Exercise-induced appetite suppression: An update on potential mechanisms.

The first systematic reviews of the effects of exercise on appetite-regulation and energy intake demonstrated changes in appetite-regulating hormones consistent with appetite suppression and decreases in subsequent relative energy intake over a decade ago. More recently, an intensity-dependent effect and several potential mechanisms were proposed, and this review aims to highlight advances in this field. While exercise-induced appetite suppression clearly involves acylated ghrelin, glucagon-like peptide-1 may also be involved, though recent evidence suggests peptide tyrosine tyrosine may not be relevant. Changes in subjective appetite perceptions and energy intake continue to be equivocal, though these results are likely due to small sample sizes and methodological inconsistencies. Of the proposed mechanisms responsible for exercise-induced appetite suppression, lactate has garnered the most support through in vitro and in vivo rodent studies as well as a growing amount of work in humans. Other potential modulators of exercise-induced appetite suppression may include sex hormones, growth-differentiation factor 15, Lac-Phe, brain-derived neurotrophic factor, and asprosin. Research should focus on the mechanisms responsible for the changes and consider these other modulators (i.e., myokines/exerkines) of appetite to improve our understanding of the role of exercise on appetite regulation.

Obesity management for the treatment of type 2 diabetes: emerging evidence and therapeutic approaches.

Excess adiposity can contribute to metabolic complications, such as type 2 diabetes mellitus (T2DM), which poses a significant global health burden. Traditionally viewed as a chronic and irreversible condition, T2DM management has evolved and new approaches emphasizing reversal and remission are emerging. Bariatric surgery demonstrates significant improvements in body weight and glucose homeostasis. However, its complexity limits widespread implementation as a population-wide intervention. The identification of glucagon-like peptide 1 (GLP-1) and the development of GLP-1 receptor agonists (GLP-1RAs) have improved T2DM management and offer promising outcomes in terms of weight loss. Innovative treatment approaches combining GLP-1RA with other gut and pancreatic-derived hormone receptor agonists, such as glucose-dependant insulinotropic peptide (GIP) and glucagon (GCG) receptor agonists, or coadministered with amylin analogues, are demonstrating enhanced efficacy in both weight loss and glycemic control. This review aims to explore the benefits of bariatric surgery and emerging pharmacological therapies such as GLP-1RAs, and dual and triple agonists in managing obesity and T2DM while highlighting the caveats and evolving landscape of treatment options.

Fucoidan alleviates high sucrose-induced metabolic disorders and enhances intestinal homeostasis through modulation of Notch signaling.

INTRODUCTION: The therapeutic potential of fucoidan (FUC), a natural polysaccharide, in metabolic disorders is recognized, yet its underlying mechanisms remain unclear. METHODS: We conducted investigations into the therapeutic mechanisms of FUC sourced from Sargassum fulvellum concerning metabolic disorders induced by a high-sucrose diet (HSD), employing Drosophila melanogaster and mice models. Drosophila larvae were subjected to HSD exposure to monitor growth inhibition, reduced pupation, and developmental delays. Additionally, we examined the impact of FUC on growth- and development-related hormones in Drosophila. Furthermore, we assessed the modulation of larval intestinal homeostasis by FUC, focusing on the regulation of Notch signaling. In mice, we evaluated the effects of FUC on HSD-induced impairments in intestinal epithelial barrier integrity and gut hormone secretion. RESULTS: FUC supplementation significantly enhanced pupal weight in Drosophila larvae and effectively countered HSD-induced elevation of glucose and triglyceride levels. It notably influenced the expression of growth- and development-related hormones, particularly augmenting insulin-like peptides production while mitigating larval growth retardation. FUC also modulated larval intestinal homeostasis by negatively regulating Notch signaling, thereby protecting against HSD-induced metabolic stress. In mice, FUC ameliorated HSD-induced impairments in ileum epithelial barrier integrity and gut hormone secretion. CONCLUSIONS: Our findings demonstrate the multifaceted therapeutic effects of FUC in mitigating metabolic disorders and maintaining intestinal health. FUC holds promise as a therapeutic agent, with its effects attributed partly to the sulfate group and its ability to regulate Notch signaling, emphasizing its potential for addressing metabolic disorders.

