The interplay between the gut microbiota and gastrointestinal hormones plays a pivotal role in the health of the host and the development of diseases. As a vital component of the intestinal microecosystem, the gut microbiota influences the synthesis and release of many gastrointestinal hormones through mechanisms such as modulating the intestinal environment, producing metabolites, impacting mucosal barriers, generating immune and inflammatory responses, and releasing neurotransmitters. Conversely, gastrointestinal hormones exert feedback regulation on the gut microbiota by modulating the intestinal environment, nutrient absorption and utilization, and the bacterial biological behavior and composition. The distributions of the gut microbiota and gastrointestinal hormones are anatomically intertwined, and close interactions between the gut microbiota and gastrointestinal hormones are crucial for maintaining gastrointestinal homeostasis. Interventions leveraging the interplay between the gut microbiota and gastrointestinal hormones have been employed in the clinical management of metabolic diseases and inflammatory bowel diseases, such as bariatric surgery and fecal microbiota transplantation, offering promising targets for the treatment of dysbiosis-related diseases.

The enteric nervous system (ENS) is a highly conserved, yet complicated network of neurons and glial cells located throughout the gut wall that controls digestive processes and gastrointestinal (GI) homeostasis. The intestinal epithelium, the immune system, and the gut microbiota are just a few examples of the cellular networks that the ENS interacts with on a variety of levels to maintain GI function. The presence or absence of nutrients in the intestinal lumen may cause short- and/or long-term changes in neurotransmitter expression, excitability, and neuronal survival, which ultimately affect gut motility, secretion, and permeability. Hence, the ENS should be identified as a key factor in initiating coordinated responses to nutrients. In this review we summarize current knowledge on nutrient-dependent ENS activity and how ENS secondary to nutrition may affect likelihood of developing inflammatory bowel disease. Our findings highlight that nutrients interact with enteroendocrine cells in the gut, triggering hormone secretion that plays a crucial role in signaling food-related information to the brain and regulating metabolic processes such as feeding behavior, insulin secretion, and energy balance; however, the complex interactions between nutrients, the ENS, and the immune system require further research to understand their contributions to GI disorders and potential therapeutic applications in treating obesity and metabolic diseases. Lay Summary: The enteric nervous system (ENS) controls digestion and interacts with nutrients in the gut to regulate processes like gut movement and hormone release, affecting metabolism and overall gut health. This review highlights the need for further research on how nutrient-ENS interactions contribute to conditions like inflammatory bowel disease, obesity, and metabolic disorders.

Background: Roux-en-Y gastric bypass (RYGB) surgery results in weight reduction and decreased energy intake and can ameliorate type 2 diabetes. These beneficial effects are usually attributed to changes in hunger and satiety and relatively rapid improvements in glycemic control, but these effects may depend on dietary adherence. The aim of this study is to investigate the relatively early effects of RYGB surgery on weight reduction (by focusing on eating patterns) and glycemic control in rats subjected to a healthy maintenance diet or an unhealthy Western-style diet. Methods: Rats were fed a high-fat diet with added sucrose (HF/S) or a low-fat (LF) diet. Body weight, high-resolution tracking of meal-related parameters, and glucose regulation after overnight fasting and during a mixed meal tolerance test (MMTT; 2 mL sweet/condensed milk) were measured before and after RYGB (RYGB+) or sham surgery (RYGB-). Results: HF/S feeding led to an increased body weight just before RYGB surgery, but it also caused enhanced weight loss following RYGB, which led to similar body weights in the HF/S and LF diet groups twenty-four days post-operatively. RYGB surgery and diet dependently and independently influenced meal-related parameter outcomes, where both RYGB+ and HF/S feeding resulted in shorter meal duration (p < 0.01), higher ingestion rates (p < 0.001), and increased satiety ratio (p < 0.05), especially in the HF/S diet group subjected to RYGB. While RYGB surgery generally improved baseline glycemic parameters including HOMA-IR (p < 0.01), it often interacted with diet to affect MMTT-induced hyperglycemia (p < 0.05), beta-cell sensitivity (p < 0.01), and the insulinogenic index (p < 0.01), with the LF rats overall maintaining better glycemic control than the HF/S-fed rats. Conclusions: This study shows the importance of controlling diet after RYGB surgery, as diet type significantly influences ingestive behavior, post-prandial glucose regulation, beta-cell sensitivity, and glucose tolerance after RYGB.

Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.

Quinine, when administered intraduodenally to activate bitter-taste receptors, in a dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1) and insulin, slows gastric emptying and lowers postprandial glucose in healthy people, with consequent implications for the management of type 2 diabetes; the effect of quinine on energy intake is uncertain. We have investigated the dose-related effects of quinine on postprandial blood glucose levels and energy intake in people with type 2 diabetes.

