The endocrine consequences of weight loss by bariatric surgery (BS) and caloric restriction are not fully understood but contribute to variable improvements in insulin sensitivity and cardiometabolic health. This study compared changes in insulin sensitivity and plasma concentrations of gut peptides 8 weeks and 1 year after BS and a low-calorie diet (LCD). Nineteen female patients with obesity self-selected BS (gastric bypass [n = 5] or sleeve gastrectomy [n = 7]) or LCD (n = 7) in this parallel-arm, prospective observational study. We assessed insulin sensitivity via a two-step hyperinsulinemic-euglycemic clamp (20 and 80 mU/min/m2 insulin). Plasma glucose, insulin, and gut peptides were measured around a mixed meal tolerance test (400 kcal). Visual analogue scales (VAS) were used to rate subjective appetite sensations. All assessments were conducted at baseline and after 8 weeks and 1 year of intervention. Whole-body insulin sensitivity was unchanged 8 weeks after the intervention. One year after surgery, insulin sensitivity at both 20 and 80 mU/m2/min insulin infusion doses increased with BS weight loss (-33.8% ± 1.4% body weight) but was unchanged in LCD with small weight loss (-3.7% ± 2.0% body weight). Postprandial total PYY increased more following BS while total and acylated ghrelin decreased more following BS compared to LCD. Hunger decreased and fullness increased with BS compared to LCD (p = .037; p = .010, respectively). Insulin sensitivity was improved only 1 year after BS, despite significant weight loss after 8 weeks. Changes in gut peptides after BS paralleled reduced hunger and increased fullness. Most improvements in cardiometabolic health were related to weight loss.

As the prevalence of obesity increases worldwide, and lifestyle modification or pharmaceutical treatment yields insufficient results for patients with severe obesity, an increasing number of patients opt for metabolic bariatric surgery as an effective and durable treatment of this disease. Seeing as 80% of these patients are women, many of whom are of reproductive age, pregnancies after metabolic bariatric surgery become increasingly common. Metabolic bariatric surgery has many benefits for overall health and pregnancy outcomes, but certain risks are also reported. This leads to the rise of a new population of patients with their own specific needs regarding follow-up. This review discusses the various benefits and risks of these types of surgery for pregnancy. We provide an overview of the current state of the evidence and look into future research goals.

Transoral outlet reduction endoscopy (TORe) and glucagon-like peptide-1 agonist, liraglutide, have individually shown promise in managing weight regain after Roux-en-Y gastric bypass. However, combined effects of adjunctive liraglutide to TORe remain unexplored. A cross-over design was utilized to evaluate the efficacy of liraglutide treatment when initiated immediately post-TORe or 1 year post-TORe.

Data was analyzed from a double-blinded randomized controlled trial conducted at three outpatient clinics in São Paulo, Brazil, from January 2019 to December 2021. Two cohorts were established: group placebo then liraglutide (group PL) received subcutaneous saline dosed daily for 12 months after TORe then liraglutide for the subsequent 12 months, while group liraglutide then placebo (group LP) started subcutaneous liraglutide followed by subcutaneous saline in a similar fashion. Each participant received placebo and liraglutide for equal duration over the 24-month treatment phase. The primary outcomes were percent total body weight loss (%TBWL) at 12 and 24 months.

The study comprised 58 participants in group PL and 51 participants in group LP, with no significant difference in mean baseline BMI between groups. Group LP showed significantly higher %TBWL than group PL at 6, 9, and 12 months. Surprisingly, at 21 and 24 months, group LP continued to exhibit greater %TBWL than group PL, even after discontinuing liraglutide.

Immediate post-procedure administration of liraglutide appears to be more effective than placebo in reversing weight regain in patients undergoing TORe. Results indicate that the timing of post-TORe liraglutide initiation may enhance the therapeutic benefits of the procedure.

Available knowledge shows that obesity is associated with an impaired endothelial function and an increase in cardiovascular risk, but the mechanisms of this association are not yet fully understood. Adipose tissue dysfunction, adipocytokines production, along with systemic inflammation and associated comorbidities (e.g., diabetes and hypertension), are regarded as the primary physiological and pathological factors. Various strategies are now available for the control of excess body weight. Dietary regimens alone, or in association with bariatric surgery when indicated, are now widely used. Of particular interest is the understanding of the effect of these interventions on endothelial homeostasis in relation to cardiovascular health. Substantial weight loss resulting from both diet and bariatric surgery decreases circulating biomarkers and improves endothelial function. Extensive clinical trials and meta-analyses show that bariatric surgery (particularly gastric bypass) has more substantial and long-lasting effect on weight loss and glucose regulation, as well as on distinct circulating biomarkers of cardiovascular risk. This review summarizes the current understanding of the distinct effects of diet-induced and surgery-induced weight loss on endothelial function, focusing on the key mechanisms involved in these effects.

Ketosis seems to attenuate, or prevent, the rise in both ghrelin concentrations and subjective hunger ratings that follow weight loss. However, most of the previous studies have employed very-low energy diets (VLED) and are therefore limited in terms of generalizability.

To compare changes in ghrelin plasma concentrations after a low-carbohydrate (LCD) versus an isocaloric low-fat low energy diet (LED) in females with lipedema. Secondary objectives were to determine potential differences between diets in changes in satiety hormones, and subjective ratings of appetite.

