ABSTRACT
OBJECTIVES: Obesity is often the result of a high-calorie and unbalanced diet for a long time and can sometimes be associated with hyperphagia and eating disorders. Neurotensin (NT) is an anorexigenic peptide, which is secreted from the central nervous system and intestines, and increases intestinal fat absorption. In the literature, conflicting results regarding serum NT level in obesity and the relation of NT with metabolic parameters were reported. Besides, there is no data regarding the relation of NT with eating disorders or food preference in obese individuals. We aimed to evaluate the relation of serum NT level with metabolic parameters, hyperphagia, binge eating disorder (BED) and food preference in obese adolescents. METHODS: The study included 65 obese adolescents and 65 healthy controls. Anthropometric measurements, biochemical analyzes and body fat analyzes were performed in all cases. Hyperphagia score, presence of BED and three-day food intake records were also evaluated. RESULTS: NT level was significantly higher in obese adolescents than in controls and it was not associated with metabolic parameters, hyperphagia or food preference. In the obese group, NT level was not significantly different according to the presence of BED. CONCLUSIONS: Serum NT level is high in obese adolescents; however, it is not associated with metabolic parameters, hyperphagia, BED or food preference.
Subject(s)
Biomarkers/blood , Energy Intake , Food Preferences/physiology , Hyperphagia/pathology , Neurotensin/blood , Pediatric Obesity/physiopathology , Adolescent , Case-Control Studies , Child , Female , Follow-Up Studies , Humans , Hyperphagia/blood , Male , PrognosisABSTRACT
BACKGROUND/OBJECTIVES: In recent years, oxytocin (OXT) and polymorphisms in the oxytocin receptor (OXTR) gene have been reported to play roles in obesity pathogenesis. However, there was no study evaluating OXTR gene variants in childhood obesity. The aim of the study was to investigate the relation of OXTR gene polymorphisms and serum OXT levels with metabolic and anthropometric parameters in obese and healthy adolescents. SUBJECTS/METHODS: The study was a multi-centered case-control study, which was conducted on obese and healthy adolescents aged between 12 and 17 years. Serum OXT and leptin levels were measured, and OXTR gene variants were studied by qPCR (rs53576) and RFLP (rs2254298) methods. RESULTS: A total of 250 obese and 250 healthy adolescents were included in this study. In the obese group, serum OXT level was lower and leptin level was higher than the control group. In the obese group, frequencies of homozygous mutant (G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were higher than the control group. Homozygous mutant(G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were found to increase the risk of obesity compared to the wild type (A/A) genotype [OR = 6.05 and OR = 3.06; p < 0.001, respectively]. In patients with homozygous mutant (G/G) and heterozygous (A/G) genotype for rs53576 polymorphism, serum OXT levels were lower than the wild type (A/A) genotype. In the obese group, hyperphagia score was higher than the control group and correlated negatively with serum OXT level. CONCLUSIONS: This study revealed that low serum OXT level, which is associated with hyperphagia may be an underlying cause for obesity in adolescents. For rs53576 polymorphism of the OXTR gene, obesity risk is higher in patients with homozygous mutant(G/G) and heterozygous(A/G)genotypes.