Pathogenesis and management of diabetic gastroparesis: An updated clinically oriented review.

BACKGROUND AND AIMS: Diabetic gastroparesis (DGp) is a common and preventable complication of uncontrolled diabetes mellitus (D.M.) and significantly affects the Quality of Life of patients. Diagnosis and management present as a clinical challenge due to the disease's complexity and limited effective therapeutic options. This review aims to comprehensively outline the pathogenesis, diagnosis, and management of diabetic gastroparesis, evaluating evolving approaches to guide clinicians and provide future recommendations. METHODS: A literature review was conducted on scholarly databases of PubMed, Google Scholar, Scopus and Web of Science encompassing published articles, gray literature and relevant clinical guidelines. Data were synthesized and analyzed to provide a comprehensive overview of diabetic gastroparesis, focusing on pathogenesis, diagnosis, and management. RESULTS: The review intricately explores the pathogenesis contributing to diabetic gastroparesis, emphasizing autonomic neuropathy, oxidative stress, inflammation, hormonal dysregulation, microbiota alterations, and gastrointestinal neuropathy. Primary management strategies are underscored, including lifestyle modifications, symptom relief, and glycemic control. The discussion encompasses pharmacological and surgical options, highlighting the importance of a multidisciplinary approach involving various healthcare professionals for comprehensive patient care. CONCLUSION: This review offers a thorough understanding of pathogenesis, diagnosis, and management of diabetic gastroparesis, underlining evolving approaches for clinicians. A multidisciplinary approach is crucial to address both the physical and mental health aspects of diabetes and its complications.

Gengricin®: A Nutraceutical Formulation for Appetite Control and Therapeutic Weight Management in Adults Who Are Overweight/Obese.

In the field of nutritional science and metabolic disorders, there is a growing interest in natural bitter compounds capable of interacting with bitter taste receptors (TAS2Rs) useful for obesity management and satiety control. This study aimed to evaluate the effect of a nutraceutical formulation containing a combination of molecules appropriately designed to simultaneously target and stimulate these receptors. Specifically, the effect on CCK release exerted by a multi-component nutraceutical formulation (Cinchona bark, Chicory, and Gentian roots in a 1:1:1 ratio, named Gengricin®) was investigated in a CaCo-2 cell line, in comparison with Cinchona alone. In addition, these nutraceutical formulations were tested through a 3-month randomized controlled trial (RCT) conducted in subjects who were overweight-obese following a hypocaloric diet. Interestingly, the Gengricin® group exhibited a significant greater weight loss and improvement in body composition than the Placebo and Cinchona groups, indicating its effectiveness in promoting weight regulation. Additionally, the Gengricin® group reported higher satiety levels and a significant increase in serum CCK levels, suggesting a physiological basis for the observed effects on appetite control. Overall, these findings highlight the potential of natural nutraceutical strategies based on the combination of bitter compounds in modulating gut hormone release for effective appetite control and weight management.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

Early chronotype favors appetite and reduced later day caloric intake among adults with obesity.

