Oleoylethanolamide in the gut-brain axis

Oleoylethanolamide (OEA), a PPAR-α agonist, is a mediator of satiety. After peripheral administration, OEA induces Fos expression and activation in areas of the CNS involved in the control of feeding behavior and energy homeostasis, such as the nucleus of the solitary tract (NST) and in the area postrema (AP) in the brainstem, the hypothalamic paraventricular (PVN), supraoptic (SON) and ventral tuberomammillary (vTMN) nuclei. Moreover, it is known to increase the noradrenergic trasmission in the NST and AP, by increasing the expression of the dopamine-β-hydroxylase (DBH). Visceral ascending fibers were hypothesized to mediate such effects, but recent findings demonstrate that abdominal vagal afferents are not necessary for the anorectic effect of OEA. In fact, OEA is able to decrease food intake both in rats that underwent a subdiaphragmatic vagal deafferentation (SDA), a surgical procedure that eliminates all abdominal vagal afferents but spares about 50% of the vagal efferents, and in SHAM controls. Thus, the aim of the present work was to better elucidate the role of abdominal vagal afferents in mediating OEA's effects on the CNS. To meet this aim, we subjected rats to SDA surgery, using SHAM rats as control. By using immunohistochemistry, Fos and DBH expression patterns were investigated in the NST, in the AP, and in the hypothalamus after OEA administration (10 mg kg -1). Consistently with the behavioral results, OEA increases Fos expression in the NST and in the AP. Moreover, in these nuclei, SDA did not cause any alteration of DBH expression. In the hypothalamus, in line with the behavioral results, OEA is able to increase Fos expression in the PVN and the vTMN, even though in the latter does not reach statistical significance. Overall, our findings indicate that vagal afferents are not strictly necessary for the satiety effect of OEA at both behavioral and neurochemical levels

Functional effects of dietary proteins and bioactive peptides on satiety and metabolic response in humans

