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2.
Sci Rep ; 12(1): 1696, 2022 02 01.
Article in English | MEDLINE | ID: mdl-35105898

ABSTRACT

Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP binds with high affinity to G-protein coupled receptor 10 (GPR10) and with lesser activity towards the neuropeptide FF receptor type 2 (NPFF2R). The present study aimed to develop long-acting PrRP31 analogues with potent anti-obesity efficacy. A comprehensive series of C18 lipidated PrRP31 analogues was characterized in vitro and analogues with various GPR10 and NPFF2R activity profiles were profiled for bioavailability and metabolic effects following subcutaneous administration in diet-induced obese (DIO) mice. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. In contrast, acylation with aliphatic C18 lipid chain (C18) resulted in dual GPR10-NPFF2R co-agonists that suppressed food intake and promoted a robust weight loss in DIO mice, which was sustained for at least one week after last dosing. Rapid in vivo degradation of C18 PrRP31 analogues gave rise to circulating lipidated PrRP metabolites maintaining dual GPR10-NPFF2R agonist profile and long-acting anti-obesity efficacy in DIO mice. Combined GPR10 and NPFF2R activation may therefore be a critical mechanism for obtaining robust anti-obesity efficacy of PrRP31 analogues.


Subject(s)
Anti-Obesity Agents/administration & dosage , Obesity/drug therapy , Prolactin-Releasing Hormone/analogs & derivatives , Prolactin-Releasing Hormone/administration & dosage , Receptors, G-Protein-Coupled/agonists , Receptors, Neuropeptide/agonists , Weight Loss/drug effects , Acylation , Animals , Appetite Regulation/drug effects , Diet, High-Fat/adverse effects , Disease Models, Animal , Eating/drug effects , Male , Mice , Mice, Inbred C57BL , Obesity/etiology , Obesity/metabolism , Prolactin-Releasing Hormone/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Treatment Outcome
3.
Article in English | MEDLINE | ID: mdl-34534676

ABSTRACT

Amylin is a 37-amino acid polypeptide that has been found to be involved in feeding regulation in some mammals, birds, and goldfish. We cloned amylin of Siberian sturgeon and detected its distribution pattern in 15 tissues. The expression levels in the periprandial period (pre-and post-feeding), the changes in the food intake, and the expression levels of related appetite factors after the intraperitoneal injection of amylin were detected. The expression of amylin was found to be the highest in the hypothalamus. Compared with 1 h pre-feeding, the expression levels of amylin in the hypothalamus and duodenum were increased significantly 1 h post-feeding. Compared with the control group (saline), intraperitoneal injection of 50 ng/g, 100 ng/g, and 200 ng/g of amylin significantly inhibited food intake at 1 h post injection, but not at 3 h and 6 h. The injection of 50 ng/g, 100 ng/g, and 200 ng/g amylin significantly inhibited the cumulative feed. After 1 h of 50 ng/g amylin injection, the levels of MC4R and somatostatin in the hypothalamus increased significantly, while the levels of amylin and NPY decreased significantly. The levels of CCK in the valvular intestine were increased significantly. Insulin in the duodenum was also increased significantly, but there was no significant change in ghrelin in the duodenum. These results show that amylin inhibits feeding in Siberian sturgeon by down-regulating the appetite-stimulating factor NPY and up-regulating the appetite-suppressing factors somatostatin, MC4R, CCK, and insulin. This study provides a theoretical basis for studying the feeding function and action mechanisms of amylin in Siberian sturgeon.


Subject(s)
Fish Proteins/metabolism , Fishes/metabolism , Islet Amyloid Polypeptide/metabolism , Amino Acid Sequence , Animals , Appetite Depressants/administration & dosage , Appetite Depressants/metabolism , Appetite Regulation/drug effects , Appetite Regulation/genetics , Appetite Regulation/physiology , Base Sequence , Cloning, Molecular , Duodenum/metabolism , Eating/drug effects , Eating/genetics , Eating/physiology , Feeding Behavior/drug effects , Feeding Behavior/physiology , Fish Proteins/administration & dosage , Fish Proteins/genetics , Fishes/genetics , Fishes/physiology , Gene Expression/drug effects , Hypothalamus/metabolism , Injections, Intraperitoneal , Islet Amyloid Polypeptide/administration & dosage , Islet Amyloid Polypeptide/genetics , Phylogeny , Sequence Homology, Amino Acid , Tissue Distribution
4.
Eur J Endocrinol ; 185(4): R93-R101, 2021 Sep 01.
Article in English | MEDLINE | ID: mdl-34370694

ABSTRACT

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.


