Glucagon-like peptide-1 (GLP-1) was discovered as an incretin hormone, which is released from the intestine upon nutrient intake and stimulates insulin secretion from the pancreatic islet β-cells. Subsequently, its ability to suppress appetite was recognized. Ghrelin, discovered as the ligand for growth hormone secretagogue-receptor (GHS-R), is released from the stomach and produces appetite. Later, its ability to inhibit insulin secretion and elevate blood glucose was found. Thus, GLP-1 and ghrelin regulate insulin secretion and appetite toward opposite directions. The receptor agonists for GLP-1 and ghrelin have been developed and are now used to treat metabolic diseases, in which insulin plays a key role. However, underlying action mechanism and possible interplay of these hormones have remained elusive. Here, we describe that GLP-1 and ghrelin reciprocally regulate the insulin system. GLP-1 enhances and ghrelin suppresses insulin secretion in pancreatic β-cells. Moreover, GLP-1 cooperates with and ghrelin counteracts insulin action in the vagal afferent and hypothalamic arcuate nucleus (ARC) neurons, the interfaces between the peripheral metabolism and brain. Notably, ghrelin rises and works preprandially and GLP-1 rises and works postprandially. The interplay of ghrelin, GLP-1, and insulin leads to optimal circadian control of feeding, glycemia, and metabolism.

Food intake serves to maintain energy homeostasis; however, overeating can result in obesity, which is associated with serious health complications. In this review, we explore the intricate relationship between overeating, obesity, and the underlying neurobiological mechanisms. We review the homeostatic and hedonic feeding systems, highlighting the role of the hypothalamus and reward systems in controlling food intake and energy balance. Dysregulation in both these systems leads to overeating, as seen in genetic syndromes and environmental models affecting appetite regulation when consuming highly palatable food. The concept of "food addiction" is examined, drawing parallels to drug addiction. We discuss the cellular substrate for addiction-related behavior and current pharmacological obesity treatments-in particular, GLP-1 receptor agonists-showcasing synaptic plasticity in the context of overeating and palatable food exposure. A comprehensive model integrating insights from addiction research is proposed to guide effective interventions for maladaptive feeding behaviors. Ultimately, unraveling the neurobiological basis of overeating holds promise for addressing the pressing public health issue of obesity.

Leptin and ghrelin are two key hormones that play opposing roles in the regulation of appetite and energy balance. Ghrelin stimulates appetite and food intake following binding to receptors and the subsequent activation of orexigenic neurons in the arcuate nucleus. Leptin, conversely, has been demonstrated to suppress appetite and reduce food intake. This occurs through the inhibition of ghrelin-activated neurons, while simultaneously activating those that promote satiety and increase energy expenditure. A lack of biological response despite elevated leptin levels, which is known as leptin resistance, is observed in individuals with excess body weight and represents a significant challenge. As the dysregulation of ghrelin and leptin signalling has been linked to the development of obesity and other metabolic disorders, an in-depth understanding of the genetic determinants affecting these two hormones may facilitate a more comprehensive grasp of the intricate interactions that underpin the pathogenesis of obesity.

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the ghrelin receptor, countering ghrelin's effects on cell signaling and feeding. However, despite an emerging interest in LEAP2's physiology and pharmacology, its endocrine regulation remains unclear. Here, we report that plasma LEAP2 levels decrease significantly upon glucagon infusions during somatostatin clamps in humans. This effect is preserved in patients with obesity and type 2 diabetes while diminished following a hypercaloric diet and a sedentary lifestyle for 2 weeks. Additionally, insulin receptor antagonism offsets the upregulation of LEAP2 during the postprandial state in mice. Finally, insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Collectively, our findings implicate insulin and glucagon in regulating LEAP2 and warrant further investigations into the exact mechanisms orchestrating this endocrine axis.

In obesity, recent research revealed that increased expression of the growth hormone secretagogue receptor (GHSR) in macrophages plays a pivotal role in the development of meta-inflammation, promoting macrophage infiltration and pro-inflammatory polarization. This study aimed to examine the association between GHSR-1a expression in atherosclerotic plaques and adjacent perivascular adipose tissue (PVAT) from 11 patients with obesity and peripheral artery disease (PAD) who underwent revascularization procedures. Immunohistochemistry was used to assess the expression of CD68, CD80, and CD14, while tissue homogenate levels of adiponectin, leptin, IL-6, and CRP were quantified via ELISA. Serum markers of inflammation were also measured. Among patients with GHSR-1a-positive (+) macrophages in atherosclerotic plaques, we observed significantly higher white blood cell counts and platelet-to-lymphocyte ratios in serum, a lower adiponectin-to-leptin ratio, and elevated IL-6 levels in both arterial and PVAT homogenates. Our findings suggest a link between GHSR-1a and macrophage/monocyte infiltration, macrophage polarization, and adipocytokine secretion in atherosclerotic plaques associated with obesity-induced PVAT dysfunction.

