Denmark. METHODS: The ACTION-DK survey was a cross-sectional, non-interventional, descriptive study conducted in Denmark. The cohort included 879 PwO (body mass index ≥30.0 kg/m2 ) based on self-reported height and body weight, and 100 HCPs from the primary and secondary sectors who frequently encountered PwO. RESULTS: Several discrepancies between PwO and HCPs were identified, including recognition of obesity as a chronic disease (PwO: 49% vs. HCPs: 84%) and whether PwO were responsible for their weight loss (PwO: 81% vs. HCPs: 17%). Among PwO, 46% were motivated to lose weight, but only 28% of HCPs shared this perception. Untimely initiation of obesity care consultations was also identified as a potential barrier to proper obesity care, as PwO waited 7 years, on average, from their initial decision to lose weight before having their first obesity care consultation. In addition, only 24% of PwO had a follow-up consultation after the initial obesity care discussion. Almost half of HCPs (46%) considered weight loss medication effective, but only 10% brought up this possibility during an obesity care discussion. CONCLUSIONS: Our findings suggest that it is pivotal to improve obesity care in Denmark by ensuring a better follow-up and alignment of the perceptions and attitudes toward obesity between PwO and HCPs.

The complex pattern of the effects of prolonged frequent exercise on appetite control, and implications for obesity.

From a public health perspective, much of the interest in the relationship between exercise and appetite rests on the implications for energy balance and obesity. Energy balance reflects a dynamic 2-way interaction between energy expenditure (EE) and energy intake (EI). Physical activity and exercise, and appetite are the behavioural components of EE and EI, respectively. Beyond EE, exercise is a powerful and complex physiological stimulus acting on several bodily systems. There are multiple effects of frequent and prolonged exercise on appetite which include inter alia an increase in fasting hunger, an enhancement of post-prandial satiety, a modulation of the hedonic responses to food and improvements in eating behaviour traits. These lead to variable adjustments in EI and in a reduction in the susceptibility to overconsumption. Frequent and prolonged physical activity and exercise behaviour can strengthen and sensitise the appetite control system, whilst physical inactivity and sedentariness (low level of EE) fails to downregulate EI and can permit overconsumption. Not all of the effects of exercise operate uniformly to drive appetite in the same direction. The complexity of the interaction between EE and EI means that the effects of prolonged exercise are characterised by substantial individual heterogeneity. This leads to variable effects on energy balance and body mass.

Impact of exercise timing on perceived appetite and food reward in early and late chronotypes: An exploratory study in a male Saudi sample.

There is very limited evidence on the influence of diurnal exercise timing on appetite control, and none on food reward or how an individual's chronotype could moderate such effects. We examined the impact of acute exercise timing on perceived appetite and food reward in young Saudi adults with early or late chronotypes. Forty-five young adults (23 ± 4 years; BMI = 25.1 ± 4.0 kg/m2) completed the Morningness-Eveningness Questionnaire (MEQ) and were divided into early (score = 59 ± 5) or late (score = 41 ± 6) chronotypes. Participants attended the laboratory after ≥4 h fast on two occasions for an AM (8:00-10:00) and PM (17:00-19:00) 30-min moderate-intensity cycling bout in a randomized counterbalanced order. Appetite ratings and food reward (Arab Leeds Food Preference Questionnaire) were measured before and after exercise. An acute exercise-induced decrease in hunger was found, which appeared to be dependent upon diurnal timing and chronotype, with hunger being more suppressed after AM exercise in the early chronotypes and after PM exercise in the late chronotypes. There was greater wanting for low-fat sweet foods after AM exercise relative to PM exercise, whereas there was greater wanting for high-fat sweet food and sweet relative to savoury food after PM exercise compared to AM exercise. These preliminary findings suggest that diurnal timing of exercise impacts food preferences, and that chronotype may influence the appetite response to an exercise bout at different times of day.