Subject(s)
Peptide Hormones/physiology , Animals , Appetite Regulation/drug effects , Appetite Regulation/genetics , Diabetes Mellitus/genetics , Diabetes Mellitus/therapy , Gastric Emptying/drug effects , Gastric Emptying/genetics , Humans , Hypertension/genetics , Hypertension/therapy , Muscle Contraction/drug effects , Muscle Contraction/genetics , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Neurons/drug effects , Neurons/physiology , Obesity/genetics , Obesity/therapy , Peptide Hormones/pharmacology , Signal Transduction/drug effects , Somatostatin/chemistry , Somatostatin/pharmacology , Somatostatin/physiology
5.
Peptides ; 144: 170608, 2021 10.
Article in English | MEDLINE | ID: mdl-34265369

ABSTRACT

Appetite is closely regulated not only by gut hormonal and neuronal peptides but also by exogenous peptides derived from food proteins. Food proteins are now recognized to contain many thousands of bioactive compounds that provide additional health benefits beyond their nutritional effects. Bioactive peptides are beneficial to the life and/or to regulate physiological functions. Although animal protein products have been widely applied in the food industry, exploring the possibilities of developing functional foods based on plant protein-derived peptides is considered attractive for achieving sustainable development goals. In addition, peptides from plant proteins have the potential to treat numerous diseases or risk factors and may therefore facilitate a healthy life expectancy. In this review, we discuss the identified plant-based bioactive peptides and their appetite regulating effects. Plant-based bioactive peptides may provide new opportunities to discover novel approaches that can improve and prevent diseases in a sustainable environment.


Subject(s)
Appetite Regulation/drug effects , Peptides/pharmacology , Plant Proteins/pharmacology , Adiposity/drug effects , Animals , Appetite Stimulants/pharmacology , Eating/drug effects , Humans , Peptide Fragments/pharmacology , Peptides/chemistry , Plant Proteins/chemistry , Ribulose-Bisphosphate Carboxylase/pharmacology
6.
Int J Mol Sci ; 22(14)2021 Jul 20.
Article in English | MEDLINE | ID: mdl-34299356

ABSTRACT

The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.


Subject(s)
Appetite Regulation/drug effects , Appetite/drug effects , Eating/drug effects , Oxytocin/pharmacology , Oxytocin/therapeutic use , Animals , Energy Metabolism/drug effects , Feeding Behavior/drug effects , Humans , Hypothalamus/drug effects , Hypothalamus/metabolism , Motivation/drug effects , Obesity/metabolism
7.
Nutr Metab Cardiovasc Dis ; 31(8): 2507-2511, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34167866

ABSTRACT

BACKGROUND AND AIMS: Glycosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to weight loss and improved diabetes control, but a significant disparity exists between observed and expected weight loss with these medications, hindering clinical effects. This study investigated whether this discrepancy could be explained by compensatory increases in appetite and associated alterations in appetite-regulating hormones. METHODS AND RESULTS: This was a prospective single-center observational pilot study. Adults 18-70 years old newly prescribed an SGLT2 inhibitor through usual care were invited to participate. Fasting and postprandial appetite was assessed immediately before, 1 week after, and 12 weeks after SGLT2 inhibitor initiation. Serum samples were collected at corresponding time points to measure ghrelin, leptin, and peptide tyrosine-tyrosine (PYY). Seven patients were included. At 1 and 12 weeks after SGLT2 inhibitor initiation, self-reported appetite did not change significantly and trended toward a decrease in appetite. There were no significant differences in fasting or postprandial ghrelin, leptin, or PYY. CONCLUSION: Results suggest the discrepancy between expected and observed weight loss with SGLT2 inhibitors cannot be explained by increases in appetite or changes in appetite-regulating hormones. Further studies are needed to investigate alternative metabolic compensatory mechanisms to optimize weight loss with SGLT2 inhibitor use.