Male participants with type 2 diabetes (age: 68±5 years; HbA1c: 49.0±5.0 mmol/mol [6.7±0.4%], BMI: 30±1 kg/m2) received in two study parts (A and B, n=12 each), on three separate occasions each, in randomised, crossover fashion, control, or 300 mg (QHCl-300) or 600 mg (QHCl-600) quinine hydrochloride, intraduodenally 30 min before a nutrient drink (2092 kJ, 74 g carbohydrate) (part A) or a standardised buffet-lunch (part B). Both the participants and investigators performing the study procedures were blinded to the treatments. In part A, plasma glucose, GLP-1, C-peptide and glucagon were measured at baseline, for 30 min after quinine alone and for 3 h post drink. Gastric emptying of the drink was measured with a 13C-acetate breath test. In part B, energy intake from the buffet-lunch was quantified.

Quinine alone had no effect. Post drink, both quinine doses reduced peak plasma glucose markedly (QHCl-600 by 2.8±0.6 mmol/l) and slowed gastric emptying (all p<0.05; n=12, except for gastric emptying, n=11). QHCl-600, but not QHCl-300, stimulated plasma GLP-1 and C-peptide modestly (both p<0.05). Quinine did not affect energy intake.

In type 2 diabetes, acute intraduodenal administration of quinine markedly reduces the plasma glucose response to oral carbohydrate, but does not affect energy intake. These findings support the potential use of quinine to reduce postprandial blood glucose levels in type 2 diabetes.

anzctr.org.au ACTRN12620000972921/ACTRN12621000218897 FUNDING: The study was funded by a Diabetes Australia Research Project Grant.

L-tryptophan ("Trp") and L-leucine ("Leu"), when administered intraduodenally, increase plasma cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) and stimulate pyloric pressures, which all slow gastric emptying and suppress subsequent energy intake. The circulating Trp-to-large-neutral-amino-acids ("Trp/LNAAs") ratio is also inversely related to energy intake.

This exploratory study characterized the impact of standardized changes in the plasma Trp/LNAAs ratio, achieved by combining a fixed-load intraduodenal infusion of Trp with increasing loads of Leu, on the appetite-inhibitory effects of enteral Trp.

Twelve males of normal weight [mean ± standard deviation; age: 23 ± 2 y; body mass index (in kg/m2: 23±1)], received on 4 separate occasions, 90-min iso-osmotic intraduodenal infusions of 1) isotonic 0.9% saline ("control"), 2) Trp (0.15 kcal/min; "Trp"), 3) Trp + Leu (0.22 kcal/min; "Trp+Leu-0.22"), or 4) Trp + Leu (0.45 kcal/min; "Trp+Leu-0.45"), in a randomized, double-blind, cross-over fashion. Immediately postinfusion ad-libitum energy intake was quantified. Plasma CCK, GLP-1, amino acid concentrations, and antropyloroduodenal pressures were measured throughout.

Although there was a transient stimulation of CCK and GLP-1 by Trp + Leu - 0.45 (at t = 15 min), only Trp led to a sustained increase in plasma CCK (P = 0.04) and GLP-1 (P = 0.009) from t = 60-90 min, and stimulated pyloric pressures (P = 0.01), compared with control. Only Trp reduced energy intake [kcal (mean ± standard error of the mean); control: 1085 ± 49, Trp: 881 ± 75, Trp + Leu - 0.22: 963 ± 57, Trp + Leu - 0.45: 932 ± 60] compared with control (P = 0.008). The Trp/LNAAs ratio was dose-dependently decreased by Trp + Leu - 0.22 and Trp + Leu - 0.45, compared with Trp (all P = 0.001), and energy intake correlated inversely with the Trp/LNAAs ratio (R = -0.38; P = 0.02).

Acute reduction in the Trp/LNAAs ratio appears to be associated with a diminished capacity of Trp to stimulate CCK and GLP-1 and suppress energy intake. Although these observations should be interpreted with caution given the exploratory nature of the study, they attest to the complexity of the relationships between pre and postabsorptive mechanisms underlying Trp's appetite-inhibitory effect. This trial was registered at the Australian New Zealand clinical trial registry as ACTRN12620001275954.

Diet, physical function and gut health are important modifiable factors in ageing. However, it is unclear how ageing affects various domains of gut function. Aims of this cross-sectional study were to explore relationships between nutrient intake, physical function, and biomarkers of gut function in older individuals. Healthy participants (n = 94, mean age 71.1 years SD 5.10, 56% female) were recruited to investigate the relationship between nutrient intake (protein, fibre, carbohydrate, fat), physical function (chair rise time, handgrip strength) and lipopolysaccharide (LPS) binding protein (LBP); a marker of gut permeability. Linear regression models, adjusted for age, fat mass/fat free mass ratio, weight and gender, reported LBP changed by; -161.9 ng/mL (95% CI -323.0, -0.8) for every 1 g increase in daily fibre/1,000 kilocalories; 80.5 ng/mL (6.7, 154.2) for 1% increase in daily energy intake as fat; and -88.1 ng/mL (-146.7, -29.6) for 1% increase in daily energy as carbohydrates. When further adjusted for C-reactive protein (CRP), a marker of inflammation, LBP decreased by an additional 6.9 ng/mL for fibre, increased by an additional 4.0 ng/mL for fat and decreased by an additional 3.7 ng/mL for carbohydrate. These findings suggest that in healthy older adults' nutrient intake is associated with LBP, and CRP appears to slightly modify these associations. There were no associations between LBP and handgrip strength or chair rise time. Results suggest that fibre, fat, and carbohydrates are important for maintaining gut function, potentially mediated by inflammation in older adults, although further research is needed to explore the implications for physical function and CRP as a mediator.