Late chronotype (LC) is related to obesity and altered food intake throughout the day. But whether appetite perception and gut hormones differ among chronotypes is unclear. Thus, we examined if early chronotype (EC) have different appetite responses in relation to food intake than LC. Adults with obesity were categorized using the Morningness-Eveningness Questionnaire (MEQ) as either EC (n = 21, 18F, MEQ = 63.9 ± 1.0, 53.7 ± 1.2 yr, 36.2 ± 1.1 kg/m2) and LC (n = 28, 24F, MEQ = 47.2 ± 1.5, 55.7 ± 1.4 yr, 37.1 ± 1.0 kg/m2). Visual analog scales were used during a 120 min 75 g oral glucose tolerance test (OGTT) at 30 min intervals to assess appetite perception, as well as glucose, insulin, GLP-1 (glucagon-like polypeptide-1), GIP (glucose-dependent insulinotrophic peptide), PYY (protein tyrosine tyrosine), and acylated ghrelin. Dietary intake (food logs), resting metabolic rate (RMR; indirect calorimetry), aerobic fitness (maximal oxygen consumption (VO2max)), and body composition dual-energy X-ray absorptiometry (DXA) were also assessed. Age, body composition, RMR, and fasting appetite were similar between groups. However, EC had higher satisfaction and fullness as well as reduced desires for sweet, salty, savory, and fatty foods during the OGTT (P <0.05). Only GIP tAUC0-120 min was elevated in EC versus LC (p = 0.01). Daily dietary intake was similar between groups, but EC ate fewer carbohydrates (p = 0.05) and more protein (p = 0.01) at lunch. Further, EC had lower caloric (p = 0.03), protein (p = 0.03) and fat (p = 0.04) intake during afternoon snacking compared to LC. Dietary fat was lower, and carbohydrates was higher, in EC than LC (p = 0.05) at dinner. Low glucose and high insulin as well as GLP-1 tAUC60-120 min related to desires for sweet foods (p < 0.05). Taken together, EC had more favorable appetite and lower caloric intake later in the day compared with LC.

Anorexia of ageing is associated with elevated fasted and lower post-prandial ghrelin, independent of ghrelin O-acyltransferase.

The role of ghrelin metabolism in anorexia of ageing is unclear. The aim of this study was to determine acyl-ghrelin, total ghrelin, and ghrelin O-acyltransferase concentrations when fasted and in responses to feeding in older adults exhibiting anorexia of ageing. Twenty-five older adults (OA; 15f, 74 ± 7 years, 24.5 kg·m-2) and twelve younger adults (YA; 6f, 21 ± 2 years, 24.4 kg·m-2) provided a fasted measure of subjective appetite and fasted blood sample (0 min) before consuming a standardised porridge breakfast meal (450 kcal). Appetite was measured every 30 min for 240 min and blood was sampled at 30, 60, 90, 120, 180 and 240 min while participants rested. At 240 min, an ad libitum pasta-based lunch meal was consumed. Older adults were identified as those with healthy appetite (HA-OA) or low appetite (LA-OA), based on habitual energy intake, self-report appetite, BMI, and ad libitum lunch intake. YA ate more at lunch (1108 ± 235 kcal) than HA-OA (653 ± 133 kcal, p = 0.007) and LA-OA (369 ± 168 kcal; p < 0.001). LA-OA, but not HA-OA, had higher fasted concentrations of acyl- and total ghrelin than YA (acyl-ghrelin: 621 ± 307 pg·mL-1 vs. 353 ± 166 pg·mL-1, p = 0.047; total ghrelin: 1333 ± 702 pg·mL-1 vs. 636 ± 251 pg·mL-1, p = 0.006). Acyl-ghrelin (60 min and 90 min) and total ghrelin (90 min) were suppressed to a greater extent for LA-OA than for YA (p < 0.05). No differences were observed in subjective appetite, acyl-to-total ghrelin ratio, or plasma GOAT content (p > 0.1). Higher fasting ghrelin and an augmented ghrelin response to feeding in LA-OA, but not HA-OA, suggests that alterations to ghrelin metabolism are not functions of ageing per se and may be independent causal mechanisms of anorexia of ageing.

Bariatric surgery, through beneficial effects on underlying mechanisms, improves cardiorenal and liver metabolic risk over an average of ten years of observation: A longitudinal and a case-control study.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04170010.

Advances in obesity pharmacotherapy; learning from metabolic surgery and beyond.