Subject(s)
Appetite Regulation/drug effects , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Weight Loss/drug effects , Aged , Biomarkers/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/physiopathology , Female , Ghrelin/blood , Humans , Leptin/blood , Male , Middle Aged , Peptide YY/blood , Pilot Projects , Prospective Studies , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Time Factors , Treatment Outcome
8.
Endocrinology ; 162(9)2021 09 01.
Article in English | MEDLINE | ID: mdl-34089599

ABSTRACT

The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight, and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, only recently has it been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our as yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these 2 entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery and chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin's metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.


Subject(s)
Obesity/prevention & control , Satiation/drug effects , Secretin/pharmacology , Animals , Appetite Regulation/drug effects , Appetite Regulation/physiology , Energy Intake/drug effects , Energy Intake/physiology , Energy Metabolism/drug effects , Energy Metabolism/physiology , Humans , Obesity/etiology , Satiation/physiology , Secretin/physiology , Secretin/therapeutic use , Thermogenesis/drug effects
9.
Physiol Res ; 70(2): 161-168, 2021 04 30.
Article in English | MEDLINE | ID: mdl-33992045

ABSTRACT

This paper reviews provenance, chemical composition and properties of tea (Camelia sinensis L.) and coffee (Coffee arabica, L. and Coffeacaniphora, L.), their general health effects, as well as the currently available knowledge concerning their action on fat storage, physiological mechanisms of their effects, as well as their safety and recommended dosage for treatment of obesity. Both tea and coffee possess the ability to promote health and to prevent, to mitigate and to treat numerous disorders. This ability can be partially due to presence of caffeine in both plants. Further physiological and medicinal effects could be explained by other molecules (theaflavins, catechins, their metabolites and polyphenols in tea and polyphenol chlorogenic acid in coffee). These plants and plant molecules can be efficient for prevention and treatment of numerous metabolic disorders including metabolic syndrome, cardiovascular diseases, type 2 diabetes and obesity. Both plants and their constituents can reduce fat storage through suppression of adipocyte functions, and support of gut microbiota. In addition, tea can prevent obesity via reduction of appetite, food consumption and food absorption in gastrointestinal system and through the changes in fat metabolism.


Subject(s)
Anti-Obesity Agents/administration & dosage , Coffee , Health Status , Obesity/prevention & control , Phytochemicals/administration & dosage , Tea , Adiposity/drug effects , Animals , Anti-Obesity Agents/adverse effects , Appetite Regulation/drug effects , Coffee/adverse effects , Humans , Lipid Metabolism/drug effects , Obesity/diagnosis , Obesity/physiopathology , Phytochemicals/adverse effects , Tea/adverse effects , Weight Gain/drug effects
10.
Sci Rep ; 11(1): 6791, 2021 03 24.
Article in English | MEDLINE | ID: mdl-33762661

ABSTRACT

To examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. A double-blind, randomised, placebo controlled trial to examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. Eighty-three men and women aged between 20 and 50 years of age completed 16 weeks of daily supplementation with either CFE or placebo. Plasma cardiometabolic (lipid profile, glucose, insulin) and satiety (ghrelin, leptin, neuropeptideY) biomarkers, body composition, diet history and gastrointenstinal function were assessed at baseline, weeks 4, 8, 12 and 16. Subjects in the CFE and placebo groups were well matched and predominatly female 93% and 87.5%, with a mean age of 40.9 ± 6.7 and 39.5 ± 7.5 years and body mass index (BMI) of 30.0 ± 3.1 and 30.2 ± 2.9 kg/m2 respectively. There was a significant difference in plasma leptin concentration change between groups at week 16 (p = 0.04), with the placebo group increasing concentration (2.27 ± 4.80 ng/mL) while the CFE group (0.05 ± 4.69 ng/mL) remained the same. At week 16, the CFE group had significantly reduced their calorie intake from baseline compared to the placebo group (245 cal vs 15.8 cal respectively p < 0.01). The CFE group also had a significant reduction in waist circumference of 2.7 cm compared to an increase of 0.3 cm in the placebo group (p = 0.02). A weight increase from baseline was seen in the placebo group that was not observed in the CFE group (1.33 kg weight gain vs 0.37 kg weight loss respectively; p = 0.03). The placebo group also had a significant increase in fat mass, android fat mass, BMI and leptin compared to the CFE group (p = 0.04, 0.02, < 0.01 respectively). CFE was effective at maintaining bodyweight during a non-calorie controlled diet compared to a placebo. The mechanism responsible for this action is requiring further research and could be due to an increase in satiety receptor sensitivity.