Females with obesity and lipedema were randomized to either an LCD (75 g carbohydrates) or low-fat diet (180 g carbohydrates) for 8 weeks. Plasma concentrations of ghrelin, peptide YY, cholecystokinin (CCK), and glucagon-like peptide 1 (GLP-1), and subjective ratings of appetite were measured in the fasting and postprandial states, pre and post intervention.

55 females (30 in LCD) were included (age 47.9 ± 11.3 years, BMI 36.8 ± 5.1 kg/m2). Both LCD and low-fat groups lost weight (10.3 %, P < 0.001 and 7.3 %, P < 0.001, respectively), but the LCD lost significantly more. No within or between groups differences were found for ghrelin in the fasting state. A reduction in postprandial (tAUC) ghrelin was seen only in the LCD group (P = 0.002), and this change was significantly different from the low-fat group (P = 0.046). The LCD group also reported an increase in postprandial (both iAUC and tAUC) fullness ratings (P = 0.035 and P = 0.005, respectively), but this was not significantly different from the low-fat group (P = 0.703 and P = 0.365, respectively), despite the latter experiencing no change (P = 0.127 and P = 0.152, respectively). Conversely, only the low-fat group reported increased hunger in fasting (P = 0.046), but changes were not significantly different from the LCD group (P = 0.711). A decrease in postprandial (both tAUC and iAUC) CCK was observed in both LCD and low-fat diet groups (P ≤ 0.005 for all).

Despite no changes in fasting ghrelin concentrations in either of the diet groups, a reduction in postprandial ghrelin and increased fullness was seen in the LCD group. These favorable changes in appetite in the LCD group might have contributed to the greater weight loss observed in this group.

NCT04632810, Effect of Ketosis on Pain and Quality of Life in Patients With Lipedema (Lipodiet).

Appetite-related hormones are secreted from the gut, signaling the presence of nutrients. Such signaling allows for cross-talk between the gut and the appetite-control regions of the brain, influencing appetite and food intake. As nutritional requirements change throughout the life course, it is perhaps unsurprising that appetite and eating behavior are not constant. Changes in appetite-related gut hormones may underpin these alterations in appetite and eating. In this article, we review evidence of how the release of appetite-related gut hormones changes throughout the life course and how this impacts appetite and eating behaviour. We focus on hormones for which there is the strongest evidence of impact on appetite, food intake, and body weight: the anorexigenic glucagon like peptide-1, peptide tyrosine tyrosine, and cholecystokinin, and the orexigenic ghrelin. We consider hormone concentrations, particularly in response to feeding, from the very early days of life, through childhood and adolescence, where responses may reflect energy requirements to support growth and development. We discuss the period of adulthood and midlife, with a particular focus on sex differences and the effect of menstruation, pregnancy, and menopause, as well as the potential influence of appetite-related gut hormones on body composition and weight status. We then discuss recent advancements in our understanding of how unfavorable changes in appetite-related gut hormone responses to feeding in later life may contribute to undernutrition and a detrimental aging trajectory. Finally, we briefly highlight priorities for future research.

Metabolic and bariatric surgery (MBS) is an effective intervention for patients with severe obesity and metabolic comorbidities, particularly when non-surgical weight loss methods prove insufficient. MBS has shown significant potential for improving quality of life and metabolic health outcomes in individuals with obesity, yet it carries inherent risks. Although these procedures offer a multifaceted approach to obesity treatment and its clinical advantages are well-documented, the limited understanding of its long-term outcomes and the role of multidisciplinary care pose challenges. With an emphasis on quality-of-life enhancements and the handling of postoperative difficulties, the present narrative review seeks to compile the most recent findings on MBS while emphasizing the value of an integrated approach to maximize patient outcomes. Effective MBS and patients' management require a collaborative team approach, involving surgeons, dietitians, psychologists, pharmacists, and other healthcare providers to address not only physiological but also psychosocial patient needs. Comparative studies demonstrate the efficacy of various MBS methods, including Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy that may considerably decrease morbidity and mortality in individuals with obesity. Future studies should target long-term patient treatment, and decision making should be aided by knowledge of obesity, comorbidity recurrence rates, and permanence of benefits.

The age-related decline in appetite and food intake - termed "anorexia of ageing" - is implicated in undernutrition in later life and hence provides a public health challenge for our ageing population. Eating behaviour is controlled, in part, by homeostatic mechanisms which sense nutrient status and provide feedback to appetite control regions of the brain. Such feedback signals, propagated by episodic gut hormones, are dysregulated in some older adults. The secretory responses of appetite-related gut hormones to feeding are amplified, inducing a more anorexigenic signal which is associated with reduced appetite and food intake. Such an augmented response would indicate an increase in gut sensitivity to nutrients. Consequently, this review explores the role of gastrointestinal tract nutrient sensing in age-related appetite dysregulation. We review and synthesise evidence for age-related alterations in nutrient sensing which may explain the observed hormonal dysregulation. Drawing on what is known regarding elements of nutrient sensing pathways in animal models, in other tissues of the body, and in certain models of disease, we identify potential causal mechanisms including alterations in enteroendocrine cell number and distribution, dysregulation of cell signalling pathways, and changes in the gut milieu. From identified gaps in evidence, we highlight interesting and important avenues for future research.