Currently, metabolic surgery (MS) constitutes the most effective means for durable weight loss of clinically meaningful magnitude, type 2 diabetes remission and resolution of non-alcoholic steatohepatitis, as well as other obesity-related comorbidities. Accumulating evidence on the mechanisms through which MS exerts its actions has highlighted the altered secretion of hormonally active peptides of intestinal origin with biological actions crucial to energy metabolism as key drivers of MS clinical effects. The initial success of glucagon-like peptide-1 (GLP-1) receptor agonists regarding weight loss and metabolic amelioration have been followed by the development of unimolecular dual and triple polyagonists, additionally exploiting the effects of glucagon and/or glucose-dependent insulinotropic polypeptide (GIP) which achieves a magnitude of weight loss approximating that of common MS operations. Through the implementation of such therapies, the feasibility of a "medical bypass", namely the replication of the clinical effects of MS through non-surgical interventions may be foreseeable in the near future. Apart from weight loss, this approach ought to be put to the test also regarding other clinical outcomes, such as liver steatosis and steatohepatitis, cardiovascular disease, and overall prognosis, on which MS has a robustly demonstrated impact. Besides, a medical bypass as an alternative, salvage, or combination strategy to MS may promote precision medicine in obesity therapeutics.

Bariatric Surgery and Gut-Brain-Axis Driven Alterations in Cognition and Inflammation.

Obesity is associated with systemic inflammation, comorbidities like diabetes, cardiovascular disease and several cancers, cognitive decline and structural and functional brain changes. To treat, or potentially prevent these related comorbidities, individuals with obesity must achieve long-term sustainable weight loss. Often life style interventions, such as dieting and increased physical activity are not successful in achieving long-term weight loss. Meanwhile bariatric surgery has emerged as a safe and effective procedure to treat obesity. Bariatric surgery causes changes in physiological processes, but it is still not fully understood which exact mechanisms are involved. The successful weight loss after bariatric surgery might depend on changes in various energy regulating hormones, such as ghrelin, glucagon-like peptide-1 and peptide YY. Moreover, changes in microbiota composition and white adipose tissue functionality might play a role. Here, we review the effect of obesity on neuroendocrine effects, microbiota composition and adipose tissue and how these may affect inflammation, brain structure and cognition. Finally, we will discuss how these obesity-related changes may improve after bariatric surgery.

Oral glucose has little or no effect on appetite and satiety sensations despite a significant gastrointestinal response.

OBJECTIVE: The effect of oral glucose-induced release of gastrointestinal hormones on satiety and appetite independently of prevailing plasma glucose excursions is unknown. The objective is to investigate the effect of oral glucose on appetite and satiety sensations as compared to isoglycemic IV glucose infusion (IIGI) in healthy volunteers. DESIGN: A crossover study involving two study days for each participant. PARTICIPANTS: Nineteen healthy participants (6 women, mean age 55.1 [SD 14.2] years; mean body mass index 26.7 [SD 2.2] kg/m2). INTERVENTIONS: Each participant underwent a 3-h 50-g oral glucose tolerance test (OGTT) and, on a subsequent study day, an IIGI mimicking the glucose excursions from the OGTT. On both study days, appetite and satiety were indicated regularly on visual analog scale (VAS), and blood was drawn regularly for measurement of pancreatic and gut hormones. PRIMARY OUTCOMES: Difference in appetite and satiety sensations during OGTT and IIGI. RESULTS: Circulating concentrations of glucose-dependent insulinotropic polypeptide (P < .0001), glucagon-like peptide 1 (P < .0001), insulin (P < .0001), C-peptide (P < .0001), and neurotensin (P = .003) increased significantly during the OGTT as compared to the IIGI, whereas glucagon responses were similarly suppressed (P = .991). Visual analog scale-assessed ratings of hunger, satiety, fullness, thirst, well-being, and nausea, respectively, were similar during OGTT and IIGI whether assessed as mean 0-3-h values or area under the curves. For both groups, a similar, slow increase in appetite and decrease in satiation were observed. Area under the curve, for prospective food consumption (P = .049) and overall appetite score (P = .044) were slightly lower during OGTT compared to IIGI, whereas mean 0-3-h values were statistically similar for prospective food consumption (P = .053) and overall appetite score (P = .063). CONCLUSIONS: Despite eliciting robust responses of appetite-reducing and/or satiety-promoting gut hormones, we found that oral glucose administration has little or no effect on appetite and satiety as compared to an IIGI, not affecting the release of appetite-modulating hormones. TRIAL REGISTRY NO: ClinicalTrials.gov: NCT01492283 and NCT06064084.

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment.