Subject(s)
Apocynaceae/chemistry , Appetite Depressants/therapeutic use , Appetite Regulation/drug effects , Overweight/diet therapy , Plant Extracts/pharmacology , Administration, Oral , Adult , Apocynaceae/metabolism , Appetite Depressants/chemistry , Appetite Depressants/pharmacology , Biomarkers/blood , Body Mass Index , Double-Blind Method , Energy Intake/drug effects , Humans , Leptin/blood , Middle Aged , Overweight/pathology , Placebo Effect , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Waist Circumference/drug effects , Young Adult
11.
JCI Insight ; 6(9)2021 05 10.
Article in English | MEDLINE | ID: mdl-33764905

ABSTRACT

Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3-5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor-mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor-mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.


Subject(s)
Appetite Regulation/physiology , Diet, High-Fat , Energy Intake/physiology , Gastric Emptying/physiology , Medulla Oblongata/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Vagus Nerve/metabolism , Animals , Appetite Regulation/drug effects , Eating/drug effects , Eating/physiology , Energy Intake/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Gastric Emptying/drug effects , Gastrointestinal Motility/drug effects , Gastrointestinal Motility/physiology , Medulla Oblongata/drug effects , Medulla Oblongata/physiology , Memantine/pharmacology , Neurons/drug effects , Patch-Clamp Techniques , Piperidines/pharmacology , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Stomach , Vagus Nerve/drug effects , Vagus Nerve/physiology
12.
Trends Endocrinol Metab ; 32(5): 264-294, 2021 05.
Article in English | MEDLINE | ID: mdl-33707095

ABSTRACT

Human obesity is accompanied by alterations in the blood concentrations of multiple circulating appetite regulators. Paradoxically, most of the appetite-inhibitory hormones are elevated in nonsyndromic obesity, while most of the appetite stimulatory hormones are reduced, perhaps reflecting vain attempts of regulation by inefficient feedback circuitries. In this context, it is important to understand which appetite regulators exhibit a convergent rather than paradoxical behavior and hence are likely to contribute to the maintenance of the obese state. Pharmacological interventions in obesity should preferentially consist of the supplementation of deficient appetite inhibitors or the neutralization of excessive appetite stimulators. Here, we critically analyze the current literature on appetite-regulatory peptide hormones. We propose a short-list of appetite modulators that may constitute the best candidates for therapeutic interventions.


Subject(s)
Appetite Regulation , Obesity , Appetite Regulation/drug effects , Dietary Supplements , Hormones , Humans , Obesity/therapy
13.
J Clin Endocrinol Metab ; 106(3): 654-664, 2021 03 08.
Article in English | MEDLINE | ID: mdl-33300990

ABSTRACT

CONTEXT: Fructose compared to glucose has adverse effects on metabolic function, but endocrine responses to oral sucrose vs glucose is not well understood. OBJECTIVE: We investigated how oral sucrose vs glucose affected appetite-regulating hormones, and how biological factors (body mass index [BMI], insulin sensitivity, sex) influence endocrine responses to these 2 types of sugar. DESIGN: Sixty-nine adults (29 men; 23.22 ±â€…3.74 years; BMI 27.03 ±â€…4.96 kg/m2) completed the study. On 2 occasions, participants consumed 300-mL drinks containing 75 g of glucose or sucrose. Blood was sampled at baseline, 10, 35, and 120 minutes post drink for plasma glucose, insulin, glucagon-like peptide (GLP-1)(7-36), peptide YY (PYY)total, and acyl-ghrelin measures. Hormone levels were compared between conditions using a linear mixed model. Interaction models were performed, and results were stratified to assess how biological factors influence endocrine responses. RESULTS: Sucrose vs glucose ingestion provoked a less robust rise in glucose (P < .001), insulin (P < .001), GLP-1 (P < .001), and PYY (P = .02), whereas acyl-ghrelin suppression was similar between the sugars. We found BMI status by sugar interactions for glucose (P = .01) and PYY (P = .03); obese individuals had smaller increases in glucose and PYY levels after consuming sucrose vs glucose. There were interactions between insulin sensitivity and sugar for glucose (P = .003) and insulin (P = .04), and a sex by sugar interaction for GLP-1 (P = .01); men demonstrated smaller increases in GLP-1 in response to oral sucrose vs glucose. CONCLUSION: Sucrose is less efficient at signaling postprandial satiation than glucose, and biological factors influence differential hormone responses to sucrose vs glucose consumption.