The crisis of metabolic and mental disorders continues to escalate worldwide. A growing body of research highlights the influence of tryptophan and its metabolites, such as serotonin, beyond their traditional roles in neural signaling. Serotonin acts as a key neurotransmitter within the brain-gut-microbiome axis, a critical bidirectional communication network affecting both metabolism and behavior. Emerging evidence suggests that the gut microbiome regulates brain function and behavior, particularly through microbial influences on tryptophan metabolism and the serotonergic system, both of which are essential for normal functioning. Additionally, sex differences exist in multiple aspects of serotonin-mediated modulation within the brain-gut-microbiome axis, affecting feeding and affective behaviors. This review summarizes the current knowledge from human and animal studies on the influence of tryptophan and its metabolite serotonin on metabolic and behavioral regulation involving the brain and gut microbiome, with a focus on sex differences and the role of sex hormones. We speculate that gut-derived tryptophan and serotonin play essential roles in the pathophysiology that modifies neural circuits, potentially contributing to eating and affective disorders. We propose the gut microbiome as an appealing therapeutic target for metabolic and affective disorders, emphasizing the importance of understanding sex differences in metabolic and behavioral regulation influenced by the brain-gut-microbiome axis. The therapeutic targeting of the gut microbiota and its metabolites may offer a viable strategy for treating serotonin-related disorders, such as eating and affective disorders, with potential differences in treatment efficacy between men and women. This review would promote research on sex differences in metabolic and behavioral regulation impacted by the brain-gut-microbiome axis.

Background: Obesity is a multifactorial disease with detrimental effects on health and quality of life; unregulated satiety plays a crucial role in food intake and obesity development. Naringenin (NAR) has shown beneficial effects on lipid and carbohydrate metabolism, although its impact on adiposity and satiety remains unclear. This study reports a Western diet (WD)-induced obesity model in rats, wherein 100 mg/kg of NAR was administered as an anti-obesity agent for 8 weeks; oxidative stress, lipid profile, and satiety biomarkers were then studied, as well as in silico interaction between NAR and cholecystokinin (CCK) and ghrelin receptors. Results: NAR supplementation resulted in a significant decrease in retroperitoneal adipose tissue and liver weight, as compared to the untreated WD group (p < 0.05), potentially associated with a decreased feed efficiency. NAR also inhibited the development of dyslipidemia, particularly by reducing serum triglycerides (p < 0.05). NAR supplementation increased CCK serum levels in the basal diet group, an effect that was abolished by the WD (p < 0.05); likewise, no changes were determined on ghrelin (p > 0.05). In silico data shows that NAR is capable of interacting with the CCK and ghrelin receptors, which suggests a potential for it to modulate hunger/satiety signaling by interacting with them. Conclusions: We conclude that NAR has anti-obesogenic effects and may regulate CCK serum levels, although further research is still needed.

The oral administration of linoleic acid immediately before glucose tolerance test (OGTT) ameliorated postprandial hyperglycemia via GPR120 pathway in normal and type 1 diabetes (T1DM) rats. Linoleic acid could promote inflammatory mediators, but 10-hydroxy-cis-12-octadecenoic acid (HYA) converted from linoleic acid by Lactobacillus plantarum has higher GPR120 agonistic activity without promoting inflammatory mediators. This study examined whether the oral-administration of HYA immediately before OGTT also ameliorated the postprandial hyperglycemia in normal rats and T1DM rats injected with bolus insulin.

Normal and T1DM male Sprague-Dawley rats received HYA immediately before OGTT. Other T1DM rats were given HYA and Humulin R immediately before OGTT. We measured the concentration of glucose, insulin, glucagon-like peptide 1 (GLP-1) and cholecystokinin in blood before and after OGTT. We also measured the amount of glucose in the gastric tract after OGTT, and the amount of uptake of methyl-α-D-glucopyranoside in CACO-2 cells.

Postprandial hyperglycemia was ameliorated by HYA in normal rats, and the postprandial blood glucose levels were slowly elevated by HYA in the T1DM model rats. HYA partially inhibited the uptake of methyl-α-D-glucopyranoside in CACO-2 cells. HYA slowed gastric motility and increased the plasma GLP-1 and cholecystokinin levels in normal rats. HYA also ameliorated the postprandial hyperglycemia in T1DM rats given bolus insulin.

Oral administration of HYA immediately before OGTT ameliorated postprandial hyperglycemia through inhibition of glucose absorption and slowing of gastric motility in normal rats. Furthermore, this beneficial effect of HYA was also revealed in T1DM rats injected with bolus insulin.

Long-term weight loss outcomes are contrasting between bariatric surgery and dietary restriction alone. This is the first study to investigate changes in gastrointestinal (GI) hormones involved in appetite regulation, and subjective appetite feelings, at 1-year follow-up, after initial weight loss induced by a very-low energy (VLED) alone (controls), or with bariatric surgery.