AIMS: Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and polycystic ovarian syndrome (PCOS). Recently, gut hormones and their receptors have been identified in various reproductive organs indicating their potential regulatory effects on reproductive function. This review aims to give an overview of their potential effects. METHODS: This review focuses on literature that outlines modifications during obesity, diabetes and related infertility with an emphasis on gut hormones and their therapeutic potential. RESULTS: Evidence suggests that bariatric surgery has positive effects on fertility and PCOS where major alterations in metabolism occurs through restoration of gut hormone levels. This is thought to be due to the indirect effect weight loss and regulation of blood glucose has on the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axis influencing reproduction. CONCLUSIONS: Further research is required to elucidate the cellular mechanisms involved in the direct effects of gut hormone receptor activation on reproductive tissues. Current observations suggest a therapeutic role for gut hormones in infertility/PCOS associated with metabolic pathophysiology.

An Association between Decreased Small Intestinal RNA Modification and Disturbed Glucagon-like Peptide-1 Secretion under High-Fat Diet Stress.

Unhealthy diets rich in fats and/or sugar are considered as the major external cause of the obesity epidemic, which is often accompanied by a significant decrease in gut hormone glucagon-like peptide-1 (GLP1) levels. Numerous studies have demonstrated notable contributions of the gut microbiota in this process. Nevertheless, the underlying mechanism still needs further investigation. The role of epigenetic modifications in gene expression and metabolism has been well demonstrated, with m6A methylation on RNAs being the most prevalent modification throughout their metabolism. In the present study, we found that the expressions of small intestinal Gcg and Pc3, two key genes regulating GLP1 expression, were significantly downregulated in obese mice, associated with reduced GLP1 level. Immunohistochemistry analysis indicated that a high-fat diet slightly increased the density of enteroendocrine L cells in the small intestine, implying that decreased GLP1 levels were not caused by the changes in L cell intensity. Instead, the small intestinal m6A level as well as the expression of known "writers", mettl3/14 and wtap, were found to be positively correlated with the expression of Gcg and Pc3. Fecal microbiota transplantation with feces from normal and obese mice daily to antibiotic-treated mice revealed that dysbiosis in diet-induced obesity was sufficient to reduce serum GLP1, small intestinal m6A level, and intestinal expressions of Gcg, Pc3, and writer genes (mettl3/14, wtap). However, as the most direct and universal methyl donor, the production of fecal S-adenosylmethionine was neither affected by the different dietary patterns nor their shaped microbiota. These results suggested that microbial modulation of the epitranscriptome may be involved in regulating GLP1 expression, and highlighted epitranscriptomic modifications as an additional level of interaction between diet and individual health.

Endogenous Ghrelin Levels and Perception of Hunger: A Systematic Review and Meta-Analysis.

BACKGROUND: Ghrelin is an orexigenic hormone primarily released by the stomach and has 2 isoforms: acylated ghrelin (AG) and de-acylated ghrelin (DAG), that appear to have different functions in humans. OBJECTIVES: To perform a systematic review and meta-analysis of the association between plasma concentrations of total ghrelin (TG), AG, and DAG and perceptions of hunger in healthy adults. METHODS: The following criteria were used for inclusion: 1) sample contained adults ≥18 y of age, 2) body mass index [BMI kg/m2] was ≥18.5, 3) ghrelin was sampled through blood, 4) subjective hunger was measured on a validated scale, 5) study reported a Pearson product correlation of ghrelin or had relevant figure(s) for data extraction, 6) participants were healthy with no overt disease, 7) protocols contained no physical activity or weight loss medication that suppressed appetite, 8) interventions were conducted without environmental manipulations. Moderators assessed were age, BMI, percentage of body fat (%BF), macronutrient content of test meals, energy intake (kcals), sex, and ghrelin isoform (AG, DAG, or TG). RESULTS: The analysis included 47 studies (110 trials, n = 1799, age: 31.4 ± 12.0 y, BMI: 26.0 ± 4.75 kg/m2) and measured AG (n = 47 trials), DAG (n = 12 trials), and TG (n = 51 trials). The overall model indicated that ghrelin concentrations and perceptions of hunger were moderately correlated (r = 0.43, P < 0.001), and ghrelin isoform significantly moderated this relationship (AG: r = 0.60, P < 0.001; TG: r = 0.215, P = 0.01; DAG: r = 0.53, P = 0.695). Other significant moderators included age (b = -0.02, P = 0.01), BMI (b = -0.03, P = 0.05), %BF (b = -0.03, P = 0.05), energy intake (b = 0.0003, P = 0.04), and percentage of carbohydrates of test meals (b = 0.008, P = 0.05). CONCLUSIONS: Ghrelin is associated with perceptions of hunger in humans, and this relationship is strengthened when AG is isolated; thus, AG may have a large impact on hunger signals in various populations. Future research should attempt to understand the role of DAG in hunger sensations.