Subject(s)
Appetite Regulation/drug effects , Glucose/pharmacology , Sucrose/pharmacology , Administration, Oral , Adolescent , Adult , Appetite/drug effects , Appetite/physiology , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Mass Index , Down-Regulation/drug effects , Eating/physiology , Female , Ghrelin/analogs & derivatives , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Glucose/administration & dosage , Glucose Tolerance Test , Humans , Insulin Resistance/physiology , Male , Obesity/blood , Peptide YY/blood , Satiation/drug effects , Satiation/physiology , Sex Characteristics , South Carolina , Sucrose/administration & dosage , Young Adult
14.
Front Endocrinol (Lausanne) ; 11: 597583, 2020.
Article in English | MEDLINE | ID: mdl-33324348

ABSTRACT

Obesity, diabetes, insulin resistance, sedentary lifestyle, and Western diet are the key factors underlying non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases in developed countries. In many cases, NAFLD further progresses to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and to hepatocellular carcinoma. The hepatic lipotoxicity and non-liver factors, such as adipose tissue inflammation and gastrointestinal imbalances were linked to evolution of NAFLD. Nowadays, the degree of adipose tissue inflammation was shown to directly correlate with the severity of NAFLD. Consumption of higher caloric intake is increasingly emerging as a fuel of metabolic inflammation not only in obesity-related disorders but also NAFLD. However, multiple causes of NAFLD are the reason why the mechanisms of NAFLD progression to NASH are still not well understood. In this review, we explore the role of food intake regulating peptides in NAFLD and NASH mouse models. Leptin, an anorexigenic peptide, is involved in hepatic metabolism, and has an effect on NAFLD experimental models. Glucagon-like peptide-1 (GLP-1), another anorexigenic peptide, and GLP-1 receptor agonists (GLP-1R), represent potential therapeutic agents to prevent NAFLD progression to NASH. On the other hand, the deletion of ghrelin, an orexigenic peptide, prevents age-associated hepatic steatosis in mice. Because of the increasing incidence of NAFLD and NASH worldwide, the selection of appropriate animal models is important to clarify aspects of pathogenesis and progression in this field.


Subject(s)
Appetite Regulation/drug effects , Disease Models, Animal , Eating , Hypoglycemic Agents/pharmacology , Inflammation/complications , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/physiopathology , Peptide Fragments/pharmacology , Animals , Disease Progression , Humans , Non-alcoholic Fatty Liver Disease/etiology
15.
Amino Acids ; 52(10): 1413-1423, 2020 Oct.
Article in English | MEDLINE | ID: mdl-33057941

ABSTRACT

Obesity is associated with altered glycine metabolism in humans. This study investigated the mechanisms regulating glycine metabolism in obese rats. Eight-week-old Zucker diabetic fatty rats (ZDF; a type-II diabetic animal model) received either 1% glycine or 1.19% L-alanine (isonitrogenous control) in drinking water for 6 weeks. An additional group of lean Zucker rats also received 1.19% L-alanine as a lean control. Glycine concentrations in serum and liver were markedly lower in obese versus lean rats. Enteral glycine supplementation restored both serum and hepatic glycine levels, while reducing mesenteric and internal white fat mass compared with alanine-treated ZDF rats. Blood glucose and non-esterified fatty acid (NEFA) concentrations did not differ between the control and glycine-supplemented ZDF rats (P > 0.10). Both mRNA and protein expression of aminomethyltransferase (AMT) and glycine dehydrogenase, decarboxylating (GLDC) were increased in the livers of obese versus lean rats (P < 0.05). In contrast, glycine cleavage system H (GCSH) hepatic mRNA expression was downregulated in obese versus lean rats, although there was no change in protein expression. These findings indicate that reduced quantities of glycine observed in obese subjects likely results from an upregulation of the hepatic glycine cleavage system and that dietary glycine supplementation potentially reduces obesity in ZDF rats.