Patients scheduled for Sleeve Gastrectomy (SG) (n = 19) or Roux-en-Y gastric Bypass (RYGB) (n = 19), and controls (n = 16) were recruited. All groups underwent 10 weeks of a VLED (initial phase), followed by a 9-month maintenance phase. Body weight/composition, plasma concentrations of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), and appetite ratings were measured before and after a meal, at baseline, week 11(W11), and 1Y follow-up.

Participants who completed all three follow ups were included in the analysis. Initial changes in body weight/composition were comparable across groups. SG (n = 11) and RYGB (n = 12) continued to lose weight from W11 to 1Y, whereas controls (n = 12) had regained weight. Postprandial GLP-1 increased over time post bariatric surgery and remained unchanged and lower in controls. Postprandial PYY increased in all groups, but greatest post-RYGB. Basal ghrelin decreased over time post-SG, while a small or marked increase was seen after RYGB and diet, respectively, with the control group exhibiting the greatest basal and postprandial concentrations at 1Y. A reduction in basal and postprandial CCK was seen in controls at 1Y, while no changes were observed post-bariatric surgery. Overall, small changes in subjective appetite ratings were seen over time.

Weight change at 1Y follow up after SG and RYGB is followed by a GI hormone profile favoring a lower drive to eat and increased satiety. The opposite is seen 1Y after WL induced by dietary restriction alone.

clinicaltrials.gov NCT04051190.

Obesity, often caused by disorders of lipid metabolism, is a global health concern. Flavonoids from staple grains and legumes are expected as a safer and more cost-effective alternative for the future development of dietary flavonoid-based anti-obesity dietary supplements or drugs. This review systematically summarized their content variation, metabolism in the human body, effects and molecular mechanisms on lipid metabolism. These flavonoids intervene in lipid metabolism by inhibiting lipogenesis, promoting lipolysis, enhancing energy metabolism, reducing appetite, suppressing inflammation, enhancing insulin sensitivity, and improving the composition of the gut microbial. Fermentation and sprouting techniques enhance flavonoid content and these beneficial effects. The multidirectional intervention of lipid metabolism is mainly through regulating AMPK signaling pathway. This study provides potential improvement for challenges of application, including addressing high extraction costs and improving bioavailability, ensuring safety, filling clinical study gaps, and investigating potential synergistic effects between flavonoids in grains and legumes, and other components.

Dumping syndrome is a complex of gastrointestinal symptoms originally studied in peptic ulcer surgery patients. At present, it is most prevalent in patients who underwent bariatric, upper gastrointestinal cancer or anti-reflux surgery. The symptom pattern comprises early and late dumping symptoms. Several management options have been reported including nutritional, pharmacological and surgical approaches.

In this study, we aimed to review the current evidence on dumping syndrome definition, diagnosis and treatment, including preliminary data from newer pharmacological studies.

Current pathophysiological concepts and analyses of provocative tests has led to a clear definition of dumping syndrome, including both early and late dumping symptoms. The term postbariatric hypoglycemia represents a limited focus on late dumping only. The diagnosis relies on recognition of symptoms and signs in a patient with appropriate surgical history; and can be confirmed by provocative testing or registration of spontaneous hypoglycemia. The initial treatment focuses on dietary intervention, to which meal viscosity enhancers and/or the glycosidase inhibitor acarbose can be added. The most effective therapy is the use of short- or long-acting somatostatin analogues, which is however expensive and entails side effect issues. In case of refractory hypoglycemia, diazoxide or SGLT2 inhibitors can be considered, based on limited evidence. In refractory patients, continuous enteral feeding or (rarely) surgical reinterventions have been advocated, although not supported by solid evidence. Therapies under current evaluation include the broad-spectrum somatostatin analogue pasireotide, GLP-1 receptor antagonists, GLP-1 receptor agonists and administration of stable forms of glucagon are currently under study.

Dumping syndrome is a well-defined but probably under-diagnosed complication of upper gastrointestinal, especially bariatric, and surgeries. Diagnosis is confirmed by a provocative test and incremental therapies starting with diet, adding meal viscosity enhancers or glycosidase inhibitors and adding somatostatin analogues in refractory cases. A number of emerging therapies targeting intestinal propulsion, peptide hormone effects and hypoglycemic events are under evaluation.

Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."

Metabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions.

PDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome.

The dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development.

These results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape.

Postoperative ileus (POI) is a common postoperative clinical complication that significantly affects postoperative rehabilitation and quality of life in patients and can even produce secondary complications, leading to serious consequences. External treatment using Shenhuang Plaster (SHP) (Shenque acupoint administration) has definite effects and unique advantages in the prevention and treatment of POI, but its mechanism is not completely clear. In this study, we investigated the therapeutic mechanism behind the effect of Shenhuang Plaster applied to the Shenque acupoint on gastrointestinal motility in POI mice based on metabolomics.

C57BL/6 mice were divided into three groups: blank control (Ctrl), model (POI), and intervention (POI + SHP) groups. SHP treatment was started 3 days before modeling. We employed several behavioral tests and gastrointestinal transit function measurements and performed qRT-PCR analysis, 16S rRNA gene sequencing, and metabolomics analysis on serum metabolites.