Subject(s)
Hyperphagia/complications , Oxytocin/analysis , Pediatric Obesity/complications , Polymorphism, Genetic , Receptors, Oxytocin/genetics , Adolescent , Case-Control Studies , Female , Humans , Hyperphagia/blood , Male , Oxytocin/blood , Pediatric Obesity/bloodABSTRACT
This study investigated metabolic, endocrine, appetite and mood responses to a maximal eating occasion in fourteen men (mean: age 28 (sd 5) years, body mass 77·2 (sd 6·6) kg and BMI 24·2 (sd 2·2) kg/m2) who completed two trials in a randomised crossover design. On each occasion, participants ate a homogenous mixed-macronutrient meal (pizza). On one occasion, they ate until 'comfortably full' (ad libitum) and on the other, until they 'could not eat another bite' (maximal). Mean energy intake was double in the maximal (13 024 (95 % CI 10 964, 15 084) kJ; 3113 (95 % CI 2620, 3605) kcal) compared with the ad libitum trial (6627 (95 % CI 5708, 7547) kJ; 1584 (95 % CI 1364, 1804) kcal). Serum insulin incremental AUC (iAUC) increased approximately 1·5-fold in the maximal compared with ad libitum trial (mean: ad libitum 43·8 (95 % CI 28·3, 59·3) nmol/l × 240 min and maximal 67·7 (95 % CI 47·0, 88·5) nmol/l × 240 min, P < 0·01), but glucose iAUC did not differ between trials (ad libitum 94·3 (95 % CI 30·3, 158·2) mmol/l × 240 min and maximal 126·5 (95 % CI 76·9, 176·0) mmol/l × 240 min, P = 0·19). TAG iAUC was approximately 1·5-fold greater in the maximal v. ad libitum trial (ad libitum 98·6 (95 % CI 69·9, 127·2) mmol/l × 240 min and maximal 146·4 (95 % CI 88·6, 204·1) mmol/l × 240 min, P < 0·01). Total glucagon-like peptide-1, glucose-dependent insulinotropic peptide and peptide tyrosine-tyrosine iAUC were greater in the maximal compared with ad libitum trial (P < 0·05). Total ghrelin concentrations decreased to a similar extent, but AUC was slightly lower in the maximal v. ad libitum trial (P = 0·02). There were marked differences on appetite and mood between trials, most notably maximal eating caused a prolonged increase in lethargy. Healthy men have the capacity to eat twice the energy content required to achieve comfortable fullness at a single meal. Postprandial glycaemia is well regulated following initial overeating, with elevated postprandial insulinaemia probably contributing.
Subject(s)
Affect/physiology , Appetite/physiology , Hyperphagia/blood , Meals/physiology , Postprandial Period/physiology , Adult , Area Under Curve , Blood Glucose/analysis , Body Mass Index , Cross-Over Studies , Dipeptides/blood , Energy Intake/physiology , Gastric Inhibitory Polypeptide/blood , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Humans , Insulin/blood , Male , Young AdultABSTRACT
Obesity is a major risk factors for type 2 diabetes, and weight loss is beneficial to diabetic patients who are obese or overweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic drugs. Although it has been known that the effect of most of the DPP-4 inhibitors on body weight is neutral, several studies suggested that some DPP-4 inhibitors suppressed body weight. Nonetheless, the mechanisms underlying DPP-4 inhibitor-induced weight loss are not fully understood. In this study, the mice fed high-fat high sucrose diet (HFHSD) containing a DPP4 inhibitor, anagliptin, showed reduced food intake and body weight compared to the mice fed non-treated HFHSD, but oxygen consumption and respiratory exchange ratio (RER) were not altered. Sequential administration of leptin suppressed food intake and body weight more apparently in anagliptin treated HFHSD fed mice than non-treated HFHSD fed mice. Oxygen consumption and RER were comparable between anagliptin treated and non-treated mice after leptin administration. The number of phospho STAT3 expressed cells in the arcuate nucleus after leptin administration was increased in anagliptin treated mice compared to non-treated mice. These data suggested that anagliptin ameliorated leptin resistance induced by HFHSD and thereby decreased food intake and body weight. These effects of anagliptin could be beneficial to the treatment of obese diabetic patients.
Subject(s)
Body Weight/drug effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Eating/drug effects , Hyperphagia/drug therapy , Leptin/pharmacology , Obesity/drug therapy , Pyrimidines/therapeutic use , Animals , Diet, High-Fat/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hyperphagia/blood , Leptin/blood , Mice , Motor Activity/drug effects , Obesity/blood , Obesity/etiology , Oxygen Consumption/drug effects , Pyrimidines/pharmacologyABSTRACT
The concept of food addiction refers to addiction-like behaviours that develop in association with the intake of highly palatable foods. Previous research indicates that a high proportion of individuals with Major Depressive Disorder (MDD) meet the criteria for food addiction, and are also at an increased risk of weight gain and chronic disease. In the central nervous system, dopamine is a neurotransmitter associated with reward salience and food intake, whereas peripheral dopamine is involved in sympathetic stress regulation, digestion and gastrointestinal motility. However, little research has examined relationships between peripheral dopamine, depressive symptoms and problematic eating behaviours in MDD. Biometrics, psychopathology and plasma dopamine levels were compared between participants with MDD (n = 80) and controls (n = 60). Participants were sub-categorised into those meeting or not meeting Yale Food Addiction Scale (YFAS) criteria. Psychometric measures of mood and appetite were used to assess MDD symptoms, problematic eating behaviours and food-addiction related symptoms. Twenty-three (23; 29%) MDD participants met the Yale criteria for food addiction. Depressed individuals meeting YFAS criteria had significantly greater psychopathology scores for both mood and eating compared to depressed individuals not meeting YFAS criteria and controls. A significant interaction between food addiction status and sex was also observed for plasma dopamine levels. Plasma dopamine levels correlated positively with disordered eating behaviours in females, and negatively in males. The results provide evidence that depressogenic excess eating and weight gain are associated with peripheral dopamine levels. Longitudinal research is warranted investigating endocrine dysregulation and excess eating in MDD, which may inform interventions and reduce chronic disease risk in affected individuals.