Subject(s)
Adipose Tissue, White/drug effects , Diabetes Mellitus, Type 2/drug therapy , Dietary Supplements , Glycine/administration & dosage , Liver/drug effects , Obesity/drug therapy , Adipose Tissue, White/metabolism , Alanine/administration & dosage , Alanine/metabolism , Aminomethyltransferase/genetics , Aminomethyltransferase/metabolism , Animals , Appetite Regulation/drug effects , Body Weight/drug effects , Diabetes Mellitus, Type 2/metabolism , Glycine/metabolism , Glycine Decarboxylase Complex H-Protein/genetics , Glycine Decarboxylase Complex H-Protein/metabolism , Glycine Dehydrogenase (Decarboxylating)/genetics , Glycine Dehydrogenase (Decarboxylating)/metabolism , Liver/metabolism , Male , Obesity/metabolism , RNA, Messenger/metabolism , Rats , Rats, Zucker
16.
Nutrients ; 12(11)2020 Oct 27.
Article in English | MEDLINE | ID: mdl-33120899

ABSTRACT

It is not known how acute sucralose and glucose alter signaling within the brain when individuals make decisions about available food. Here we examine this using Food Bid Task in which participants bid on visually depicted food items, while simultaneously undergoing functional Magnetic Resonance Imaging. Twenty-eight participants completed three sessions after overnight fast, distinguished only by the consumption at the start of the session of 300 mL cherry flavored water with either 75 g glucose, 0.24 g sucralose, or no other ingredient. There was a marginally significant (p = 0.05) effect of condition on bids, with 13.0% lower bids after glucose and 16.6% lower bids after sucralose (both relative to water). Across conditions, greater activity within regions a priori linked to food cue reactivity predicted higher bids, as did greater activity within the medial orbitofrontal cortex and bilateral frontal pole. There was a significant attenuation within the a priori region of interest (ROI) after sucralose compared to water (p < 0.05). Activity after glucose did not differ significantly from either of the other conditions in the ROI, but an attenuation in signal was observed in the parietal cortex, relative to the water condition. Taken together, these data suggest attenuation of central nervous system (CNS) signaling associated with food valuation after glucose and sucralose.


Subject(s)
Brain/drug effects , Brain/physiology , Choice Behavior/drug effects , Food , Glucose/pharmacology , Sucrose/analogs & derivatives , Adult , Appetite Regulation/drug effects , Appetite Regulation/physiology , Choice Behavior/physiology , Fasting , Female , Food Preferences , Humans , Hunger/physiology , Magnetic Resonance Imaging , Male , Sucrose/pharmacology
17.
Am J Physiol Regul Integr Comp Physiol ; 319(6): R673-R683, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33026822

ABSTRACT

Oxytocin (OT) is a neuropeptide whose central receptor-mediated actions include reducing food intake. One mechanism of its behavioral action is the amplification of the feeding inhibitory effects of gastrointestinal (GI) satiation signals processed by hindbrain neurons. OT treatment also reduces carbohydrate intake in humans and rodents, and correspondingly, deficits in central OT receptor (OT-R) signaling increase sucrose self-administration. This suggests that additional processes contribute to central OT effects on feeding. This study investigated the hypothesis that central OT reduces food intake by decreasing food seeking and food motivation. As central OT-Rs are expressed widely, a related focus was to assess the role of one or more OT-R-expressing nuclei in food motivation and food-seeking behavior. OT was delivered to the lateral ventricle (LV), nucleus tractus solitarius (NTS), or ventral tegmental area (VTA), and a progressive ratio (PR) schedule of operant reinforcement and an operant reinstatement paradigm were used to measure motivated feeding behavior and food-seeking behavior, respectively. OT delivered to the LV, NTS, or VTA reduced 1) motivation to work for food and 2) reinstatement of food-seeking behavior. Results provide a novel and additional interpretation for central OT-driven food intake inhibition to include the reduction of food motivation and food seeking.