The developmental origins of adult disease theory support the concept that undernourished fetuses are at risk of developing metabolic syndrome due to the energy-saving 'Thrifty Phenotype'. This metabolic plasticity represents an evolutionary adaptation that allows individuals to resist the intense pressure caused by cyclically recurring periods of nutritional deprivation. A comprehensive review was conducted following an extensive literature search in the PubMed/Medline and EMBASE databases concerning reports on fetal/intrauterine growth restriction and its metabolic-related long-term outcomes. We only included articles written in English that were published before 1 July 2024. There are several underlying mechanisms and metabolic and endocrine adjustments shaped by the perinatal environment, and they all contribute to progression towards adult disease. From in utero malnutrition or other insults during the fetal period to fetal programing and postnatal catch-up growth, it is difficult to identify the exact moment when this adaptative phenomenon meant to assure fetal survival and to set children on their own physiological growth curves lose its beneficial effect, establishing the trajectory to obesity, insulin resistance, and other hallmarks of metabolic syndrome. With clinical correspondence to an altered body mass, composition, and eating behaviors, it is evident that the metabolic complications linked to FGR are intricate and arise from disturbances in several pathways and organs, but the underlying processes responsible for the long-term consequences are just starting to be understood. The lack of continuity in perinatal-to-pediatric FGR research sets the challenge of exploring new directions in future scientific opportunities. These will hopefully represent a cornerstone in the management of FGR-related metabolic disorders in children, preventing these disorders from evolving into adult disease.

Ghrelin, also known as the "hunger hormone," is a pivotal hormone in controlling appetite, and it is the only known gastrointestinal hormone that promotes food intake, contributing to the regulation of energy balance and body weight. However, studies on the long-term effects of exercise on ghrelin levels in obese populations have shown conflicting results. This study aims to summarize RCT experiments exploring changes in ghrelin levels following long-term exercise in obese or overweight individuals through meta-analysis.

This study employed meta-analytical techniques, searching databases such as PubMed, Web of Science, and EMBASE, to gather research on exercise and ghrelin. The quality of the studies was assessed according to the Cochrane Handbook standards, and data analysis for ghrelin, BMI, and weight was performed using RevMan 5.4 and Stata 16.0 software. A total of 13 interventions involving 944 participants were included to systematically investigate the regulatory effects of exercise on ghrelin levels in obese and overweight individuals. Meta-analytical results were calculated using standardized mean differences (SMDs).

Exercise interventions significantly increased ghrelin levels (SMD =1.16, 95% CI = 0.52 to 1.80, p < 0.0001), with high inter-study heterogeneity (I 2 = 90%). Subgroup analysis suggested that RT and AE + RT were more effective than AE. For BMI, exercise led to a significant reduction (SMD = -0.43, 95% CI = -0.69 to -0.16, p = 0.002), with low heterogeneity (I 2 = 21%). Similarly, exercise significantly reduced weight (SMD = -0.54, 95% CI = -0.98 to -0.11, p = 0.01), though with high heterogeneity (I 2 = 75%). These results suggest exercise effectively improves ghrelin levels, BMI, and weight.

Prolonged exercise interventions demonstrated a statistically significant effect on ghrelin levels. This indicates that exercise interventions can elevate ghrelin levels, which may be associated with reductions in BMI and weight.

https://www.crd.york.ac.uk/prospero/, CRD42024588259.

Associations between variants in the FTO locus and plasma concentrations of appetite related hormones are inconsistent, and might not work in a dose dependent fashion in people with obesity. Moreover, it is relevant to report meal related plasma concentrations of these hormones in persons with obesity given the growing interest in their pharmacological potential in obesity therapy. We find it clinically relevant to examine associations between the SNP rs9939609 genotypes and homeostatic appetite regulation in individuals with BMI ≥35 kg/m2. This study explored associations of the rs9939609 genotypes to plasma concentrations of acylated ghrelin, active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY), and moderating effects of fat mass (FM), in 96 adults (69% female) with BMI ≥35 kg/m2, using a cross sectional observation study designed to have 1/3 of participants each with genotypes TT, AT and AA, respectively. Participants were median (25th, 75th percentile) 42.5 (32, 50) years of age, weighed 120.9 (109.6, 142.4) kg, and had a BMI of 42.8 (39.5, 46.4) kg/m2. Acylated ghrelin, active GLP-1, and total PYY were measured in the fasted state and half-hourly for 2.5h after a standardized meal. We evaluated associations between genotype and appetite hormones in regression analysis controlling for FM and sex. Genotype did not associate with fasting or postprandial (area under curve, AUC) GLP-1 or PYY. Genotype did not associate with fasting acylated ghrelin, but in females with genotype AA, increased FM was associated with higher fasting and postprandial (AUC) acylated ghrelin concentrations relative to genotypes TT (fasting p = 0.025; AUC p = 0.004) and AT (fasting p = 0.002; AUC p < 0.001). This novel finding warrants further investigation.