Gut-brain axis is a crucial hub of the food intake and energy balance regulation. Dichotomy between homeostatic and non-homeostatic/hedonic systems should be replaced by a larger, highly interactive system that unifies homeostasis with reward, cognition, and emotion. Understanding the integrative role of the CNS in energy and reward homeostasis has become increasingly important considering the prevalence of obesity and functional gastrointestinal disorders (FGIDs). The GIT is the largest endocrine organ in the human body and it represents the gateway for communication between the human body and the external environment. Distress (i.e. inflammation) or adaptations in the communication of sensory information may contribute to the development or maintenance of disease. Several diseases such as celiac disease, Crohn’s disease, type 1 diabetes and some food allergies, are known to increase the GIT mucosa permeation of macromolecules. As reported in Chapter 2 FGIDs are classified as morphologic and physiological abnormalities often occurring in combination with motility disturbance, visceral hypersensitivity, as well as altered mucosa, immune function, gut microbiota and CNS processes. The incidence of FGIDs among population is about 11%. Some of the symptoms reported for the functional dyspepsia are similar to those of non-celiac gluten sensitivity such as postprandial fullness, early satiety, epigastric pain, and epigastric burning. These symptoms may appear isolated or combined after consumption of specific foods. The nutritional consequence of this symptomatology is that people arbitrarily exclude from diet the foods which are mainly associated with the symptoms such as spicy foods, high-fat meals, dairy products or cereal-based foods. Life-lasting dietary exclusions may cause nutritional deficiency as well as metabolic adaptation that may be even worst of the previous symptomatology. This is the reason why in the case of a specific food/nutrient-induced disorder the usual dietetic approach is the exclusion from the diet of the specific food/nutrient for a certain period and a slow re-introduction in the follow-up period. The exclusion from the diet of gluten represents the cure only for people with celiac disease but literature was still lacking on the knowledge of the metabolic response to a gluten-free meal in patients with celiac disease compared to healthy subjects. The human study reported in Chapter 3 aimed at filling that gap of knowledge. From a dietetic perspective, the effect of a meal is more relevant in exerting metabolic responses than a single nutrient/food. Celiac subjects (CD) at the diagnosis or on a gluten free diet since 12 months and healthy subjects consumed a standard gluten-free meal and the post-prandial blood glucose and hormone response as well as appetite feelings were monitored. The main results of the study was that CD showed a lower postprandial blood glucose response than healthy subjects with a lower response of GLP-1, GIP and insulin. The different hormonal status was associated with a different evolution of the post-prandial hunger sensation that was higher in CD at diagnosis than in the others. These findings suggested that CD subjects after more than 1 year on a gluten free diet did not recover a complete functionality of the intestine and this might determine an adaptive hormone postprandial response that may influence post-prandial appetite sensations and insulin resistance over long period. From a food science and nutrition perspective, some bioactive compounds are present in foods and may be effective in the control of appetite, intestinal inflammation and glycaemia. In this thesis the potential of food bioactive peptides contained in milk proteins, casein and soy hydrolysates towards appetite, inflammation and glycaemia was tested and described in the human study in Chapter 4, and in in vitro studies of Chapter 5 and 6, respectively. In Chapter 4 two beverages, one enriched with milk proteins and one with carbohydrates (control) were developed and a human study with women consuming the beverage after an exercise session was carried out aiming at evaluating the effect of the beverages on the energy intake at the subsequent dinner. Data showed that the milk protein-enriched beverage was able to influence hunger sensation and reduce energy intake at subsequent meal only in women having a strong cognitive control of eating behaviour. In Chapter 5 casein and soy hydrolysates were tested in Caco-2 cells cultivated in a normal condition and in the presence of TNF-α to induce intestinal inflammation. Data showed that digested casein and soy protein hydrolysates positively influenced cells viability, particularly in inflamed condition. Data about monolayer integrity (TEER) showed an absence of irreversible damage at the normal and inflamed cell monolayer when it was treated with digested samples. In Chapter 6 casein (CH) and soy (SH) protein hydrolysates were tested as functional ingredients for glycaemia control, through inhibition of Dipeptidyl peptidase-IV (DPP-IV) activity. This study showed that when used in a model food CH and SH loosed their inhibitory activity against DPP-IV possibly because of other food components that could hide the bioactivity of CH and SH at the doses used in the model food. This scenario highlights the importance of validation of efficacy of new foods/whole meals both in vitro to assess the potential functionalities before performing human studies as well as in vivo in a well-characterized population. Indeed, growing evidence shows that the effect of food on wellness and dietary behaviour may be also influenced by psychological attitude of people as well as by gut microbiota reactivity to a food/diet. In the context of new foods/diets to tackle obesity and FGIDs the gut-brain interconnection is central and should be better targeted both at the step of the food design and validation

Papel de las N-aciletanolaminas y el sistema circadiano en la homeostasis energética en peces teleósteos

La ingestión de alimentos es un proceso multifactorial en el que intervienen una gran cantidad de elementos tanto ambientales como fisiológicos, cuya regulación se encuentra muy conservada a lo largo de la evolución, desde peces teleósteos hasta mamíferos. Así, en todos los vertebrados, tanto el sistema nervioso central como una gran cantidad de órganos periféricos funcionan de forma coordinada para establecer una óptima regulación de la ingesta. Actualmente se conocen un gran número de señales neuroendocrinas implicadas en la regulación de la homeostasis energética en los peces, como neuropéptidos, hormonas y monoaminas. Sin embargo, se ha prestado poca atención a moléculas de otra naturaleza, como los derivados lipídicos N-aciletanolaminas (NAEs), las cuáles además se han propuesto como candidatas a actuar como nexo entre el metabolismo y el sistema circadiano en los mamíferos, a través de su receptor PPARα. Por todo ello, el objetivo general de la presente Tesis Doctoral es el estudio del papel de las NAEs en la homeostasis energética de los peces e investigar la relación entre el sistema circadiano y dicha homeostasis energética, utilizando como modelo el ciprínido Carassiusauratus..