We found that SHP could reduce the mRNA expression of inflammatory mediators in the smooth muscle tissue of the small intestine, regulate the structure and function of the intestinal microbiota, and modulate serum phenylalanine, carnitine, and glutamic acid levels.

POI mice had obvious intestinal flora disorders and metabolic disorders of amino acids and their derivatives, and there was a significant correlation between differential flora and differential metabolites. SHP could effectively regulate the concentration of intestinal flora and serum metabolites and the metabolic pathway related to amino acids in vivo and, ultimately, achieve a therapeutic purpose in POI. In this study, it was found, for the first time, that applying SHP to the Shenque acupoint could effectively regulate the serum metabolites of phenylalanine, carnitine, and glutamate, and improve postoperative intestinal motile disturbance through association with the intestinal flora.

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.

Obesity is a global health concern. Progress in understanding the physiology of obesity and weight reduction has provided new drug targets. Development and testing of new antiobesity medications (AOMs) has the potential to quickly expand options for treatment. In this review, we briefly summarize the physiology of obesity and weight reduction, as well as medications currently approved for weight management. We highlight the increasing use of incretin and nutrient-stimulated hormone-based therapies. We conclude with an overview of AOMs progressing through the pipeline and discuss their implications for the rapidly evolving field of obesity management.

Notwithstanding the documented short- and long-term weight loss and remission of physical and mental diseases following bariatric surgery, a significant proportion of patients fail to respond (fully) to treatment in terms of physical and mental health improvement. Mounting evidence links food-specific impulsivity, prefrontal cortex (PFC) hypoactivity and disrupted hormone secretion in bariatric surgery candidates to poorer post-surgical health outcomes. Neuromodulatory treatments like transcranial direct current stimulation (tDCS) uniquely target these neurobehavioral impairments. We present a pilot study protocol offering tDCS combined with an inhibitory control training and a structured psychosocial intervention to patients after bariatric surgery.

A total of N = 20 patients are randomized to 6 sessions of verum or sham tDCS over the PFC, combined with an individualized food-specific inhibitory control training and a structured psychosocial intervention within 18 months after bariatric surgery (t0). Beyond acceptability, feasibility and satisfaction of the intervention, effects of verum versus sham tDCS on food-specific impulsivity and on secondary outcomes quality of life, general impulsivity and psychopathology, food-related cravings, eating disorder psychopathology, weight trajectory and endocrine markers are assessed 4 weeks (t1) and 3 months after the intervention (t2).

Results will provide information on the potential of combining tDCS with an inhibitory control training and a structured psychosocial intervention to enhance physical and mental outcomes after bariatric surgery. The present study may guide the development of future research with regard to tDCS as a brain-based intervention and of future post-surgical clinical programs, paving the way for randomized-controlled trials in larger samples.

The trial was prospectively registered on July 8, 2024, under the registration number DRKS00034620 in the German Clinical Trials Register ( https://drks.de/search/de/trial/DRKS00034620 ).

Obesity is a pandemic currently affecting the world's population that decreases the quality of life and promotes the development of chronic non-communicable diseases. Lactobacillus rhamnosus is recognized for multiple positive effects on obesity and overall health. In fact, such effects may occur even when the microorganisms do not remain alive (paraprobiotic effects). This raises the need to elucidate the mechanisms by which obesity-associated factors can be modulated. This narrative review explores recent findings on the effects of L. rhamnosus, particularly, its postbiotic and paraprobiotic effects, on the modulation of adiposity, weight gain, oxidative stress, inflammation, adipokines, satiety, and maintenance of intestinal integrity, with the aim of providing a better understanding of its mechanisms of action in order to contribute to streamlining its clinical and therapeutic applications. The literature shows that L. rhamnosus can modulate obesity-associated factors when analyzed in vitro and in vivo. Moreover, its postbiotic and paraprobiotic effects may be comparable to the more studied probiotic actions. Some mechanisms involve regulation of gene expression, intracellular signaling, and enteroendocrine communication, among others. We conclude that the evidence is promising, although there are still multiple knowledge gaps that require further study in order to fully utilize L. rhamnosus to improve human health.

The gut is traditionally recognized as the central organ for the digestion and absorption of nutrients, however, it also functions as a significant endocrine organ, secreting a variety of hormones such as glucagon-like peptide 1, serotonin, somatostatin, and glucocorticoids. These gut hormones, produced by specialized intestinal epithelial cells, are crucial not only for digestive processes but also for the regulation of a wide range of physiological functions, including appetite, metabolism, and immune responses. While gut hormones can exert systemic effects, they also play a pivotal role in maintaining local homeostasis within the gut. This review discusses the role of the gut as an endocrine organ, emphasizing the stimuli, the newly discovered functions, and the clinical significance of gut-secreted hormones. Deciphering the emerging role of gut hormones will lead to a better understanding of gut homeostasis, innovative treatments for disorders in the gut, as well as systemic diseases.

The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCKVMH). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCKVMH neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCKVMH neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCKVMH neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.