Discordance between gut-derived appetite hormones and energy intake in humans.

Gut-derived hormones affect appetite and are thought to play an important role in body weight regulation. Dietary macronutrient composition can influence gut-derived appetite hormone concentrations, thereby providing theoretical basis for why some diets might facilitate weight loss better than others. We investigated postprandial gut-derived appetite hormones in 20 inpatient adults after 2 weeks of eating either a low carbohydrate (LC) or a low fat (LF) diet followed by the alternate diet in random order. A LC meal resulted in significantly greater postprandial GLP-1, GIP, and PYY but lower ghrelin compared to an isocaloric LF meal (all p≤0.02). However, differences in gut-derived appetite hormones were incommensurate with subsequent ad libitum energy intake over the rest of the day, which was 551±103 kcal (p<0.0001) greater with the LC as compared to the LF diet. The effects of gut-derived appetite hormones on ad libitum energy intake can be dominated by other diet-related factors, at least in the short-term.

Future therapies for obesity.

Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.

Distinct adaptations of endocrine and cognitive functions may contribute to high variability in long-term weight loss outcome after bariatric surgery.

BACKGROUND: Bariatric surgery has been widely recognized as the most efficient long-term treatment method in severe obesity, yet therapy success shows considerable interindividual variability. Postoperative metabolic adaptations, including improved gut hormone secretion (GLP-1, PYY and ghrelin), and restored executive function may play an explanatory role in weight loss, yet causes for poor success in individual patients remain unknown. This study investigates gut-hormonal and cognitive characteristics in extreme weight loss responders to bariatric surgery. METHODS: Patients (n = 47) with high or low excessive weight loss (EWL) at least 2 years after Roux-en-Y-gastric bypass or sleeve gastrectomy were allocated into good responders (GR, EWL 82.4 ± 11.6%) and poor responders (PR, EWL 24.0 ± SD 12.8%) to study differences in postprandial secretion of GLP-1, PYY, ghrelin and in working memory (WM). RESULTS: Mean BMI was 47.1 ± 6.2 kg/m² in PR (n = 21) and 28.9 ± 3.1 kg/m² in GR (n = 26, p < 0.001). Fasted GLP-1 and PYY were comparable for GR and PR (p > 0.2) and increased strongly after a standardized test meal (300 kcal liquid meal) with a peak at 15 to 30 min. The increase was stronger in GR compared to PR (GLP-1, PYY: Time x Group p < 0.05). Plasma ghrelin levels already differed between groups at fasted state, showing significantly higher levels for GR (p < 0.05). Postprandially, ghrelin secretion was suppressed in both groups, but suppression was higher in GR (Time x Group p < 0.05). GR showed significantly higher WM scores than PR (p < 0.05). Postprandial ghrelin (iAUC), but not GLP-1 or PYY plasma levels, significantly mediated the relationship between EWL and a WM subscore (IS score, CI = 0.07 - 1.68), but not WM main score (MIS score, CI = -0.07 - 1.54), in mediation analyses. CONCLUSION: Excess weight loss success after bariatric surgical procedures is associated with distinct profiles of gut-hormones at fasted and postprandial state, and differences in working memory. Better working memory performance in GR might be mediated by higher postprandial reduction in ghrelin plasma levels. Future studies need to integrate longitudinal data, larger samples and more sensitive cognitive tests.