Pharmacological effects of palmitoylethanolamide on hypertension, insulin-resistance and obesity in murine models

N-Palmitoylethanolamide (PEA) is an endogenous N-acylethanolamine, first identified in lipid extracts from brain, liver, and muscle of rat and guinea pig. PEA is formed “on demand” from membrane phospholipids and it is gaining ever-increasing interest not only for its anti-inflammatory and analgesic effects mediated by peroxisome-proliferator activated receptor (PPAR)-α, but also for its novel metabolic effects. Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Main consequence of obesity is cardiovascular disease (CVD). The sum of the risk factors that predisposes to CVD goes by the name of “metabolic syndrome” (MetS). Hypertension is an important hallmark of MetS and a common cause of kidney disease. In the first part of this thesis, we investigated the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids (EETs), CYP-dependent arachidonic acid (AA) metabolites, as endothelium derived hyperpolarizing factors (EDHF), and renin-angiotensin system (RAS) modulation. To achieve this aim, SHR and Wistar-Kyoto normotensive (WKY) rats were treated with PEA (30 mg/kg/day, s.c.) for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure the soluble epoxide hydrolase (sEH), which is the enzyme responsible for EETs degradation in their corresponding inactive diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme (ACE) and angiotensin receptor (AT)1 expression. We showed that EDHF-mediated dilation in response to acetylcholine (Ach) was increased in mesenteric beds of PEA-treated SHR. Interestingly, in both vascular tissues, PEA significantly decreased the sEH protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid (DHET), implying a reduction in EET hydrolysis. Moreover, PEA treatment down-regulated AT1 and ACE expression, indicating a reduction in Ang II-mediated effects. Our data clearly demonstrate the involvement of EETs and RAS in the blood pressure lowering effect of PEA. The relationship between obesity, insulin-resistance (IR) type 2 diabetes mellitus (T2DM) and MetS is well known. IR is defined as an inefficient glucose uptake and utilization in peripheral tissues in response to insulin stimulation. IR in the prediabetes stage is a feature of glucose intolerance, which includes impaired fasting glucose and/or impaired glucose tolerance. When insulin binds to its transmembrane receptor (InsR), promotes its autophosphorylation (pInsR). Activated pInsR recruits insulin receptor substrate (IRS), leading to insulin signaling cascade. A potential link between inflammation and IR has been shown. Indeed, obesity is characterized by chronic low grade inflammation, where the release of adipose tissue-derived cytokines can block insulin action and cause systemic IR. In fact, serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 are significantly increased in serum from obese patients. All cytokines induce IRS1 protein degradation, which suppresses insulin signaling pathway and subsequently suppresses glucose transporter (GLUT) translocation and glycogen synthesis, contributing to IR and hyperglycemia. Our study was focused on the pharmacological effect of PEA in an animal model of diet-induced obesity (DIO), feeding mice with a high-fat diet (HFD), and on the mechanisms by which this lipid mediator could modulate the storage and availability of energy sources, restoring lipid/glucose homeostasis. To achieve this aim, mice were fed a standard chow diet (STD group) or HFD (DIO group). After twelve weeks, both STD or HFD mice were treated with PEA (30 mg/kg/day, o.s.) for ten weeks. At the end of the experimental period, body parameters were determined, and serum and tissues collected for following determinations. Interestingly, PEA caused a reduction in body weight and fat mass, improved glucose tolerance and prevented IR, induced by HFD feeding. Moreover, PEA restored the alterations of serum biochemical and inflammatory parameters, inducing a marked reduction of ALT, AST, cholesterol, and pro-inflammatory cytokines, such as TNF-α, IL-1 and monocyte chemoattractant protein (MCP)-1. PEA also normalized metabolic hormone levels and restored insulin sensitivity. At hepatic level, PEA treatment significantly induced an increase in the activation AMPK/ACC pathway, stimulating fatty acid oxidation, compromised in obese mice. To evaluate tissue insulin-sensitivity, we determined the hepatic expression of the InsR, whose expression decreased in liver of DIO mice compared to that of STD animals, and increased in PEA-treated mice. Then, we evaluated the effectiveness of hepatic insulin signaling through the evaluation of InsR and Akt phosphorylated state and the expression of GLUT-2. PEA treatment restored insulin signaling. The protective effect of PEA was strengthened by the evaluation of hepatic IL-6 and TNF-α, whose transcription, upregulated by HFD feeding, was reduced. To address the direct effect of PEA on hepatic insulin-sensitivity, we evaluated the restoration of insulin signaling, altered by the induction of IR, in HepG2 cells, a human hepatocarcinoma cell line. Therefore, we demonstrated in vitro that PEA increased the phosphorylation of Akt in insulin resistant cells, following insulin stimulation. PEA was also able to modulate glucose homeostasis at hypothalamic level. Therefore, we examined neuronal activation at the arcuate (ARC) and ventromedial (VMH) nuclei, evaluating c-fos immunostaining. In the ARC nucleus of DIO mice, a decrease in c-fos labeling was found. Interestingly, in the PEA-treated DIO group, a trend of c-fos labeling increase was evidenced. Consistently, in the VHM of DIO mice a significant decrease in the neuronal activation was shown compared to STD mice, although, no differences were found between DIO and PEA-treated DIO mice. The involvement of the hypothalamic control of glucose homeostasis by PEA was confirmed in in vitro experiments, using human SH-SY5Y neuroblastoma cell line. When insulin-resistant cells were treated with PEA, the re-stimulation with insulin showed a restoration of Akt phosphorylation, and therefore of insulin-sensitivity. These findings show that this acylethanolamide also displays a central effect on glucose homeostasis, reducing neuronal IR. Our data strengthened evidence on the metabolic activity of PEA, through the involvement of central and peripheral mechanisms. PEA clearly ameliorates glucose-tolerance and insulin-sensitivity, indicating its therapeutic potential for the treatment of metabolic dysfunctions associated to obesity, such as IR and T2DM