Stress predicts unhealthy eating, obesity, and metabolic deterioration, likely mediated by altered levels of appetite-regulating hormones. Yet, evidence regarding the association between long-term stress and levels of appetite-regulating hormones in humans is lacking.

We included 65 patients with obesity (44 women) to investigate the cross-sectional association of long-term biological stress (scalp hair cortisol and cortisone) and long-term psychological stress (Perceived Stress Scale) with overnight-fasted serum levels of the hormonal appetite regulators leptin, adiponectin, insulin, pancreatic polypeptide, gastric-inhibitory peptide, peptide tyrosine-tyrosine, cholecystokinin and agouti-related protein, adjusted for age, sex, and body mass index.

Hair cortisone and, in trend, hair cortisol were positively associated with cholecystokinin (p = 0.003 and p = 0.058, respectively). No other associations between stress measures and hormonal appetite regulators were observed.

Long-term biological stress, measured using scalp hair glucocorticoid levels, is associated with elevated levels of circulating cholecystokinin. More research is needed to pinpoint potential effects on appetite.

Extraoral bitter taste receptors offer intriguing potential for modulating metabolism and the gut-brain axis through dietary interventions. Our understanding of these receptors is limited, and data on their effects on ageing are scarce. The complexity conveyed by their high diversity, low expression levels and species-dependent variability challenges our comprehension. We used real-time PCR to examine the relative abundance of multiple TAS2R across different segments of gastrointestinal mucosa in four human cohorts and related them to enteroendocrine secretions at the colon site. TAS2R14 exhibited the highest expression levels in all analyzed tissues. In contrast, TAS2R39, -38 and -42 consistently exhibited lower expression levels. Ageing was found to upregulate TAS2R4, -5, -13, -20 and GLP-1 mRNA in the descending colon. Stimulating TAS2R14 in Hutu-80 cells induced GLP-1 secretion, while stimulating TAS2R5 modulated GLP-1 and PYY secretion. Given the modifications TAS2R agonists may undergo along the GIT, as well as the distinctive expression patterns and possible functional roles of TAS2R receptors along the intestinal tract, our findings suggest the viability of a targeted strategy aimed at enhancing specific functions to improve health outcomes. This study offers valuable insights into the intricate interplay between bitter taste receptors, gut physiology and potential dietary interventions.

Glucagon-like peptide-1 (GLP-1) plays a crucial role in regulating glucose homeostasis by stimulating insulin secretion and suppressing glucagon release. Our previous study observed that pea protein hydrolysate (PPH) exhibited the function of triggering GLP-1 secretion. However, the underlying mechanisms have not been revealed. Herein, the mechanisms of PPH-stimulated GLP-1 secretion were investigated in NCI-H716 cells. The PPH-induced GLP-1 secretion was reduced (p < 0.05) after adding the sensing receptor antagonists NPS-2143 and 4-AMBA, indicating that activation of both calcium-sensing receptor (CaSR) and peptide-transporter 1 (PepT1) was involved in PPH-triggered GLP-1 release. Moreover, the intracellular Ca2+ level increased by 2.01 times during the PPH-induced GLP-1 secretion. Similarly, the cAMP content also increased by 1.43 times after stimulation by PPH. The RT-qPCR results showed that PPH increased the gene expression of prohormone convertase 1/3 (PCSK-1) by 2.79-fold, which effectively promoted the conversion of proglucagon (GCG) to GLP-1. The specific pathway of PPH-induced GLP-1 secretion may involve both CaSR and PepT1 activation-induced Ca2+ influx and cAMP generation, which effectively enhanced the enzyme activity of prohormone convertase 1/3 (PCSK-1) and ultimately promoted GLP-1 secretion.

Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists.

The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity.

In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation.

Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.

Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity.

This study aimed at comparing the carbohydrate composition of three banana varieties (cv. Nanica, Nanicão, and Prata) and investigating the effect of a single dose of cooked green banana pulp beverage (GBPd) on plasma glycemic homeostasis indexes (glucose, PYY, GIP, insulin) and hunger and satiety sensation (visual analog scale-VAS). The bananas were classified according to the color scale. The fiber, total carbohydrate, and resistant starch (RS) were determined using validated methods. Glucose homeostasis indexes and hunger/satiety sensation were determined in ten healthy women in two stages before and after intake: (1) glucose solution (250 g/L); (2) one week later, consumption of the glucose solution plus 75 g/L of GBPd. Blood samples were collected twice in stage-1 and every 15 min for 2 h in stage-2. Cv. Nanicão was selected, because it presented a higher content in RS and dietary fiber on dry base than the other cultivars. Thus, it was used to test glycemic response. After 2 h of GBPd intake, no difference was observed in hunger/satiety sensation and plasma glycemic homeostasis indexes, except for a decrease in plasma glucose concentration (-15%, p = 0.0232) compared to stage-1. These results suggest that cv. Nanicão has a higher potential as a functional ingredient and can influence the reduction in the glycemic index of a meal compared to other cultivars. However, it had not a short-term effect on hormones GIP and PYY in healthy women. Further research is needed to understand the long-term effects and mechanisms of green banana on glycemic control and satiety.