This trial aimed to compare three low-energy diets (LEDs) with different amounts of carbohydrates (CHO) on ketosis and changes in hunger feelings in adults with obesity.

A total of 101 adults (51 female) with obesity (BMI, mean [SEM], 34.7 [0.4] kg/m2) were randomized to follow three isocaloric LEDs (1000 kcal/day) for 8 weeks, containing either low, medium, or high CHO (70, 100, and 130 g/day, respectively), and 4 weeks of refeeding and weight stabilization. Body weight (BW) and composition, hunger and other appetite ratings, concentrations of β-hydroxybutyrate (βHB), and appetite-related hormones were measured at baseline and at the end of weeks 8 and 12.

At week 8, weight loss and βHB concentrations were significantly different among groups: Low CHO group versus Medium CHO group (BW: 2.32 [0.95] kg, 95% CI: 0.44 to 4.21, p = 0.016; βHB: -0.40 [0.09] mM, 95% CI: -0.67 to -0.09, p < 0.001); Low CHO group versus High CHO group (BW: 2.29 [0.96] kg, 95% CI: 0.39 to 4.19, p = 0.016; βHB: -0.644 [0.10] mM, 95% CI: -0.84 to -0.44, p < 0.001); and Medium CHO group versus High CHO group (BW: -0.03 [0.94] kg, 95% CI: -1.89 to 1.84, p = 0.977; βHB: -0.15 [0.08] mM, 95% CI: -0.30 to 0.002, p = 0.054). No significant differences in hunger were found among groups: Low CHO group versus Medium CHO group (-10.87 [5.92] mm, 95% CI: -0.82 to 22.57, p = 0.068); Low CHO group versus Medium CHO group (7.74 [7.36] mm, 95% CI: -6.77 to 22.26, p = 0.294); and Medium CHO group versus High CHO group (-3.13 [7.48] mm, 95% CI: -17.89 to 11.63, p = 0.676).

Although the findings of this trial are not definitive, changes in hunger ratings with weight loss did not differ among groups. Additional studies with CHO intake of up to 130 g in 1000-kcal/day LEDs are warranted to replicate these findings.

Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and adipokines, including ghrelin and resistin, are linked to obesity, studies analyzing the changes in fasting ghrelin and resistin levels in patients following one anastomosis gastric bypass (OAGB) are lacking.

The authors aimed to investigate resistin and ghrelin levels before and after two commonly used bariatric procedures with different mechanisms of action: sleeve gastrectomy (SG) and OAGB.

Fasting serum ghrelin and resistin levels were evaluated by using ELISA in a nonrandomized, prospective cohort study for the pattern of changes in the preoperative period and 1 week, 1 month, 3 months and, 12 months after surgery in age and sex-matched patients with BMI ≥40 kg/m 2 undergoing either SG ( n =40) or OAGB ( n =40). Their relationships with demographic parameters such as body weight, BMI, presence of T2DM, HbA 1 C, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were also evaluated.

OAGB was superior in weight control compared to the SG group. There were significant differences in resistin and ghrelin levels between the OAGB and SG groups. Ghrelin decreased more in the SG group than the preoperative values. This change in ghrelin levels was more significant at 1 year after SG [preoperative mean (range) level of 334.2 (36.6-972.1) pg/ml decreased to 84 (9.1-227) pg/ml at 1 year] whereas in the OAGB group no significant change was observed [preoperative mean (range) level of 310 (146-548) pg/ml decreased to 264 (112-418) pg/ml at 1 year]. Resistin levels decreased in both groups, especially after 3 months and onward following both operations [the mean (range) resistin levels were 2.6 (0.87-5.4) ng/ml and decreased to 1.1 (0.5-2.4) ng/ml in the SG group vs 2.48 (0.89-6.43) ng/ml decreased to 0.72 (0.35-1.8) ng/ml in OAGB group at 1 year], which was in parallel with changes in HOMA-IR index, body weight, and BMI changes at 1st year. HOMA-IR index changes were similar, but more prominent after OAGB. OAGB was als3 three months and onward), and HOMA-IR changes.

This is the first study to compare fasting ghrelin and resistin levels after OAGB and SG. Although similar changes were observed, ghrelin changes were more prominent after SG, whereas resistin were observed after OAGB. OAGB was superior in T2DM control, which was in parallel with weight loss, fasting resistin levels, and HOMA-IR changes suggesting a possible effect of resistin after OAGB in glucose metabolism and insulin resistance.

Obesity is a significant risk factor for metabolic-associated steatotic liver disease (MASLD). The association between Helicobacter pylori (HP) infection and liver fibrosis has not been fully elucidated in patients with obesity and MASLD.

This observational retrospective study included clinical and biochemical parameters of patients with obesity undergoing bariatric surgery. HP infection was confirmed by gastric endoscopy, and liver biopsies were performed during surgery. Bivariate and logistic regression analyses were employed to evaluate independent associations with liver fibrosis and steatosis by biopsy.

The mean age of the subjects was 42 ± 10 years, with 84.7% being women, and they had a mean BMI of 42.97 ± 7.56 kg/m2. Overall, 41.7% of patients had an HP infection. Multiple logistic regression models were conducted to assess the association between HP infection, liver steatosis, and fibrosis by biopsy. HP infection was independently associated with liver fibrosis [OR = 3.164 (95% CI 1.011-9.900)].