Position statement on nutrition therapy for overweight and obesity: nutrition department of the Brazilian association for the study of obesity and metabolic syndrome: ABESO 2022

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Obesity is a chronic disease resulting from multifactorial causes mainly related to lifestyle (sedentary lifestyle, inadequate eating habits) and to other conditions such as genetic, hereditary, psychological, cultural, and ethnic factors. The weight loss process is slow and complex, and involves lifestyle changes with an emphasis on nutritional therapy, physical activity practice, psychological interventions, and pharmacological or surgical treatment. Because the management of obesity is a long-term process, it is essential that the nutritional treatment contributes to the maintenance of the individual's global health. The main diet-related causes associated with excess weight are the high consumption of ultraprocessed foods, which are high in fats, sugars, and have high energy density; increased portion sizes; and low intake of fruits, vegetables, and grains. In addition, some situations negatively interfere with the weight loss process, such as fad diets that involve the belief in superfoods, the use of teas and phytotherapics, or even the avoidance of certain food groups, as has currently been the case for foods that are sources of carbohydrates. Individuals with obesity are often exposed to fad diets and, on a recurring basis, adhere to proposals with promises of quick solutions, which are not supported by the scientific literature. The adoption of a dietary pattern combining foods such as grains, lean meats, low-fat dairy, fruits, and vegetables, associated with an energy deficit, is the nutritional treatment recommended by the main international guidelines. Moreover, an emphasis on behavioral aspects including motivational interviewing and the encouragement for the individual to develop skills will contribute to achieve and maintain a healthy weight. Therefore, this Position Statement was prepared based on the analysis of the main randomized controlled studies and meta-analyses that tested different nutrition interventions for weight loss. Topics in the frontier of knowledge such as gut microbiota, inflammation, and nutritional genomics, as well as the processes involved in weight regain, were included in this document. This Position Statement was prepared by the Nutrition Department of the Brazilian Association for the Study of Obesity and Metabolic Syndrome (ABESO), with the collaboration of dietitians from research and clinical fields with an emphasis on strategies for weight loss.info:eu-repo/semantics/publishedVersio