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.

Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter 'tastants' affect gastrointestinal functions and ingestive behaviour through local and gut-brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response.

The hypothalamus is widely recognized as one of the most extensively studied brain regions involved in the central regulation of energy homeostasis. Within the hypothalamus, peptidergic neurons play a crucial role in monitoring peripheral concentrations of metabolites and hormones, and they finely adjust the sensing of these factors, leading to the activation of either anorexigenic (appetite-suppressing) or orexigenic (appetite-stimulating) pathways. While cortical innervation of the hypothalamus does influence these processes, it is generally considered of secondary importance. Eating-related disorders, such as obesity and anorexia nervosa, are strongly associated with imbalances in energy intake and expenditure. The phenotypes of these disorders can be attributed to dysfunctions in the hypothalamus. Traditionally, it has been believed that hypothalamic dysfunction in these disorders primarily stems from defects in neural pathways. However, recent evidence challenges this perception, highlighting the active participation of neuroglial cells in shaping both physiologic and behavioral characteristics. This review aims to provide an overview of the latest insights into glial biology in three specific eating disorders: obesity, Prader-Willi syndrome, and anorexia. In these disorders, neural dysfunction coincides with glial malfunction, suggesting that neuroglia actively contribute to the development and progression of various neurologic disorders. These findings underscore the importance of glial cells and open up potential new avenues for therapeutic interventions.

Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.

Social isolation affects physical functioning owing to psychological stress. We constructed a rat model to clarify the unexplored effects of social isolation and to determine whether environmental changes as an intervention against social isolation can reduce the stress-inducing effects of social isolation on physiological factors. Eight-week-old male rats were divided into three groups: group-housed, isolated, and intervention. Group-housed rats were kept 2 animals per cage. Isolated rats were kept 1 rat per cage. The intervention group alternated between the isolation and group-housed conditions. All rats were euthanized after 21 days. Their plasma, masseter muscles, and lower limb muscles were collected. Body weight, food intake, locomotor activity, muscle weight, and plasma corticosterone, ghrelin, and myostatin levels were measured. The results indicated that there were no significant differences between the group-housed and intervention groups for all outcomes. However, weight gain, food intake, and plasma corticosterone levels were higher in the isolated group than in the group-housed group. Plasma myostatin levels were higher in the isolated group than in the intervention group. Plasma ghrelin concentrations were lower in the isolated group than in the group-housed or intervention groups. In the isolated group, locomotor activity decreased compared to that in the intervention group. The lower limb muscle weight ratio also decreased in the isolated group compared to that in the group-housed and intervention groups. In conclusion, isolation decreased physical activity and affected body weight, food intake, and muscle weight; these changes were associated with corticosterone as a stress marker, ghrelin as an appetite-related factor, and myostatin, which is a growth inhibitor of skeletal muscles. Moreover, these changes were suppressed when the isolation time was reduced in the intervention group. The present study suggests that intermittent breaking of isolation may reduce the physical effects of isolation.

One of the still-debated topics regarding the olfactory function concerns the presence or absence of sex-related differences in individuals. In this study, we checked for a relationship between the olfactory function of females and males and their ability to perceive single molecules, and researched how this can influence the intensity with which the complex odor formed by a set of single molecules is perceived. First, females and males were classified as normosmic or hyposmic based on the TDI olfactory score obtained using the Sniffin' Sticks test. Subsequently, the headspace of roasted coffee beans, as a complex olfactory stimulus, was broken down into single molecules by means of a chromatographic column; these were simultaneously conveyed to a mass spectrometer (for their subsequent classification) and to the human nose, which acts as a chemical sensor by means of an olfactometer port. The results obtained with this gas chromatography-olfactometry approach show both qualitative and quantitative differences between females and males, with females performing better than males. In addition, the odor intensity reported by females when sniffing pen #10, containing coffee aroma, is significantly higher than that reported by males. In conclusion, these data highlight that the human ability to perceive both single compounds and complex odors is strongly conditioned, not only by the olfactory function of individuals, but also by their sex.