In humans, intraduodenal infusion of L-tryptophan (Trp) increases plasma concentrations of gastrointestinal hormones and stimulates pyloric pressures, both key determinants of gastric emptying and associated with potent suppression of energy intake. The stimulation of gastrointestinal hormones by Trp has been shown, in preclinical studies, to be enhanced by extracellular calcium and mediated in part by the calcium-sensing receptor.

This study aim was to determine whether intraduodenal calcium can enhance the effects of Trp to stimulate gastrointestinal hormones and pyloric pressures and, if so, whether it is associated with greater suppression of energy intake, in healthy males.

Fifteen males with normal weight (mean ± standard deviation; age: 26 ± 7 years; body mass index: 22 ± 2 kg/m2), received on 3 separate occasions, 150-min intraduodenal infusions of 0, 500, or 1000 mg calcium (Ca), each combined with Trp (load: 0.1 kcal/min, with submaximal energy intake-suppressant effects) from t = 75-150 min, in a randomized, double-blind, crossover study. Plasma concentrations of GI hormones [gastrin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and peptide tyrosine-tyrosine (PYY)], and Trp and antropyloroduodenal pressures were measured throughout. Immediately postinfusions (t = 150-180 min), energy intake at a standardized buffet-style meal was quantified.

In response to calcium alone, both 500- and 1000-mg doses stimulated PYY, while only the 1000-mg dose stimulated GLP-1 and pyloric pressures (all P < 0.05). The 1000-mg dose also enhanced the effects of Trp to stimulate cholecystokinin and GLP-1, and both doses stimulated PYY but, surprisingly, reduced the stimulation of GIP (all P < 0.05). Both doses substantially and dose dependently enhanced the effects of Trp to suppress energy intake (Ca-0+Trp: 1108 ± 70 kcal; Ca-500+Trp: 961 ± 90 kcal; and Ca-1000+Trp: 922 ± 96 kcal; P < 0.05).

Intraduodenal administration of calcium enhances the effect of Trp to stimulate plasma cholecystokinin, GLP-1, and PYY and suppress energy intake in healthy males. These findings have potential implications for novel nutrient-based approaches to energy intake regulation in obesity. The trial was registered at the Australian New Zealand Clinical Trial Registry (www.anzctr.org.au) as ACTRN12620001294943).

In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the <1 kDa peptide fraction from TBSH (TBP) exhibited a more potent DPP-IV inhibitory effect (IC50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.

Smoking cessation is crucial for reducing complications of type 2 diabetes mellitus (T2DM), but associated weight gain can worsen glycemic control, discouraging quitting attempts. Varenicline, a partial agonist of α4β2 nicotinic receptors, aids smoking cessation. This study examines the effects of varenicline on body weight and metabolic parameters in patients with T2DM and prediabetes.

Fifty-three patients were enrolled, of which 32 successfully quit smoking after a three-month course of varenicline and were examined after an additional month with no medication. Measurements taken at baseline, 2.5 months, and 4 months included body weight, blood pressure, resting metabolic rate (RMR), glycated hemoglobin (HbA1c), fasting glucose, blood lipids, C-reactive protein (CRP), appetite-related hormones, and physical activity.

Post-treatment, there were no significant changes in body weight, blood pressure, RMR, or glycemic control. Total (CHOL) and low-density lipoprotein (LDL-C) cholesterol decreased significantly at 4 months of the study (from 168 to 156 mg/dL, p = 0.013, and from 96 to 83 mg/dL, p = 0.013, respectively). Leptin levels increased (from 11 to 13.8 ng/dL, p = 0.004), as did glucagon-like peptide-1 (GLP-1) levels (from 39.6 to 45.8 pM, p = 0.016) at 4 months of follow-up. The percentage of participants who reported moderate-intensity activity increased from 28% to 56%, while those reporting high-intensity activity increased from 19% to 22%, respectively (p = 0.039).

Our study showed that smoking cessation with varenicline in smokers with T2DM and prediabetes led to significant improvements in lipid profile, significant increase in plasma leptin and GLP-1 levels, and increased physical activity, without significant weight gain. Thus, smoking cessation without weight gain or deteriorated glycemic control is feasible for these smokers, with added benefits to lipid profiles, GLP-1 regulation, and physical activity.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

While clinical studies indicate that dietary protein may benefit glucose homeostasis in type 2 diabetes (T2D), the impact of dietary protein, including whether the protein is of animal or plant origin, on the risk of T2D is uncertain. We conducted a systematic review and meta-analysis to evaluate the associations of total, animal, and plant protein intakes with the risk of T2D.

A systematic search was performed using multiple data sources, including PubMed/Medline, ISI Web of Science, Scopus, and Google Scholar, with the data cut-off in May 2023. Our selection criteria focused on prospective cohort studies that reported risk estimates for the association between protein intake and T2D risk. For data synthesis, we calculated summary relative risks and 95% confidence intervals for the highest versus lowest categories of protein intake using random-effects models. Furthermore, we conducted both linear and non-linear dose-response analyses to assess the dose-response associations between protein intake and T2D risk.