Subject(s)
Depressive Disorder, Major , Dopamine/blood , Eating , Feeding Behavior , Feeding and Eating Disorders , Food Addiction , Hyperphagia , Adolescent , Adult , Affect , Appetite , Behavior, Addictive/blood , Behavior, Addictive/physiopathology , Binge-Eating Disorder , Bulimia , Depression/blood , Depression/physiopathology , Depressive Disorder, Major/blood , Depressive Disorder, Major/physiopathology , Eating/physiology , Eating/psychology , Feeding Behavior/physiology , Feeding Behavior/psychology , Feeding and Eating Disorders/blood , Feeding and Eating Disorders/physiopathology , Female , Food , Food Addiction/blood , Food Addiction/physiopathology , Humans , Hyperphagia/blood , Hyperphagia/physiopathology , Middle Aged , Psychometrics , Sex Factors , Weight Gain , Young AdultABSTRACT
Objective. Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats.Methods. Thirty two male Wistar rats (200-220g) were randomly divided into: control, VitC, CIS, and CIS + VitC groups. Animals received VitC (500 mg/kg/day)/saline by gavage for 3 weeks. For 24 h cumulative and post 18-20 h fasting food intake, fasting plasma ghrelin level, and body weight were measured. Gastric histopathology was also evaluated.Results. Results showed a marked increase in fasting plasma ghrelin and food intake in stressed rats compared to controls. VitC prevented the increases in stressed rats. Histological assessment indicated a positive effect of VitC on gastric glandular cells compared to control, an effect that might partially be a reason of significant increase of plasma ghrelin levels in VitC rats. Elevated plasma ghrelin in VitC group was even higher than that one in stressed group, whereas there were no significant changes in the food intake. Assessment of the percentage of changes in body weight during 21 days showed a significant increase in stressed rats compared to controls. Vitamin C treatment prevented this increase. Stressed rats also displayed depression-like behavior as indicated by sucrose test, whereas VitC ameliorated it.Conclusions. The data of the present study indicate that VitC may overcome ghrelin-induced hyperphagia and improve the abnormal feeding and depressive behavior in CIS rats.
Subject(s)
Ascorbic Acid/pharmacology , Depression , Ghrelin/drug effects , Hyperphagia , Social Isolation , Stress, Psychological , Weight Gain/drug effects , Animals , Ascorbic Acid/administration & dosage , Behavior, Animal/drug effects , Behavior, Animal/physiology , Depression/blood , Depression/etiology , Depression/prevention & control , Disease Models, Animal , Eating/drug effects , Hyperphagia/blood , Hyperphagia/etiology , Hyperphagia/prevention & control , Male , Rats , Rats, Wistar , Stress, Psychological/blood , Stress, Psychological/etiology , Stress, Psychological/prevention & controlABSTRACT
OBJECTIVE: Potential mechanisms of abnormal food intake, such as dysregulation of meal-related appetite hormones, including acyl ghrelin (AG) and des-acyl ghrelin (DAG), were investigated among men and women with obesity, with and without binge eating (BE). METHODS: Participants (n = 42: 19 female, 23 male) were assigned to a liquid meal and water condition in counterbalanced order, and blood samples for measuring hormones were obtained before and after these conditions. RESULTS: Participants with BE had significantly lower fasting and postingestive AG concentrations than participants without BE in both conditions. During the meal condition, postprandial decreases in AG concentrations were significantly smaller for the BE group than for the non-BE group. There were no significant differences in DAG by BE group. Leptin increased significantly less after meals for those with BE compared with those without BE. There were no differences in other hormones by BE group. Fasting and postmeal hunger ratings were significantly higher for those with BE than for those without BE. CONCLUSIONS: In individuals with BE, lower fasting AG may be due to downregulation by habitual overeating, and a smaller postmeal decline in AG may contribute to overeating. Lower postmeal leptin concentrations may also contribute to overeating.