Targeted expression of plasminogen activator inhibitor(PAI)-1 to the stomach inhibits gut-brain signalling by the satiety hormone cholecystokinin (CCK)

Energy homeostasis is a tightly regulated system that is vital for survival involving anorectic and orexigenic signals. Obesity is a maladaptive response where the balance becomes disrupted. Obesity is one of the most concerning health problems of our time. It is no longer considered a consequence of a western lifestyle, with more developing countries now reporting an increased incidence of obesity and associated illnesses. While obesity itself can be debilitating and decrease quality of life, it is the associated comorbidities that are the main cause for concern; including type two diabetes, cancer and thrombo-occlusive diseases. One of the molecules thought to be responsible for occlusive events is plasminogen activator inhibitor (PAI)-1. This inhibitor of the plasminogen system is also reported to be up to 5 fold higher in obese subjects in plasma, and similar to leptin, is released from adipose tissue. PAI-1 is considered to play a protective role in circumstances of gastric mucosal attack, thus a transgenic mouse (PAI-1HKβ) was generated, with targeted expression of PAI-1 to the gastric parietal cells, to study this. However, an unexpected phenotype emerged, most notably hyperphagia and increased body weight, which formed the basis of these present studies. The gut-brain axis is a major and well-studied regulator of energy homeostasis and this was the focus of this project. The PAI-1HKβ mice when compared to wild-type had decreased brain stem responses to the satiety hormone, Cholecystokinin (CCK). Brainstem responses were also attenuated in wild types pre-treated with exogenous PAI-1. Furthermore, it was shown that the urokinase plasminogen activator (uPA) receptor by which PAI-1 binds, was required to influence the observed decrease in brainstem responses. CCK also has other physiological functions in the role of energy homeostasis, including gastric emptying. While delayed gastric emptying was observed following a protein rich liquid test meal in C57BL/6 mice, PAI-1HKβ mice had a blunted response. Blockade of the CCK1 receptor in C57BL/6 mice also attenuated the delay in gastric emptying. Moreover, exogenous PAI-1 attenuated CCK-mediated inhibition of gastric emptying. The PAI-1HKβ mice had an attenuated inhibition of gastric emptying of a non-nutrient containing liquid test meal in response to CCK. Treatment with gastrin was shown to increase plasma PAI-1 and attenuated delayed gastric emptying in C57BL/6 mice. Food intake is stimulated by orexigens, most notably ghrelin, working via appetite-stimulating neurons in the arcuate nucleus. While ghrelin stimulated feeding in fed ad libitum C57BL/6 mice, PAI-1 increased feeding in previously fasted C57BL/6 mice only. This response to ghrelin and PAI-1 was also replicated in PAI-1 -/- mice, suggesting PAI-1 is not required for the orexigenic effect of ghrelin. Moreover, intrapertoneal (ip.) administered ghrelin increased fos expression in arcuate neurons of both C57BL/6 and PAI-1 -/- mice, whereas ip. PAI-1 did not. Weight loss in the PAI-1HKβ mice appeared to reverse the insensitivity to CCK in terms of gastric emptying. PAI-1HKβ mice were also found to be insensitive to other gut-derived satiety hormones, suggesting gastric PAI-1 is an anti-satiety factor. However, mice null for wild-type gastric PAI-1 responded normally to CCK prior to feeding, indicating that wild type is necessary for CCK insensitivity in the PAI-1HKβ mice. The current findings demonstrate that PAI-1 plays a role in the control of food intake. PAI-1 is an example of a novel anti-satiety factor that can modulate gut-brain signalling via the vagus nerve in order to preserve nutrient intake. This work provides a platform for future investigations into novel pathways implicated in the development and treatment of obesity

Brain opioid and endocannabinoid systems as risk factors for obesity. Positron emission tomography studies of μ-opioid and CB1 receptors with glucose uptake analysis