Biopsy findings associated HP infection with increased liver fibrosis.

Diabetes mellitus (DM) and obesity have become public issues of global concern. Bariatric surgery for the treatment of obesity combined with type 2 DM has been shown to be a safe and effective approach; however, there are limited studies that have systematically addressed the challenges of surgical treatment of obesity combined with DM. In this review, we summarize and answer the most pressing questions in the field of surgical treatment of obesity-associated DM. I believe that our insights will be of great help to clinicians in their daily practice.

Metabolic and bariatric surgeries have been shown to be the most effective strategy to induce and maintain significant weight loss for people living with severe obesity. However, ongoing concerns regarding operative risks, irreversibility and excess costs limit their broader clinical use. Endoscopic bariatric therapies are pragmatic alternatives for patients who are not suitable for metabolic and bariatric surgeries or who are concerned regarding their long-term safety. Endoscopic sleeve gastroplasty has emerged as a novel technique of endoscopic bariatric therapies, which have garnered significant interest and evidence in the past few years. Its safety, efficacy and cost-effectiveness have been shown in various studies, while comparisons with sleeve gastrectomy have been widely made. This review brings together current evidence pertaining to the technicality of the procedure itself, current indications, safety and efficacy, cost-effectiveness, as well as its future role and development.

Obesity presents with structural and functional hypothalamic dysfunction. However, it is unclear whether weight loss can lead to hypothalamic changes. We therefore aimed to conduct a systematic review and meta-analysis to determine the effect of body mass reduction in obese individuals on hypothalamic structure and function.

PubMed, Embase and Cochrane databases were searched for studies that reported the change in hypothalamic structure and function after weight loss. Qualitative and quantitative analyses were performed on magnetic resonance imaging techniques, medio-basal hypothalamus T2-relaxation time, blood oxygen level dependent (BOLD) contrast, voxel-based morphometry (VBM) and biomarkers including glucose, insulin, leptin, ghrelin and inflammatory markers of interleukins. Mean differences between pre- and post-weight loss and 95% confidence intervals (CIs) were pooled using random-effects models.

Thirteen pre-post studies were included, of which six accounted for the meta-analysis. Studies showed a favorable decrease in T2-relaxation time (n = 1), favorable change in hypothalamic activity after weight loss on BOLD contrast (n = 4), with higher peak activities after surgical weight loss (n = 2). No differences were found in the gray matter density of the hypothalamus on VBM (n = 1). Pooled mean differences between pre- and post-surgical weight loss revealed a decrease of 8.53 mg/dl (95% CI: 5.17, 11.9) in glucose, 7.73 pmol/l (95% CI: 5.07, 10.4) in insulin, 15.5 ng/ml (95% CI: 9.40, 21.6) in leptin, 142.9 pg/ml (95% CI: 79.0, 206.8) in ghrelin and 9.43 pg/ml (95% CI: -6.89, 25.7) in IL-6 level.

Our study showed weight reduction in obesity led to limited structural change and significant functional changes in the hypothalamus.

It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.

Type 2 diabetes mellitus (T2DM) is a highly prevalent metabolic disease, causing a heavy burden on healthcare systems worldwide, with related complications and anti-diabetes drug prescriptions. Recently, it was demonstrated that T2DM can be put into remission via significant weight loss using low-carbohydrate diets (LCDs) and very low-energy diets (VLEDs) in individuals with overweight and obesity. Clinical trials demonstrated remission rates of 25-77%, and metabolic improvements such as improved blood lipid profile and blood pressure were observed. In contrast, clinical trials showed that remission rate declines with time, concurrent with weight gain, or diminished weight loss. This review aims to discuss existing literature regarding underlying determinants of long-term remission of T2DM including metabolic adaptations to weight loss (e.g., role of gastrointestinal hormones), type of dietary intervention (i.e., LCDs or VLEDs), maintaining beta (β)-cell function, early glycemic control, and psychosocial factors. This narrative review is significant because determining the factors that are associated with challenges in maintaining long-term remission may help in designing sustainable interventions for type 2 diabetes remission.

Obesity is a complex chronic disease and requires a long-term multidisciplinary management. Even patients undergoing bariatric surgery, one the most effective treatments for obesity, can have insufficient weight loss (IWL) than expected (primary non responder) or weight regain (WR) after a successful primary procedure (secondary non responder). A poor response represents a challenge of bariatric surgery that can induce persistence or recurrence of obesity-related comorbidities, prejudicing benefits of surgery. Increasing evidence suggests that weight loss medications represent a useful strategy in obesity care also after bariatric surgery procedures. This narrative review summarizes the evidence concerning anti-obesity therapy in the management of no-responders to primary bariatric surgery. Available data on liraglutide (one randomized double-blind placebo-controlled trial, three prospective and three retrospective studies), naltrexone/bupropion (three retrospective studies), orlistat (one case control prospective and one retrospective studies) and topiramate and phentermine (five retrospective studies) have been considered. Available data suggest that weight loss medications could offer a significant adjunctive benefit to lifestyle and behavioral modifications in the life-long management of obesity. Newer treatment modalities including the use of anti-obesity drugs provide patients and healthcare providers with more options in the management of poor response after bariatric surgery.