Olfaction acuity, which includes detection thresholds, discrimination and identification, appears to decline with age, obesity, and various neurological disorders. Knowing that smell influences energy intake, there is a growing interest in protecting this sense. Physical activity could be a key intervention to counteract the loss of olfaction. This systematic review aims to explore the literature on the effect of physical activity on olfaction acuity. The search strategy consisted of using index terms and keywords in MEDLINE, EMBASE, EBM Reviews - Cochrane Central Register of Controlled Trials, CINAHL, SPORTDiscus, and Web of Science search engine. Data from 17 trials involving 10,861 participants showed that physical activity improved olfaction thresholds, discrimination, identification and perceived intensity. Regular practice of physical activity seemed to have better effects on olfaction components than acute exercise. Although this review has clarified the evidence on the effects of physical activity on olfaction, better methodological consistency is needed.

Chronic stress lead to dysregulation of metabolic hormones, creating risk for obesity and type 2 diabetes. Based on previous work suggesting the potential for sexual activity to relieve psychological stress and reduce stress-related neuroendocrine activity, the present research explored sexual activity as a protective factor. We focused on chronic stress in the form of caregiving stress, comparing premenopausal mothers of a child with an autism spectrum disorder vs. a neurotypical child, in relation to metabolic hormones - insulin (and insulin resistance as assessed by HOMA), leptin, and ghrelin. Then, we explored the moderating role of sexual activity. Our results showed that high-stress mothers showed higher levels of insulin, insulin resistance, and lower levels of ghrelin compared to low-stress mothers. However, sexual activity modulated these associations such that among mothers who were sexually active (as coded from their daily diaries), no significant differences in these outcomes were observed between groups. This buffering effect of sexual activity was distinguishable from the buffering effect of physical activity and independent of global relationship satisfaction. Together, our findings provide novel evidence supporting the potential protective effects of sexual activity from chronic stress-related metabolic disease risk.

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

Cancer cachexia is a complex systemic wasting syndrome. Nutritional mechanisms that span energy intake, nutrient metabolism, body composition, and energy balance may be impacted by, and may contribute to, the development of cachexia. To date, clinical management of cachexia remains elusive. Leaning on discoveries and novel methodologies from other fields of research may bolster new breakthroughs that improve nutritional management and clinical outcomes. Characteristics that compare and contrast cachexia and obesity may reveal opportunities for cachexia research to adopt methodology from the well-established field of obesity research. This review outlines the known nutritional mechanisms and gaps in the knowledge surrounding cancer cachexia. In parallel, we present how obesity may be a different side of the same coin and how obesity research has tackled similar research questions. We present insights into how cachexia research may utilize nutritional methodology to expand our understanding of cachexia to improve definitions and clinical care in future directions for the field.

Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations.

Appetite hormones are considered a promising target in fighting obesity as impaired appetite hormone levels have already been associated with obesity. However, further insights in the drivers of appetite hormone levels are needed.

In this study, we investigated the associations of fasting appetite hormone levels with lifestyle and environmental exposures in children and adolescents.

A total of 534 fasting blood samples were collected from children and adolescents (4-16y,50% boys) and appetite hormone levels (glucagon-like peptide-1 (GLP-1), peptide YY (PYY), pancreatic polypeptide (PP), leptin and ghrelin) were measured. Exposures included dietary quality (fiber-rich food intake, sugar propensity, fat propensity), psychosocial stress (happiness, negative emotions, negative life events and emotional problems), sleep duration, physical activity and environmental quality (long term black carbon (BC), particulate matter <2.5 μM (PM2.5), nitrogen dioxide (NO2) exposure, and green space in a 100 m and 2000 m radius around the residence). A multi-exposure score was calculated to combine all the exposures at study in one measure. Associations of individual exposures and multi-exposure score with appetite hormone levels were evaluated using linear mixed regression models adjusting for sex, age, socioeconomic status, waist-to-height ratio and multiple testing.

GLP-1 was associated with air pollution exposure (NO2 β* = -0.13, BC β* = -0.15, PM2.5 β* = -0.16, all p < 0.001). Leptin was associated with green space in a 100 m radius around the residence (β* = -0.11; p = 0.002). Ghrelin was associated with negative emotions (active ghrelin β* = -0.16; p = 0.04, total ghrelin β* = -0.23; p = 0.0051) and happiness (active ghrelin β* = 0.25; p < 0.001, total ghrelin β* = 0.26; p < 0.001). Furthermore, total ghrelin levels were associated with the multi-exposure score, reflecting unhealthy exposures and lifestyle (β* = -0.22; p = 0.036).

Our findings provide new insights into the associations of exposures with appetite hormone levels, which are of high interest for preventive obesity research. Further research is crucial to reveal the underlying mechanisms of the observed associations.