Sixteen prospective cohort studies, involving 615,125 participants and 52,342 T2D cases, were identified, of which eleven studies reported data on intake of both animal and plant protein. Intakes of total (pooled effect size: 1.14, 95% CI: 1.04-1.24) and animal (pooled effect size: 1.18, 95% CI: 1.09-1.27) protein were associated with an increased risk of T2D. These effects were dose-related - each 20-g increase in total or animal protein intake increased the risk of T2D by ∼3% and ∼7%, respectively. In contrast, there was no association between intake of plant protein and T2D risk (pooled effect size: 0.98, 95% CI: 0.89-1.08), while replacing animal with plant protein intake (per each 20 g) was associated with a reduced risk of T2D (pooled effect size: 0.80, 95% CI: 0.76-0.84).

Our findings indicate that long-term consumption of animal, but not plant, protein is associated with a significant and dose-dependent increase in the risk of T2D, with the implication that replacement of animal with plant protein intake may lower the risk of T2D.

In recent years, there has been a gradual increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM), with bariatric surgery remaining the most effective treatment strategy for these conditions. Vertical sleeve gastrectomy (VSG) has emerged as the most popular surgical procedure for bariatric/metabolic surgeries, effectively promoting weight loss and improving or curing T2DM. The alterations in the gastrointestinal tract following VSG may improve insulin secretion and resistance by increasing incretin secretion (especially GLP-1), modifying the gut microbiota composition, and through mechanisms dependent on weight loss. This review focuses on the potential mechanisms through which the enhanced action of incretin and metabolic changes in the digestive system after VSG may contribute to the remission of T2DM.

It is well established that high-protein diets (i.e. ~25-30% of energy intake from protein) provide benefits for achieving weight loss, and subsequent weight maintenance, in individuals with obesity, and improve glycemic control in type 2 diabetes (T2D). These effects may be attributable to the superior satiating property of protein, at least in part, through stimulation of both gastrointestinal (GI) mechanisms by protein, involving GI hormone release and slowing of gastric emptying, as well as post-absorptive mechanisms facilitated by circulating amino acids. In contrast, there is evidence that the beneficial effects of greater protein intake on body weight and glycemia may only be sustained for 6-12 months. While both suboptimal dietary compliance and metabolic adaptation, as well as substantial limitations in the design of longer-term studies are all likely to contribute to this contradiction, the source of dietary protein (i.e. animal vs. plant) has received inappropriately little attention. This issue has been highlighted by outcomes of recent epidemiological studies indicating that long-term consumption of animal-based protein may have adverse effects in relation to the development of obesity and T2D, while plant-based protein showed either protective or neutral effects. This review examines information relating to the effects of dietary protein on appetite, energy intake and postprandial glycemia, and the relevant GI functions, as reported in acute, intermediate- and long-term studies in humans. We also evaluate knowledge relating to the relevance of the dietary protein source, specifically animal or plant, to the prevention, and management, of obesity and T2D.

Metabolic syndrome refers to the pathological state of metabolic disorder of protein, fat, carbohydrate, and other substances in the human body. It is a syndrome composed of a group of complex metabolic disorders, whose pathogenesis includes multiple genetic and acquired entities falling under the category of insulin resistance and chronic low-grade inflammationand. It is a risk factor for increased prevalence and mortality from diabetes and cardiovascular disease. Cardiovascular diseases are the predominant cause of morbidity and mortality globally, thus it is imperative to investigate the impact of metabolic syndrome on alleviating this substantial disease burden. Despite the increasing number of scientists dedicating themselves to researching metabolic syndrome in recent decades, numerous aspects of this condition remain incompletely understood, leaving many questions unanswered. In this review, we present an epidemiological analysis of MetS, explore both traditional and novel pathogenesis, examine the pathophysiological repercussions of metabolic syndrome, summarize research advances, and elucidate the mechanisms underlying corresponding treatment approaches.

Polymorphisms in the melanocortin 4 receptor (MC4R) gene with occurrence and progression of chronic diseases such as obesity and cardiovascular disease (CVD) have long been addressed but there is a lack of evidence for complex interrelationships, including direct and indirect effects of these variables. This review specifically focuses on studying the effects of healthy diet interaction and MC4R polymorphisms on the development of CVD. The quantity and quality of carbohydrates and proteins consumed are related to obesity susceptibility and cardiometabolic risk factors. A healthy dietary pattern such as a Mediterranean dietary can modulate the association between MC4R polymorphisms (rs17782313) and the risk of CVDs. Also, the Nordic diet can reduce lipid profiles such as low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels. On the other hand, MC4R interaction with the dietary inflammatory index decreases high-density lipoprotein cholesterol levels and increases LDL-C and triglyceride (TG) levels. Additionally, the DASH diet decreases TG, atherogenic index of plasma, systolic blood pressure, diastolic blood pressure, and serum glucose. The interaction between MC4R genes and diets plays an important role in the development of CVD. Adherence to healthy diets such as the Mediterranean, Nordic, Anti-inflammatory, and Dash diets might be an efficient strategy to prevent CVD. The potential for personalized diets to be developed for the treatment and prevention of CVD and its related comorbidities is expected to expand as this field develops.