Obesity is considered the leading public health problem in the medical sector. The phenotype includes overweight conditions that lead to several other comorbidities that drastically decrease health. Glucagon-like receptor agonists (GLP-1RAs) initially designed for treating type 2 diabetes mellitus (T2DM) had demonstrated weight loss benefits in several clinical trials. In vivo studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. Additionally, GLP-1RAs were found to regulate food intake through stimulation of sensory neurons in the vagus, interaction with the hypothalamus and hindbrain, and through inflammation and intestinal microbiota. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. We could identify three different ways that could lead to weight gain. Potential factors might include temporary hormonal adjustment in response to weight reduction, the central nervous system's (CNS) incompetence in regulating weight augmentation owing to the lack of GLP-1RA, and β-cell malfunction due to sustained exposure to GLP-1RA. Here, we also review the data from clinical studies that reported withdrawal symptoms. Although the use of GLP-1RA could be beneficial in multiple ways, withdrawal after years has the symptoms reversed. Clinical studies should emphasize the downside of these views we highlighted, and mechanistic studies must be carried out for a better outcome with GLP-1RA from the laboratory to the bedside.

Ghrelin is an orexigenic peptide secreted mainly by the stomach. Serum ghrelin concentrations are suppressed after a meal, probably due to insulin release. Individuals with obesity are characterized by a lower fasting serum ghrelin and a lower ghrelin decrease after a meal. The effect of weight loss on the ability of insulin to suppress serum ghrelin concentration remains unknown.

The aim of the present study was to analyze the effect of weight-reducing dietary intervention on the ability of hyperinsulinemia to suppress serum ghrelin concentration in young individuals with uncomplicated obesity.

We examined 38 individuals with marked overweight or obesity, who underwent a 12-wk dietary intervention program. Serum ghrelin concentration was measured before and after a 2-h hyperinsulinemic-euglycemic clamp, both pre- and post-intervention. Twenty normal-weight individuals served as a control group and were examined at baseline only.

Individuals with overweight/obesity were characterized by a lower fasting serum ghrelin concentration than normal-weight individuals (P = 0.006). Insulin decreased serum ghrelin concentration in both groups (P < 0.001); however, this decrease was markedly lower in individuals with overweight/obesity than in normal-weight individuals (99.70 ± 136.37 vs. 215.45 ± 250.28 pg/mL; P = 0.026). Fasting serum ghrelin concentration increased after the intervention. After weight-reducing dietary intervention, the decrease in serum ghrelin concentration after the clamp was significantly greater than the pre-intervention value (99.70 ± 136.37 vs. 221.82 ± 228.75 pg/mL; P = 0.002).

Weight-reducing dietary intervention restores the ability of hyperinsulinemia to suppress serum ghrelin concentration. It may suggest an enhanced feeling of satiety after moderate weight loss in individuals with overweight/obesity.

Background and study aims Transoral outlet reduction (TORe) has long been employed in treating weight regain after Roux-en-Y gastric bypass. However, its impact on gut hormones and their relationship with weight loss remains unknown. Patients and methods This was a substudy of a previous randomized clinical trial. Adults with significant weight regain and dilated gastrojejunostomy underwent TORe with argon plasma coagulation (APC) alone or APC plus endoscopic suturing (APC-suture). Serum levels of ghrelin, GLP-1, and PYY were assessed at fasting, 30, 60, 90, and 120 minutes after a standardized liquid meal. Results were compared according to allocation group, clinical success, and history of cholecystectomy. Results Thirty-six patients (19 APC vs. 17 APC-suture) were enrolled. There were no significant baseline differences between groups. In all analyses, the typical postprandial decrease in ghrelin levels was delayed by 30 minutes, but no other changes were noted. GLP-1 levels significantly decreased at 12 months in both allocation groups. Similar findings were noted after dividing groups according to the history of cholecystectomy and clinical success. The APC cohort presented an increase in PYY levels at 90 minutes, while the APC-suture group did not. Naïve patients had significantly lower PYY levels at baseline ( P = 0.01) compared with cholecystectomized individuals. This latter group experienced a significant increase in area under the curve (AUC) for PYY levels, while naïve patients did not, leading to a higher AUC at 12 months ( P = 0.0001). Conclusions TORe interferes with the dynamics of gut hormones. APC triggers a more pronounced enteroendocrine response than APC-suture, especially in cholecystectomized patients.

This study aimed to investigate the efficacy and safety of repeated photodynamic therapy (PDT) with a chlorin e6 (Ce6)-embedded intragastric satiety-inducing device (ISD) to maintain therapeutic effects of obesity in a juvenile pig.

The Ce6-embedded ISD was fabricated with a dipping method. Twelve pigs were divided into four groups of three and were administered control, single, biweekly, or weekly PDT, respectively. The therapeutic effects were assessed by comparing the results of phototoxicity, endoscopy, fluoroscopy, hormone and weight changes, and histological examination.

The percentage of total body weight gain was significantly suppressed in PDT-treated pigs compared with control pigs (all p < 0.001). This suppression persisted in the repeated PDT groups, but percentage of total body weight gain gradually increased when PDT was stopped. Ghrelin levels in the PDT-treated groups were significantly lower and leptin levels were significantly higher than those in the control group (all p < 0.05). Inflammatory cell infiltration, collagen, TUNEL, and anti-ghrelin-positive deposition in the weekly group were significantly higher than those in the control, single, and biweekly groups (all p < 0.01).