Subject(s)
Appetite Depressants/administration & dosage , Appetite Regulation/drug effects , Eating/drug effects , Feeding Behavior/drug effects , Lateral Ventricles/drug effects , Motivation/drug effects , Oxytocin/administration & dosage , Solitary Nucleus/drug effects , Ventral Tegmental Area/drug effects , Animals , Infusions, Intraventricular , Lateral Ventricles/physiology , Male , Rats, Sprague-Dawley , Solitary Nucleus/physiology , Ventral Tegmental Area/physiology
18.
Horm Behav ; 125: 104825, 2020 09.
Article in English | MEDLINE | ID: mdl-32771417

ABSTRACT

The endocannabinoid system (ECs) is a well known contributor to the hedonic regulation of food intake (FI) in mammals whereas in fish, the knowledge regarding hedonic mechanisms that control FI is limited. Previous studies reported the involvement of ECs in FI regulation in fish since anandamide (AEA) treatment induced enhanced FI and changes of mRNA abundance of appetite-related neuropeptides through cannabinoid receptor 1 (cnr1). However, no previous studies in fish evaluated the impact of palatable food like high-fat diets (HFD) on mechanisms involved in hedonic regulation of FI including the possible involvement of ECs. Therefore, we aimed to evaluate the effect of feeding a HFD on the response of ECs in rainbow trout (Oncorhynchus mykiss). First, we demonstrated a higher intake over 4 days of HFD compared with a control diet (CD). Then, we evaluated the postprandial response (1, 3 and 6 h) of components of the ECs in plasma, hypothalamus, and telencephalon after feeding fish with CD and HFD. The results obtained indicate that the increased FI of HFD occurred along with increased levels of 2-arachidonoylglycerol (2-AG) and AEA in plasma and in brain areas like hypothalamus and telencephalon putatively involved in hedonic regulation of FI in fish. Decreased mRNA abundance of EC receptors like cnr1, gpr55 and trpv1 suggest a feed-back counter-regulatory mechanism in response to the increased levels of EC. Furthermore, the results also suggest that neural activity players associated to FI regulation in mammals as cFOS, γ-Amino butyric acid (GABA) and brain derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase (NTRK) systems could be involved in the hedonic eating response to a palatable diet in fish.


Subject(s)
Diet, High-Fat , Endocannabinoids/metabolism , Oncorhynchus mykiss/metabolism , Receptor, Cannabinoid, CB1/metabolism , Animals , Appetite/drug effects , Appetite/genetics , Appetite Regulation/drug effects , Appetite Regulation/physiology , Brain/drug effects , Brain/metabolism , Dietary Fats/pharmacology , Eating/drug effects , Eating/genetics , Energy Metabolism/drug effects , Energy Metabolism/genetics , Gene Expression Regulation/drug effects , Hypothalamus/drug effects , Hypothalamus/metabolism , Neuropeptides/drug effects , Neuropeptides/genetics , Neuropeptides/metabolism , Oncorhynchus mykiss/physiology , Receptor, Cannabinoid, CB1/genetics , Telencephalon/drug effects , Telencephalon/metabolism
19.
Benef Microbes ; 11(4): 347-359, 2020 Aug 12.
Article in English | MEDLINE | ID: mdl-32720835