The intestinal epithelium plays an important role in maintaining the intestinal barrier and facilitating nutrient absorption. It also serves as a critical physical barrier against the infiltration of foreign substances from the intestinal lumen into the circulation. Intestinal barrier dysfunction has been implicated in the development of several diseases. Isomaltooligosaccharides (IMOs), which are a type of dietary fiber, possess multiple health benefits. However, there is limited information regarding their efficacy against gastrointestinal diseases. This review explores the therapeutic potential of IMOs in obesity, diabetes mellitus, inflammatory bowel disease (IBD), hyperlipidemia, and constipation. High-fat diet (HFD)-induced obesity models have shown that IMOs, administered alone or in combination with other compounds, exhibit potent antiobesity effects, making them promising agents in the treatment of obesity and its associated complications. Moreover, IMOs exhibit preventive effects against HFD-induced metabolic dysfunction by modulating gut microbiota and short-chain fatty acid levels, thereby ameliorating symptoms. Furthermore, IMOs can reduce IBD and alleviate hyperlipidemia, as indicated by the reduced histological colitis scores and improved lipid profiles observed in clinical trials and animal studies. This review highlights IMOs as a versatile intervention strategy that can improve gastrointestinal health by modulating gut microbiota, immune responses, and metabolic parameters, providing a multifaceted approach to address the complex nature of gastrointestinal disorders.

Fetal alcohol spectrum disorders (FASD) are a severe developmental condition resulting from exposure to alcohol during pregnancy. The aim of this study was to examine the concentrations of hormones involved in appetite regulation-ghrelin, leptin, and putative peptide YY-3 (PYY)-in the serum of individuals with FASD. Additionally, we investigated the relationship between these hormone levels and clinical indicators. We conducted an enzyme-linked immunosorbent assay on samples collected from 62 FASD patients and 23 individuals without the condition. Our results revealed a significant decrease in leptin levels among FASD patients compared to the control group (5.124 vs. 6.838 ng/mL, p = 0.002). We revealed no statistically significant differences in the levels of other hormones studied (ghrelin and PYY). Comparisons of hormone levels were also conducted in three subgroups: FAS, neurobehavioral disorders associated with prenatal alcohol exposure and FASD risk, as well as by sex. Assignment to FASD subgroups indicated changes only for leptin. Sex had no effect on the levels of hormones. Moreover, the levels of leptin showed a negative correlation with cortisol levels and a positive correlation with BMI and proopiomelanocortin. Alterations in appetite regulation can contribute to the improper development of children with FASD, which might be another factor that should be taken into consideration in the proper treatment of patients.

Several hallmarks of metabolic syndrome, such as dysregulation in the glucose and lipid metabolism, endothelial dysfunction, insulin resistance, low-to-medium systemic inflammation, and intestinal microbiota dysbiosis, represent a pathological bridge between metabolic syndrome and diabesity, cardiovascular, and neurodegenerative disorders. This review aims to highlight some therapeutic strategies against metabolic syndrome involving integrative approaches to improve lifestyle and daily diet. The beneficial effects of foods containing antioxidant polyphenols, intestinal microbiota control, and physical activity were also considered. We comprehensively examined a large body of published articles involving basic, animal, and human studie, as well as recent guidelines. As a result, dietary polyphenols from natural plant-based antioxidants and adherence to the Mediterranean diet, along with physical exercise, are promising complementary therapies to delay or prevent the onset of metabolic syndrome and counteract diabesity and cardiovascular diseases, as well as to protect against neurodegenerative disorders and cognitive decline. Modulation of the intestinal microbiota reduces the risks associated with MS, improves diabetes and cardiovascular diseases (CVD), and exerts neuroprotective action. Despite several studies, the estimation of dietary polyphenol intake is inconclusive and requires further evidence. Lifestyle interventions involving physical activity and reduced calorie intake can improve metabolic outcomes.

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.

Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas, and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (eg, septo-optic dysplasia, Prader-Willi syndrome) and acquired (eg, central nervous system tumors) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarize our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb.

The primary objective of this study was to find the association between dietary zinc intake and the prevalence of olfactory disorders using data from the National Health and Nutrition Examination Survey (NHANES).

A cross-sectional study was conducted using the 2013-2014 NHANES data. A linear regression model was constructed with dietary zinc intake as the independent variable and olfactory dysfunction as the dependent variable. Initially, in the unadjusted model, weighted logistic regression analysis was carried out for continuous variables, and stratified analysis was conducted for categorical variables. Subsequently, three models were created to perform subgroup analysis by adjusting for different confounding factors, further investigating the relationship between dietary zinc intake and olfactory dysfunction. Finally, restricted cubic spline (RCS) models adjusting for all confounding factors were utilized to study the nonlinear associations of age and dietary zinc intake with olfactory dysfunction and their relevant thresholds.