Repeated and periodic PDT was technically feasible and safe and successfully maintained the therapeutic effects against obesity while eliminating the indwelling time and reducing ISD-related complications in pigs.

Hypothalamic centres have been recognized to play a central role in body weight regulation for nearly 70 years.

In this review, we will explore the current undersanding of the role the hypothalamus plays in controlling food intake behaviours.

Review of relevant literature from PubMed searches and review article citations.

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.

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.

Understanding the hypothalamic control of food intake forms the foundation for understanding and managing obesity as a chronic disease.

Bariatric surgery has long-term beneficial effects on body weight and metabolic status, but there is an apparent lack of comprehensive cardiometabolic, renal, liver, and metabolomic/lipidomic panels, whereas the underlying mechanisms driving the observed postoperative ameliorations are still poorly investigated. We aimed to study the long-term effects of bariatric surgery on metabolic profile, cardiorenal and liver outcomes in association with underlying postoperative gut hormone adaptations.

28 individuals who underwent bariatric surgery [17 sleeve gastrectomy (SG), 11 Roux-en-Y gastric bypass (RYGB)] were followed up 3, 6 and 12 and at 10 years following surgery. Participants at 10 years were cross-sectionally compared with an age-, sex- and adiposity-matched group of non-operated individuals (n = 9) and an age-matched pilot group of normal-weight individuals (n = 4).

There were durable effects of surgery on body weight and composition, with an increase of lean mass percentage persisting despite some weight regain 10 years postoperatively. The improvements in metabolic and lipoprotein profiles, cardiometabolic risk markers, echocardiographic and cardiorenal outcomes persisted over the ten-year observation period. The robust improvements in insulin resistance, adipokines, activin/follistatin components and postprandial gastrointestinal peptide levels persisted 10 years postoperatively. These effects were largely independent of surgery type, except for a lasting reduction of ghrelin in the SG subgroup, and more pronounced increases in proglucagon products, mainly glicentin and oxyntomodulin, and in the cardiovascular risk marker Trimethylamine-N-oxide (TMAO) within the RYGB subgroup. Despite similar demographic and clinical features, participants 10 years after surgery showed a more favorable metabolic profile compared with the control group, in conjunction with a dramatic increase of postprandial proglucagon product secretion.

We demonstrate that cardiorenal and metabolic benefits of bariatric surgery remain robust and largely unchanged ten years postoperatively and are associated with durable effects on gastrointestinal- muscle- and adipose tissue-secreted hormones.

ClinicalTrials.gov: NCT04170010.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in premenopausal women and is a common cause of anovulatory subfertility. Although obesity does not form part of the diagnostic criteria, it affects a significant proportion of women with PCOS and is strongly implicated in the pathophysiology of the disease. Both PCOS and obesity are known to impact fertility in women; obesity also reduces the success of assisted reproductive technology (ART). With or without pharmacotherapy, lifestyle intervention remains the first-line treatment in women with PCOS and obesity. Bariatric surgery is still an experimental treatment in women with PCOS and subfertility. This review will present an overview of the pathophysiology of PCOS and obesity and the role of bariatric surgery. Although data are sparse regarding the impact of bariatric surgery on subfertility in women with PCOS and obesity, existing studies point to a beneficial role in treating metabolic and reproductive dysfunction.

Excessive added sugar intake has been associated with obesity; however, the effect of dietary sweetness on energy intake (EI) and appetite in adults with and without obesity has not yet been determined.

To assess the effect of mouth rinses with and without energy and sweetness on measures of appetite, and to compare responses between subjects with body mass index (BMI) between 18.5 and 24.9 kg/m2 or ≥30 kg/m2.

In this randomized, double-blind crossover study, 39 subjects (age 23±5y; 17 male, 22 female; BMI 18.5-24.9 kg/m2: n = 21; ≥30 kg/m2: n = 18) performed modified sham-feeding (MSF) with a mouth rinse containing either sucrose, sucralose, maltodextrin, or water for 2min before expectorating the solution. Blood sampling and subjective appetite assessments occurred at baseline (-5) and 15, 30, 60, and 90min post-MSF. After, EI was assessed at a buffet meal and post-meal appetite ratings were assessed hourly for 3h.

Post-MSF ghrelin increased for water vs. maltodextrin (water: p = 0.03). Post-MSF cholecystokinin increased following maltodextrin-MSF (p = 0.03) and sucralose-MSF (p = 0.005) vs. sucrose for those with BMI:18.5-24.9 kg/m2 only. There was greater post-MSF desire to eat in response to water vs. sucrose (p = 0.03) and reduced fullness with sucralose for those with BMI≥30 vs. 18.5-24.9 kg/m2 (p < 0.001). There was no difference in EI at the buffet meal by mouth rinse (p = 0.98) or by BMI (p = 0.12). However, there was greater post-meal fullness following sucralose-MSF vs. water (p = 0.03) and sucrose (p = 0.004) for those with BMI≥30 vs. 18.5-24.9 kg/m2.

Sucralose rinsing led to greater cephalic phase CCK release in adults with a BMI:18.5-24.9 kg/m2 only; however, ghrelin responses to unsweetened rinses were energy-specific for all adults. As subsequent EI was unaffected, further investigation of cephalic phase appetite is warranted.