The prevalence of obesity is increasing globally. Obesity is a major threat to public health since it predisposes individuals to multiple non-communicable diseases. Obesity is difficult to treat or prevent. The modern environment has been blamed for the obesity epidemic, due to the abundance of energy-dense and aggressively advertised foods. The brain is the most important organ controlling energy homeostasis and feeding. However, we do not know which brain pathways render some individuals susceptible to the obesity development in the current environment. The aim of this thesis was to examine whether variation in the brain opioid and endocannabinoid pathways explains differences in the risk for obesity development. Two receptor systems associated with food intake and reward processing were investigated: μ-opioid receptors (MOR) and cannabinoid CB1 receptors (CB1R). MORs were measured with [11C]carfentanil, and CB1Rs with [18F]FMPEP-d2. In addition, brain glucose uptake (BGU) was quantified with [18F]FDG. Healthy, non-obese humans were studied with positron emission tomography in four studies investigating I) the effects of demographic factors on MORs, II) the associations of obesity risk factors on MORs, CB1Rs and BGU, III) the physical fitness and MOR function, and IV) how MORs and CB1Rs associate with feeding behavior. Age, sex and smoking influenced MOR availability, which may contribute to obesity development in specific populations. Familial obesity risk associated with increased BGU but low neuroreceptor availability, suggesting that vulnerability to obesity may be mediated by disruption of these interconnected pathways. Impulsive feeding was associated with reduced MOR availability, which may underlie excessive food intake and weight gain. Central capacity for releasing endogenous MOR ligands was dependent on aerobic fitness, suggesting that the MOR function may be critical in habitual exercise and weight maintenance. Obesity risk factors and circulating cannabinoids associated with reduced CB1R availability, suggesting that an overactive cannabinoid system may facilitate weight gain. In conclusion, multiple neurochemical alterations previously associated with obesity are already present in a number of non-obese individuals, which may increase their risk for future obesity.Aivojen opioidi- ja endokannabinoidijärjestelmät lihavuuden riskitekijöinä. Positroniemissiotomografiatutkimuksia μ-opioidi- ja CB1-reseptoreista sekä glukoosin otosta Lihavuus yleistyy ympäri maailmaa. Lihavuus on yksi merkittävimmistä uhista väestön terveydelle, sillä painon kertyminen altistaa useille kansansairauksille. Lihavuutta on vaikea hoitaa tai ehkäistä. Nykyistä elinympäristöä on syytetty lihavuusepidemiasta, sillä ympäristö on täynnä energiatiiviitä ja voimakkaasti markkinoituja ruokatuotteita. Aivot ovat tärkein energiatasapainoa ja syömistä säätelevä elin. Emme kuitenkaan tiedä, mitkä muutokset aivojen toiminnassa saavat osan ihmisistä lihomaan tässä ympäristössä. Väitöskirjan tavoitteena oli selvittää, selittävätkö aivojen opioidi- ja endokannabinoidijärjestelmän muutokset eroja ihmisten välisessä lihomisriskissä. Tutkimme kahta aivojen välittäjäainejärjestelmää, jotka säätelevät syömisen palkkiokokemuksia: μ-opioidireseptoreja (MOR) ja CB1-kannabinoidireseptoreja (CB1R). MOR-sitoutumista mitattiin [11C]karfentaniililla, ja CB1R-sitoutumista [18F]FMPEP-d2-merkkaineella. Aivojen glukoosinottoa mitattiin lisäksi [18F]FDG-merkkiaineella. Tutkimme terveitä, ei-lihavia ihmisiä positroniemissiotomografialla neljässä tutkimuksessa, joissa selvitettiin: I) väestömuuttujien vaikutusta MOR-sitoutumiseen, II) lihavuuden riskitekijöiden vaikutusta MOR- ja CB1R-sitoutumiseen sekä aivojen glukoosinottoon, III) fyysistä kuntoa ja MOR-toimintaa, ja IV) MOR- ja CB1R-sitoitumisen yhteyttä syömiskäyttäytymiseen. Ikä, sukupuoli ja tupakointi vaikuttivat MOR-sitoutumiseen, mikä voi selittää eroja lihavuuden kehittymisessä eri väestöryhmissä. Perheeseen liittyvä lihomisriski oli yhteydessä aivojen glukoosinottoon ja reseptorimääriin, ja näiden järjestelmien häiriintyminen saattaa altistaa lihavuudelle. Impulsiivinen syömiskäyttäytyminen liittyi alentuneeseen MOR-sitoutumiseen, mikä voi altistaa liialliselle syömiselle ja painon nousulle. Sisäsyntyisten opioidien vapauttamiskyky oli yhteydessä fyysiseen kuntoon, viitaten MOR-toiminnan merkitykseen liikuntaharrastuksen ylläpidossa ja painonhallinnassa. Lihavuuden riskitekijät ja verenkierron kannabinoidit liittyivät alentuneeseen CB1R-sitoutumiseen, mikä viittaa siihen, että yliaktiivinen kannabinoidijärjestelmä voi altistaa lihomiselle. Osalla terveistä ihmisistä on siis havaittavissa useita aivokemiallisia muutoksia, jotka saattavat altistaa lihavuudelle