Subject(s)
Appetite/physiology , Bulimia/blood , Eating/physiology , Ghrelin/blood , Obesity/blood , Adult , Binge-Eating Disorder/blood , Binge-Eating Disorder/complications , Bulimia/complications , Cholecystokinin/blood , Female , Glucagon-Like Peptide 1/blood , Humans , Hyperphagia/blood , Hyperphagia/complications , Insulin/blood , Leptin/blood , Male , Meals , Middle Aged , Obesity/complications , Peptide YY/blood , Postprandial Period/physiology , Young AdultABSTRACT
The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female cycling and pregnant rats. In the nonpregnant state, female Sprague-Dawley rats offered a 3-wk free-choice high-fat, high-sucrose diet had greater energy intake, adiposity, serum leptin, and triglyceride concentrations compared with rats fed with standard chow and developed glucose intolerance. In addition, choice-diet-fed rats had larger cardiac ventricular weights, smaller kidney and pancreas weights, and higher blood pressure than chow-fed rats, but they did not exhibit resistance artery endothelial dysfunction. When the free-choice diet continued throughout pregnancy, rats remained hyperphagic, hyperleptinemic, and obese. Choice pregnant rats exhibited uterine artery endothelial dysfunction and had smaller fetuses compared with chow pregnant rats. Pregnancy normalized mean arterial blood pressure and pancreas weights in choice rats. These studies are the first to provide a comprehensive evaluation of free-choice high-fat, high-sucrose diet on metabolic and cardiovascular functions in female rats, extending the previous studies in males to female cycling and pregnant rodents. Free-choice diet may provide a new model of preconceptual maternal obesity to study the role of increased energy intake, individual food components, and preexisting maternal obesity on maternal and offspring physiological responses during pregnancy and after birth.
Subject(s)
Cardiovascular Diseases/etiology , Diet, High-Fat/adverse effects , Dietary Sucrose/toxicity , Energy Metabolism , Estrous Cycle , Fetal Growth Retardation/etiology , Hyperphagia/etiology , Obesity/etiology , Adiposity , Animal Nutritional Physiological Phenomena , Animals , Behavior, Animal , Biomarkers/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/physiopathology , Choice Behavior , Dietary Sucrose/metabolism , Feeding Behavior , Female , Fetal Growth Retardation/blood , Fetal Growth Retardation/physiopathology , Hemodynamics , Hyperphagia/blood , Hyperphagia/physiopathology , Hyperphagia/psychology , Maternal Nutritional Physiological Phenomena , Nutritional Status , Obesity/blood , Obesity/physiopathology , Pregnancy , Rats, Sprague-Dawley , Weight GainABSTRACT
BACKGROUND: The neurobiological mechanisms involved in divergent appetitive phenotypes in major depressive disorder (MDD) are not well understood, although recent data suggest disruption in mesolimbic reward circuitry. Ghrelin, an orexigenic hormone, has been shown to modulate the reward circuitry. We aimed to investigate the relationship between acylated ghrelin levels and the neural response to food stimuli in individuals with hyperphagic and hypophagic MDD in remission. METHODS: Women with hyperphagic MDD (nâ¯=â¯10), hypophagic MDD (nâ¯=â¯18), and healthy controls (HC; nâ¯=â¯18) underwent fMRI scanning during which they viewed images of food. The fMRI session was followed by a standardized meal, appetite ratings, and serial blood draws. RESULTS: In individuals with hyperphagic MDD, greater change in acylated ghrelin in response to a meal was associated with increased BOLD response to high-calorie food in the bilateral ventral tegmental area and left hypothalamus. In contrast, negative associations were observed between acylated ghrelin AUC and BOLD activity in the right hypothalamus in the hypophagic MDD group. LIMITATIONS: Unbalanced group sizes with a relatively small sample in the hyperphagic MDD group. CONCLUSIONS: In the absence of differences in absolute ghrelin levels between the hyperphagic MDD and HC groups, results in hyperphagic MDD might suggest a ghrelinergic signaling mechanism for increased appetite during an MDD episode in this group. Our findings shed light on interactions between appetite hormones and mesolimbic circuitry which could contribute to development of therapeutic targets for opposing appetite phenotypes in depression.