A total of 2958 samples were analyzed in this study. Weighted logistic regression analysis displayed a negative relationship between dietary zinc intake and the prevalence of olfactory dysfunction in the population of non-Hispanic whites and other Hispanics, as well as in individuals with body mass index (BMI) ≥ 25 kg/m2 (OR < 1, P < 0.05). The P values for the multiplicative interaction terms adjusting for all confounding factors were not significant (P for interaction > 0.05). In the three regression models adjusting for different confounding factors, dietary zinc intake was significantly negatively related to olfactory dysfunction in all populations (Crude: OR 0.63, 95% CI 0.44-0.91; Model I: OR 0.58, 95% CI 0.38-0.90; Model II: OR 0.59, 95% CI 0.35-1.00). Subgroup analysis based on BMI showed a remarkable negative relationship between dietary zinc intake and olfactory dysfunction in the group with BMI of 25-30 kg/m2 (Crude: OR 0.50, 95% CI 0.28-0.90, P = 0.012; Model I: OR 0.49, 95% CI 0.24-1.00, P = 0.021) and the group with BMI ≥ 30 kg/m2 (Crude: OR 0.55, 95% CI 0.33-0.92, P = 0.013; Model I: OR 0.51, 95% CI 0.29-0.88, P = 0.005; Model II: OR 0.51, 95% CI 0.29-0.91, P = 0.004). RCS analysis revealed a remarkable nonlinear association of age and dietary zinc intake with olfactory dysfunction (P-non-linear < 0.05). The prevalence of olfactory dysfunction was considerably higher in individuals aged 60 and above compared to those under 60 years old. Daily dietary zinc intake within the range of 9.60-17.45 mg was a protective factor for olfactory dysfunction, while intake outside this range increased the prevalence of olfactory dysfunction.

Daily dietary zinc intake within the range of 9.60-17.45 mg has a protective effect against olfactory dysfunction. Intake outside this range increases the prevalence of olfactory dysfunction. The prevalence of olfactory dysfunction is significantly higher in individuals aged 60 and above compared to those under 60 years old. For individuals with a BMI of 25-30 kg/m2 and a BMI ≥ 30 kg/m2, dietary zinc intake is negatively correlated with olfactory dysfunction. Therefore, it is recommended that these populations increase their dietary zinc intake to develop healthier lifestyles and maintain olfactory health.

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.

Aims: Part of hypothalamic (mediobasal hypothalamus [MBH]) neurons detect changes in blood glucose levels that in turn coordinate the vagal control of insulin secretion. This control cascade requires the production of mitochondrial reactive oxygen species (mROS), which is altered in models of obesity and insulin resistance. Obese, insulin-resistant Zücker rats are characterized by hypothalamic hypersensitivity to glucose. This initiates an abnormal vagus-induced insulin secretion, associated with an overproduction of mROS in response to a low glucose dose. Here, we hypothesized that ghrelin, known to buffer reactive oxygen species (ROS) via mitochondrial function, may be a major component of the hypothalamic glucose hypersensitivity in the hypoghrelinemic obese Zücker rat. Results: Hypothalamic glucose hypersensitivity-induced insulin secretion of Zücker obese rats was reversed by ghrelin pretreatment. The overproduction of MBH mROS in response to a low glucose load no longer occurred in obese rats that had previously received the cerebral ghrelin infusion. This decrease in mROS production was accompanied by a normalization of oxidative phosphorylation (OXPHOS). Conversely, blocking the action of ghrelin with a growth hormone secretagogue receptor antagonist in a model of hyperghrelinemia (fasted rats) completely restored hypothalamic glucose sensing-induced insulin secretion that was almost absent in this physiological situation. Accordingly, ROS signaling and mitochondrial activity were increased by the ghrelin receptor antagonist. Innovation: These results demonstrate for the first time that ghrelin addressed only to the brain could have a protective effect on the defective control of insulin secretion in the insulin-resistant, hypoghrelinemic obese subject. Conclusions: Ghrelin, through its action on OXPHOS, modulates mROS signaling in response to cerebral hyperglycemia and the consequent vagal control of insulin secretion. In insulin-resistant obese states, brain hypoghrelinemia could be responsible for the nervous defect in insulin secretion.

The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations.

We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).

Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner.

LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans.

The study was retrospectively registered in clinicaltrials.gov (April 2023).

gov Identifier: NCT05815641.

Obesity, prevalent in approximately 80% of Qatar's adult population, increases the risk of complications like type 2 diabetes and cardiovascular diseases. Predictive biomarkers are crucial for preventive strategies. Salivary α-amylase activity (sAAa) inversely correlates with obesity and insulin resistance in adults and children. However, the connection between sAAa and cardiometabolic risk factors or chronic low-grade inflammation markers remains unclear. This study explores the association between serum sAAa and adiposity markers related to cardiovascular diseases, as well as markers indicative of chronic low-grade inflammation.