Influence of moderate alcohol consumption on emotional and physical well-being

Abstract Background and aim: Moderate alcohol consumption has been suggested to contribute to emotional well-being. However, the effects of moderate alcohol consumption on emotional well-being in common drinking situations and the influence of alcohol on physical well-being remain unclear. The aims of this thesis were 1) to further explore the acute effects of moderate alcohol consumption on emotional well-being and the association between habitual alcohol consumption and emotional well-being and 2) to provide more insight into physiological markers that may be related to alcohol-induced emotional well-being. Methods: We compared the acute effects of alcohol (20-30 g) vs. alcohol-free drinks on mood, food reward and mental stress in three randomized crossover trials. To explore the short-term effects of alcohol on physiological markers of emotional well-being, we conducted four randomized crossover trials of 3-6 weeks in which 25-41 g alcohol/day, or no alcohol was consumed. In addition, we conducted a meta-analysis of 14 randomized intervention trials with at least 2 weeks of alcohol intervention. Finally, the association between long-term alcohol consumption and health-related quality of life was investigated with a bidirectional, longitudinal analysis among 92,448 U.S. women of the Nurses’ Health Study II cohort. Results: Moderate alcohol consumption in an unpleasant ambiance resulted in higher happiness scores in women as compared to the consumption of alcohol-free drinks. Consumption of 20 gram alcohol increased subsequent intake and rewarding value of savoury foods in men, as measured by an increased implicit wanting and explicit liking of savoury foods. When alcohol was consumed by male volunteers immediately after a mental stressor, a reduced response of the stress hormones ACTH and cortisol, the inflammatory marker IL-8, and the percentage of monocytes in blood were observed. Furthermore, alcohol consumption was found to attenuate meal-induced NF-κB and to increase total antioxidant capacity in men. Four weeks of moderate alcohol consumption reduced circulating fetuin-A, while increasing urinary F2-isoprostanes in men. In women, short-term moderate alcohol consumption did not reduce fetuin-A but it tended to increase insulin sensitivity. Habitual moderate alcohol consumption was associated with a higher physical health-related quality of life 2 years later. Vice versa, higher physical health-related quality of life was associated with a higher alcohol intake 2 years later. Moderate alcohol consumption was not associated with mental health-related quality of life in either direction, although moderate alcohol consumption was associated with higher scores on the scales for social functioning and vitality. Conclusions: Moderate alcohol consumption may acutely improve emotional well-being by improving mood, increasing food reward and reducing mental stress. In the short-term, moderate alcohol consumption may attenuate meal-induced oxidative stress and circulating fetuin-A in men. In women, moderate alcohol consumption may improve insulin sensitivity. Habitual moderate alcohol consumption may be associated with a small increase in physical health related quality of life but not with mental health related quality of life in women. </p