ABSTRACT

The pig is a valuable animal model to study obesity in humans due to the physiological similarity between humans and pigs in terms of digestive and associated metabolic processes. The dietary use of vegetal protein, probiotics and omega-3 fatty acids is recommended to control weight gain and to fight obesity-associated metabolic disorders. Likewise, there are recent reports on their beneficial effects on brain functions. The hypothalamus is the central part of the brain that regulates food intake by means of the production of food intake-regulatory hypothalamic neuropeptides, as neuropeptide Y (NPY), orexin A and pro-opiomelanocortin (POMC), and neurotransmitters, such as dopamine and serotonin. Other mesolimbic areas, such as the hippocampus, are also involved in the control of food intake. In this study, the effect of a high fat diet (HFD) alone or supplemented with these additives on brain neuropeptides and neurotransmitters was assessed in forty-three young pigs fed for 10 weeks with a control diet (T1), a high fat diet (HFD, T2), and HFD with vegetal protein supplemented with Bifidobacterium breve CECT8242 alone (T3) or in combination with omega-3 fatty acids (T4). A HFD provoked changes in regulatory neuropeptides and 3,4-dihydroxyphenylacetic acid (DOPAC) in the hypothalamus and alterations mostly in the dopaminergic system in the ventral hippocampus. Supplementation of the HFD with B. breve CECT8242, especially in combination with omega-3 fatty acids, was able to partially reverse the effects of HFD. Correlations between productive and neurochemical parameters supported these findings. These results confirm that pigs are an appropriate animal model alternative to rodents for the study of the effects of HFD on weight gain and obesity. Furthermore, they indicate the potential benefits of probiotics and omega-3 fatty acids on brain function.


Subject(s)
Appetite Regulation/drug effects , Diet, High-Fat/adverse effects , Dietary Supplements , Fatty Acids, Omega-3/pharmacology , Neuropeptides/metabolism , Neurotransmitter Agents/metabolism , Probiotics/pharmacology , 3,4-Dihydroxyphenylacetic Acid/analysis , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Disease Models, Animal , Fatty Acids, Omega-3/administration & dosage , Female , Hippocampus/drug effects , Hippocampus/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Neuropeptides/analysis , Neurotransmitter Agents/analysis , Obesity/etiology , Obesity/metabolism , Obesity/prevention & control , Swine , Weight Gain/drug effects
20.
Food Funct ; 11(8): 7095-7103, 2020 Aug 01.
Article in English | MEDLINE | ID: mdl-32729586

ABSTRACT

Circulating tryptophan/large neutral amino acids (tryptophan/LNAA) ratio, an indicator of brain serotonin levels, may be important in appetite regulation, together with gastrointestinal (gastric emptying, plasma cholecystokinin) mechanisms. We have compared effects of intragastric tryptophan ('Trp') on the plasma tryptophan/LNAA ratio in lean and obese men, and the associations of the tryptophan/LNAA ratio, gastric emptying and CCK concentrations with energy intake. Lean and obese male participants (n = 16 each) received 3 g Trp or volume-matched control intragastrically, 15 min before a mixed-nutrient drink (300 mL, 400 kcal) (t = 0 min) in randomised, double-blind fashion. Plasma amino acid (for calculation of the plasma tryptophan/LNAA ratio) and CCK concentrations were measured from t = -20-60 min. Gastric emptying was assessed from t = 0-60 min, and ad-libitum energy intake from a standardised buffet-style meal from t = 60-90 min. The increase in the plasma tryptophan/LNAA ratio was less in obese, than lean, participants (P < 0.05), and greater in lean participants who reduced their energy intake (by >0 kcal) after Trp compared with those who did not (by ≤0 kcal) (P < 0.05). Moreover, in participants who reduced their energy intake, the ratio was lower in obese, than in lean (P < 0.05). There was a trend for an inverse correlation between energy intake with the plasma tryptophan/LNAA ratio in lean (r = -0.4, P = 0.08), but not in obese, participants. There was no significant difference in gastric emptying or CCK between participants who reduced their energy intake and those who did not. In conclusion, the plasma tryptophan/LNAA ratio appears to be a determinant of the suppression of energy intake in response to tryptophan in normal-weight people, but not in those with obesity. The role of the plasma tryptophan/LNAA ratio to regulate energy intake, and potential changes in obesity, warrant evaluation in prospective studies.


Subject(s)
Amino Acids, Neutral/blood , Energy Intake/drug effects , Obesity/blood , Tryptophan/administration & dosage , Tryptophan/blood , Adult , Amino Acids/blood , Appetite Regulation/drug effects , Body Mass Index , Cholecystokinin/blood , Double-Blind Method , Gastric Emptying/drug effects , Humans , Ideal Body Weight , Infusions, Parenteral , Male , Meals/drug effects , Obesity/drug therapy
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