No effect of prefrontal transcranial direct current stimulation (tDCS) on food craving, food reward and subjective appetite in females displaying mild-to-moderate binge-type behaviour.

Previous work suggests there may be an effect of transcranial direct current stimulation (tDCS) on appetite control in people at risk of overconsumption, however findings are inconsistent. This study aimed to further understand the potential eating behaviour trait-dependent effect of tDCS, specifically in those with binge-type behaviour. Seventeen females (23 ± 7 years, 25.4 ± 3.8 kg m-2) with mild-to-moderate binge eating behaviour completed two sessions of double-blind, randomised and counterbalanced anodal and sham tDCS applied over the right dorsolateral prefrontal cortex at 2.0 mA for 20 min. Subjective appetite visual analogue scales (VAS), the Food Craving Questionnaire-State (FCQ-S), and Leeds Food Preference Questionnaire (LFPQ) were completed pre- and post-tDCS. Participants then consumed a fixed-energy meal, followed by the VAS, FCQ-S and LFPQ. No difference between pre- and post-tDCS scores were found across fullness (p = 0.275, BF10 = 0.040), prospective consumption (p = 0.127, BF10 = 0.063), desire to eat (p = 0.247, BF10 = 0.054) or FCQ-S measures (p = 0.918, BF10 = 0.040) when comparing active and sham protocols. Only explicit liking and wanting for high-fat sweet foods were significantly different between conditions, with increased scores following active tDCS. When controlling for baseline hunger, the significant differences were removed (p = 0.138 to 0.161, BF10 = 0.810 to 1.074). The present data does not support the eating behaviour trait dependency of tDCS in a specific cohort of female participants with mild-to-moderate binge eating scores, and results align with those from individuals with healthy trait scores. This suggests participants with sub-clinical binge eating behaviour do not respond to tDCS. Future work should further explore effects in clinical and sub-clinical populations displaying susceptibility to overconsumption and weight gain.

Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

AIMS: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. MATERIALS/METHODS: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. RESULTS: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. CONCLUSIONS: GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

NPFF Decreases Activity of Human Arcuate NPY Neurons: A Study in Embryonic-Stem-Cell-Derived Model.

Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.

The Mediterranean diet increases glucagon-like peptide 1 and oxyntomodulin compared with a vegetarian diet in patients with type 2 diabetes: A randomized controlled cross-over trial.

AIM: To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS: Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS: GLP-1 and oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS: In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.

An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight.

Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.

Cerebral effects of glucagon-like peptide-1 receptor blockade before and after Roux-en-Y gastric bypass surgery in obese women: A proof-of-concept resting-state functional MRI study.

AIM: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. MATERIALS AND METHODS: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). RESULTS: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. CONCLUSIONS: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.

Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men.

AIM: To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon-like peptide-1 (GLP-1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration. METHODS: We examined 10 healthy young men on three separate occasions using a placebo (PBO)-controlled crossover design. A KE versus taste-matched isovolumetric and isocaloric 50% GLU and taste-matched isovolumetric PBO vehicle was orally administered. Our main outcome measures were plasma concentrations of AG, UAG, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 along with appetite sensation scores assessed by visual analogue scale. RESULTS: KE ingestion resulted in an average peak beta-hydroxybutyrate concentration of 5.5 mM. AG and UAG were lowered by approximately 25% following both KE and GLU intake compared with PBO. In the case of AG, the differences were -52.1 (-79.4, -24.8) for KE and -48.4 (-75.4, -21.5) pg/mL for GLU intake (P < .01). Concentrations of AG remained lower with KE but returned to baseline and were comparable with PBO levels after GLU intake. GLP-1, GIP, gastrin and cholecystokinin were not affected by KE ingestion. CONCLUSION: Our results suggest that the suppressive effects on appetite sensation scores associated with hyperketonaemia are more probable to be mediated through reduced ghrelin concentrations than by increased activity of cholecystokinin, gastrin, GIP or GLP-1.