Metabolic bariatric surgery (MBS) helps reduce comorbidities, such as hypertension and gestational diabetes, and is more effective than diet management for women with obesity-related health issues. Vitamin B12, vitamin D, and iron play important roles in ensuring the health of a neonate. However, pregnancies occurring after MBS may face complications related to micronutrient deficiencies, particularly of vitamins B12 and D and iron. This study aimed to investigate the vitamin B12, vitamin D, ferritin, and iron status of pregnant women who underwent MBS compared with women without MBS history. The study included 217 pregnant women (105 with a history of MBS and 112 without a history of MBS) who visited a major maternity hospital in Abu Dhabi, United Arab Emirates (UAE) between July 2021 and November 2022. The maternal vitamin B12, vitamin D, iron, and ferritin levels were measured twice, initially during the first or second trimester and subsequently during the third trimester. The iron was measured once during the pregnancy. Vitamin B12 deficiency was higher among pregnant women with MBS history compared to non-bariatric pregnant women (24.4% vs. 3.9%, p < 0.001). Women with a history of MBS had a higher prevalence of vitamin D deficiency (62.3% vs. 37.7%, p < 0.002). Linear regression analysis indicated that vitamin B12 levels decreased by 55 pg/mL in women with a history of MBS and by 4.6 pg/mL with a unit increase in body mass index (kg/m2). Furthermore, vitamin D levels in women with a history of MBS decreased by 4.9 ng/mL during pregnancy. Metabolic bariatric surgery is associated with vitamin B12, vitamin D, and iron deficiencies during pregnancy.

Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and β cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and β cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher β cell numbers from decreased β cell apoptosis drove the increase in β cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the β cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in β cells, which supports decreased β cell apoptosis and/or increased β cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes.

Bariatric surgery is an effective treatment modality for obesity and obesity-associated complications. Weight loss after bariatric surgery was initially attributed to anatomic restriction or reduced energy absorption, but now it is understood that surgery treats obesity by influencing the subcortical areas of the brain to lower adipose tissue mass. There are three major phases of this process: initially the weight loss phase, followed by a phase where weight loss is maintained, and in a subset of patients a phase where weight is regained. These phases are characterized by altered appetitive behavior together with changes in energy expenditure. The mechanisms associated with the rearrangement of the gastrointestinal tract include central appetite control, release of gut peptides, change in microbiota and bile acids. However, the exact combination and timing of signals remain largely unknown.

Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress.

Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period.

There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009).

Timing of ghrelin measurements, and stimulation of only left vagus nerve.

tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Obesity is the major modifiable risk factor for osteoarthritis (OA). A major focus of management in OA is weight loss. Although we live in an obesogenic environment, obesity has a predominantly genetic and epigenetic basis. This explains a person's weight set point which is defended by biological mechanisms making weight loss difficult to achieve and maintain long term, regardless of the methods used. Significant weight regain occurs after weight loss, with weight tending to return to pre-treatment levels after cessation of interventions including the glucagon-like peptide-1 (GLP-1) agonists. An area that has received little attention is the slow, insidious weight creep of 0.5-1 kg/year over adulthood that sees individuals relentlessly increase weight. There is evidence that low intensity, personalised lifestyle interventions can prevent this weight creep, providing patients with achievable goals. In this narrative review, we examine the evidence for weight loss in OA, the biological mechanisms that make weight loss difficult to achieve and maintain and the potential negative impacts on patients. We review the evidence for preventing weight gain, the improvement in patient outcomes and the potential for significant healthcare savings through reduced knee replacements. We propose a combined approach of weight loss when indicated, together with targeting weight creep across adult years and the potential role of metformin. Implementing these combined approaches is likely to be more effective in improving patient related outcomes, reducing joint damage and healthcare costs, than our current focus on achieving weight loss in OA.

Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.

Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to "reduce food and avoid drinking to fullness" and begin "running during the night." Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.

Decreasing levels of patient motivation or compliance are far from being the only causes of postinterventional weight regain after lifestyle, psychological, pharmacological and surgical interventions. Weight regain originates from a complex and individually varying set of central and peripheral mechanisms, with the overall purpose of increasing food intake by both stimulating hunger and reducing satiety (mediated by gastrointestinal hormones) and decreasing the body's energy demands (via metabolic adaption). These mechanisms counteract any attempts to reduce or maintain body weight in today's increasingly prevalent adipogenic environments. The knowledge about the biological mechanisms of body weight regulation should be taken into consideration when planning treatment programs for long-term weight reduction, including follow-up treatment for the prevention and individualized treatment of postinterventional weight regain. Therapeutic measures as well as the frequency of medical follow-ups should be based on the extent of weight regain.

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.

Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress-induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.

Ghrelin, a gastrointestinal peptide, is an endogenous ligand of growth hormone secretagogue receptor 1a (GHSR1a), which is mainly produced by X/A-like cells in the intestinal mucosa. Beyond its initial description as a growth hormone (GH) secretagogue stimulator of appetite, ghrelin has been revealed to have a wide range of physiological effects, for example, the modulation of inflammation; the improvement of cardiac performance; the modulation of stress, anxiety, taste sensation, and reward-seeking behavior; and the regulation of glucose metabolism and thermogenesis. Ghrelin secretion is altered in depressive disorders and metabolic syndrome, which frequently co-occur, but it is still unknown how these modifications relate to the physiopathology of these disorders. This review highlights the increasing amount of research establishing the close relationship between ghrelin, nutrition, microbiota, and disorders such as depression and metabolic syndrome, and it evaluates the ghrelinergic system as a potential target for the development of effective pharmacotherapies.