Serum samples and clinical data of 1500 adult, non-diabetic, Overweight/Obese participants were obtained from Qatar Biobank (QBB). We quantified sAAa and C reactive protein (CRP) levels with an autoanalyzer. Cytokines, adipokines, and adiponectin of a subset of 228 samples were quantified using a bead-based multiplex assay. The associations between the sAAa and the adiposity indices and low-grade inflammatory protein CRP and multiple cytokines were assessed using Pearson's correlation and adjusted linear regression.

The mean age of the participants was 36 ± 10 years for both sexes of which 76.6% are women. Our analysis revealed a significant linear association between sAAa and adiposity-associated biomarkers, including body mass index β -0.032 [95% CI -0.049 to -0.05], waist circumference β -0.05 [95% CI -0.09 to -0.02], hip circumference β -0.052 [95% CI -0.087 to -0.017], and HDL β 0.002 [95% CI 0.001 to 0.004], albeit only in women. Additionally, sAAa demonstrated a significant positive association with adiponectin β 0.007 [95% CI 0.001 to 0.01]while concurrently displaying significant negative associations with CRP β -0.02 [95% CI -0.044 to -0.0001], TNF-α β -0.105 [95% CI -0.207 to -0.004], IL-6 β [95% CI -0.39 -0.75 to -0.04], and ghrelin β -5.95 [95% CI -11.71 to -0.20], specifically within the female population.

Our findings delineate significant associations between sAAa and markers indicative of cardiovascular disease risk and inflammation among overweight/obese adult Qatari females. Subsequent investigations are warranted to elucidate the nuances of these gender-specific associations comprehensively.

The sense of smell plays an important role in influencing the eating habits of individuals and consequently, their body weight, and its impairment has been associated with modified eating behaviors and malnutrition problems. The inter-individual variability of olfactory function depends on several factors, including genetic and physiological ones. In this study, we evaluated the role of the Kv1.3 channel genotype and age, as well as their mutual relationships, on the olfactory function and BMI of individuals divided into young, adult and elderly groups. We assessed olfactory performance in 112 healthy individuals (young n = 39, adult n = 36, elderly n = 37) based on their TDI olfactory score obtained through the Sniffin' Sticks test and their BMI. Participants were genotyped for the rs2821557 polymorphism of the human gene encoding Kv1.3 channels, the minor C allele of which was associated with a decreased sense of smell and higher BMIs compared to the major T allele. The results show that TT homozygous subjects obtained higher TDI olfactory scores and showed lower BMIs than CC homozygous subjects, in all age groups considered. Furthermore, the positive effect of the T allele on olfactory function and BMI decreased with increasing age. The contribution of the genetic factor is less evident with advancing age, while the importance of the age factor is compensated for by genetics. These results show that genetic and physiological factors such as age act to balance each other.

The co-occurrence of asthma and obesity is becoming an increasingly common health problem. It became clear that both diseases are closely related, since overweight/obesity are associated with an increased risk of asthma development, and more than half of the subjects with severe or difficult-to-treat asthma are obese. Currently, there are no specific guidelines for the treatment of this group of patients. The mechanisms involved in the asthma-obesity phenotype include low-grade chronic inflammation and changes in pulmonary physiology. However, genetic predispositions, gender differences, comorbid conditions, and gut microbiota also seem to be important. Regulatory peptides affect many processes related to the functioning of the respiratory tract and adipose tissue. Adipokines such as leptin, adiponectin, resistin, and the less studied omentin, chemerin, and visfatin, as well as the gastrointestinal hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and neuropeptides, including substance P or neuropeptide Y, can play a significant role in asthma with obesity. The aim of this article is to provide a concise review of the contribution of particular peptides in inflammatory reactions, obesity, asthma, and a combination of both diseases, as well as emphasize their potential role in the effective treatment of the asthma-obesity phenotype in the future.

Exposure to air pollution is associated with adverse cardiometabolic health effects and increased mortality, even at low concentrations. Some of the biological mechanisms through which air pollution can affect cardiometabolic health overlap with health outcomes associated with diet quality and changes in diet.

The objective of this study is to investigate associations of air pollutants at average concentrations below the World Health Organization, 2021 air quality guidelines with cardiometabolic outcomes. Furthermore, potential interaction between air pollutants and diet quality will be assessed.

82 individuals with obesity participated in a combined weight loss and weight loss maintenance study for a total of 33 weeks. A secondary analysis was conducted incorporating air pollution measurements. Data were analysed with linear mixed-effects models.