Obesity and type 2 diabetes(T2D) lead to defects in intestinal hormones secretion, abnormalities in the composition of bile acids (BAs), increased systemic and adipose tissue inflammation, defects of branched-chain amino acids (BCAAs) catabolism, and dysbiosis of gut microbiota. Bariatric surgery (BS) has been shown to be highly effective in the treatment of obesity and T2D, which allows us to view BS not simply as weight-loss surgery but as a means of alleviating obesity and its comorbidities, especially T2D. In recent years, accumulating studies have focused on the mechanisms of BS to find out which metabolic parameters are affected by BS through which pathways, such as which hormones and inflammatory processes are altered. The literatures are saturated with the role of intestinal hormones and the gut-brain axis formed by their interaction with neural networks in the remission of obesity and T2D following BS. In addition, BAs, gut microbiota and other factors are also involved in these benefits after BS. The interaction of these factors makes the mechanisms of metabolic improvement induced by BS more complicated. To date, we do not fully understand the exact mechanisms of the metabolic alterations induced by BS and its impact on the disease process of T2D itself. This review summarizes the changes of intestinal hormones, BAs, BCAAs, gut microbiota, signaling proteins, growth differentiation factor 15, exosomes, adipose tissue, brain function, and food preferences after BS, so as to fully understand the actual working mechanisms of BS and provide nonsurgical therapeutic strategies for obesity and T2D.

Intestinal nutrient sensing regulates food intake and energy metabolism by acting locally and relaying nutritional status to the brain. It is unclear whether these mechanisms are altered in obese humans.

We aimed to investigate differences in duodenal nutrient sensing in humans with or without obesity and the effects of transiently blocking vagal transmission on nutrient sensing, hunger, and appetite.

In a single-blinded, randomized, cross-over design, subjects with or without obesity (n = 14 and n = 11, respectively) were infused intraduodenally with saline or a combination of glucose and oleic acid for 90 min (glucose load: 22.5 g, 1 kcal/min; oleic acid load: 10 g, 1 kcal/min) in the presence or absence of local anesthetic (benzocaine). Blood was sampled at 10-min intervals (120-240 min) and 15-min intervals until termination of the study for measurements of gut hormones, insulin, leptin, and C-peptide. Hunger and satiety sensations were scored using the visual analog scale, and hepatic glucose production and glucose oxidation rates were measured.

Duodenal nutrient infusion in lean subjects led to a 65% drop in acyl ghrelin release and robustly increased cholecystokinin 8 (CCK-8) release (65%; P = 0.023); benzocaine infusion delayed this response (2-factor repeated-measures analysis of variance, P = 0.0065). In contrast, subjects with obesity had significantly blunted response to nutrient infusion, and no further effects were observed with benzocaine. Additionally, significant delays were observed in peptide YY (3-36), pancreatic polypeptide, glucose inhibitory peptide, and glucagon-like peptide 1 (7-36) response. No significant interactions were found between body mass index (BMI) or baseline hormone levels and areas under the curve for hormones except CCK-8 (BMI, P = 0.018; baseline CCK, P = 0.013). Nutrient-induced hunger and satiety sensations were impeded by benzocaine only in the lean cohort. Hunger and satiety sensations in subjects with obesity were not responsive to nutrient entry into the duodenum, and no additional effects were observed by blocking neural signaling.

Nutrient-induced gut hormone release and response to transient vagal blockade are significantly blunted in subjects with obesity. This trial was registered at clinicaltrials.org as NCT02537314.

Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.

Chronic exposure to social defeat stress (SDS) has been used to investigate the neurobiology of depressive- and anxiety-like responses and mnemonic processes. We hypothesized that these affective, emotional, and cognitive consequences induced by SDS are regulated via glutamatergic neurons located in the bed nucleus of the stria terminalis (BNST), amygdaloid complex, and hippocampus in mice.

Here, we investigated the influence of chronic SDS on (i) the avoidance behavior assessed in the social interaction test, (ii) the anxiety-like behavior (e.g., elevated plus-maze, and open field tests) (iii) depressive-like behaviors (e.g., coat state, sucrose splash, nesting building, and novel object exploration tests), (iv) the short-term memory (object recognition test), (v) ΔFosB, CaMKII as well as ΔFosB + CaMKII labeling in neurons located in the BNST, amygdaloid complex, dorsal (dHPC) and the ventral (vHPC) hippocampus.

The main results showed that the exposure of mice to SDS (a) increased defensive and anxiety-like behaviors and led to memory impairment without eliciting clear depressive-like or anhedonic effects; (b) increased ΔFosB + CaMKII labeling in BNST and amygdala, suggesting that both areas are strongly involved in the modulation of this type of stress; and produced opposite effects on neuronal activation in the vHPC and dHPC, i.e., increasing and decreasing, respectively, ΔFosB labeling. The effects of SDS on the hippocampus suggest that the vHPC is likely related to the increase of defensive- and anxiety-related behaviors, whereas the dHPC seems to modulate the memory impairment.

Present findings add to a growing body of evidence indicating the involvement of glutamatergic neurotransmission in the circuits that modulate emotional and cognitive consequences induced by social defeat stress.