A total of 17 significant associations were observed for single pollutants with 10 cardiometabolic outcomes, predominantly related to blood lipids, hormones, and glucose regulation. Diet quality, as measured by the Baltic Sea Diet score, did not appear to mediate the association of air pollution with cardiometabolic outcomes, however, diet quality was observed to significantly modify the association of PM2.5 with total cholesterol, and the associations of NO and O3 with ghrelin.

These findings suggest that exposure to ambient air pollutants, especially particulate matter, at levels below World Health Organization, 2021 air quality guidelines, were associated with changes in cardiometabolic risk factors. Diet may be a personal-level approach for individuals to modify the impact of exposure to air pollution on cardiometabolic health.

Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6 weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.

Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN.

During an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs).

A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK.

Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

Animals rely on learned cues to guide their behaviour for rewards such as food. The Pavlovian-instrumental transfer (PIT) task can be used to investigate the influence of Pavlovian stimuli on instrumental responding. Ghrelin, an orexigenic peptide, and its receptor, growth hormone secretagogue receptor 1A (GHS-R1A), has received growing interest for its role in reward-motivated learning and behaviours. A significant population of GHS-R1A have been identified within the ventral tegmental area (VTA), a critical node in the mesolimbic reward circuit that is necessary for the expression of PIT. As ghrelin has been found to increase dopaminergic activity in the VTA, we predicted that GHS-R1A antagonism with JMV-2959 would attenuate PIT. Further, given the relationship between hunger levels and changes in ghrelin signalling, we sought to compare the effects GHS-R1A antagonism with those of satiety, hypothesizing parallel effects, with each attenuating PIT. Rats received daily sessions of Pavlovian and then instrumental training over 3 weeks. Across three experiments, we examined the effects of a shift to satiety, or treatment with the GHS-R1A antagonist JMV-2959, either peripherally or directly into the VTA. We found that presentations of a stimulus paired with food reward enhanced responding for food across all conditions, thus demonstrating the expected PIT effect. Further, GHS-R1A antagonism, both peripherally and within the VTA, as well as satiety significantly reduced the magnitude of the PIT effect compared to control conditions. These results clarify our understanding of ghrelin signalling in PIT and begin to elucidate the role of feeding-related peptides in the modulation of reward-related responding.

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.

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.

The underlying mechanisms for the development and progression of nonalcoholic fatty liver disease (NAFLD) are complex and multifactorial. Within the last years, experimental and clinical evidences support the role of ghrelin in the development of NAFLD. Ghrelin is a gut hormone that plays a major role in the short-term regulation of appetite and long-term regulation of adiposity. The liver constitutes a target for ghrelin, where this gut-derived peptide triggers intracellular pathways regulating lipid metabolism, inflammation, and fibrosis. Interestingly, circulating ghrelin levels are altered in patients with metabolic diseases, such as obesity, type 2 diabetes, and metabolic syndrome, which, in turn, are well-known risk factors for the pathogenesis of NAFLD. This review summarizes the molecular and cellular mechanisms involved in the hepatoprotective action of ghrelin, including the reduction of hepatocyte lipotoxicity via autophagy and fatty acid β-oxidation, mitochondrial dysfunction, endoplasmic reticulum stress and programmed cell death, the reversibility of the proinflammatory phenotype in Kupffer cells, and the inactivation of hepatic stellate cells. Together, the metabolic and inflammatory pathways regulated by ghrelin in the liver support its potential as a therapeutic target to prevent NAFLD in patients with metabolic disorders.

After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure.

Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting.

On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]).

Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

This article reviews the previous studies on the distinction between food cravings and appetite, and how they are regulated by hormones and reflected in brain activity. Based on existing research, food cravings are defined as individual preferences influenced by hormones and psychological factors, which differ from appetite, as they are not necessarily related to hunger or nutritional needs. The article also evaluates the neuroimaging findings about food cravings, and interventions to reduce food cravings, such as mindfulness training, alternative sweeteners, non-invasive brain stimulation techniques, cognitive-behavioral therapy, and imaginal retraining, and points out their advantages, disadvantages, and limitations. Furthermore, the article delves into the potential future directions in the field, emphasizing the need for a neuroendocrine perspective, considerations for associated psychiatric disorders, innovative clinical interventions, and emerging therapeutic frontiers in obesity management. The article outlines the neuro-endocrine basis of food cravings, including ghrelin, leptin, melanocortin, oxytocin, glucagon-like peptide-1, baclofen, and other hormones and their brain regions of action. The article argues that food cravings are an important target for obesity, and more research is needed to explore their complex characteristics and mechanisms, and how to effectively interact with their neuro-endocrine pathways. The article provides a new perspective and approach to the prevention and treatment of obesity.