Subject(s)
Depressive Disorder, Major/blood , Food Preferences , Food , Ghrelin/blood , Hyperphagia/blood , Adult , Appetite/physiology , Brain Mapping , Depressive Disorder, Major/psychology , Energy Intake , Female , Humans , Hyperphagia/psychology , Magnetic Resonance Imaging , Reward , Young AdultABSTRACT
PURPOSE: Glucagon-like peptide 1 (GLP-1) is an incretin hormone that appears to play a major role in the control of food intake. The aim of this investigation was to evaluate and quantify the association of circulating GLP-1 concentration with ad libitum total calorie and macronutrient intake. METHODS: One-hundred and fifteen individuals (72 men) aged 35 ± 10 years were admitted for an inpatient study investigating the determinants of energy intake. Ad libitum food intake was assessed during 3 days using a reproducible vending machine paradigm. Fasting plasma GLP-1 concentrations were measured on the morning of the first day and on the morning of the fourth day after ad libitum feeding. RESULTS: Plasma GLP-1 concentrations increased by 14% after 3 days of ad libitum food intake. Individuals overate on average 139 ± 45% of weight-maintaining energy needs. Fasting plasma GLP-1 on day 1 was negatively associated with carbohydrate intake (r = - 0.2, p = 0.03) and with daily energy intake from low fat-high simple sugar (r = - 0.22, p = 0.016). CONCLUSION: Higher plasma GLP-1 concentrations prior to ad libitum food intake were associated with lower carbohydrate intake and lower simple sugar ingestion, indicating a possible role of the GLP-1 in the reward pathway regulating simple sugar intake. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00342732.
Subject(s)
Carbohydrates/administration & dosage , Eating/drug effects , Energy Intake/drug effects , Fasting/blood , Glucagon-Like Peptide 1/blood , Hyperphagia/blood , Adult , Female , Follow-Up Studies , Humans , MaleABSTRACT
CONTEXT AND OBJECTIVE: Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available. METHODS AND DESIGN: Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50-70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures. RESULTS: AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion. CONCLUSIONS: AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.
Subject(s)
Feeding Behavior/drug effects , Ghrelin/therapeutic use , Hyperphagia/drug therapy , Hypoglycemic Agents/therapeutic use , Peptide Fragments/therapeutic use , Peptides, Cyclic/therapeutic use , Prader-Willi Syndrome/drug therapy , Adolescent , Adult , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/therapeutic use , Appetite/drug effects , Appetite/physiology , Blood Glucose/drug effects , Body Composition/drug effects , Body Weight/drug effects , Double-Blind Method , Feeding Behavior/physiology , Female , Follow-Up Studies , Ghrelin/adverse effects , Humans , Hyperphagia/blood , Hyperphagia/genetics , Hypoglycemic Agents/adverse effects , Male , Middle Aged , Peptide Fragments/adverse effects , Peptides, Cyclic/adverse effects , Prader-Willi Syndrome/blood , Prader-Willi Syndrome/genetics , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: Overfeeding is a strategy for evaluating the effects of excess energy intake. In this secondary analysis we tested the possibility that different levels of dietary protein might differentially modify the response of fatty acyl-carnitines to overfeeding. METHODS: Twenty-three healthy adult men and women were overfed by 40% for 8â¯weeks while in-patients with diets containing 5% (LPD), 15% (NPD) or 25% (HPD) protein. Plasma fatty acyl-carnitines were measured by gas chromatography/mass spectrometry (GC/MS) at baseline and after 8â¯weeks of overfeeding. Measurements included: body composition by DXA, energy expenditure by ventilated hood and doubly-labeled water, fat cell size from subcutaneous fat biopsies, and fat distribution by CT scan. RESULTS: Analysis was done on 5 groups of fatty acyl-carnitines identified by principal components analysis and 6 individual short-chain fatty acyl carnitines. Higher protein intake was associated with significantly lower 8â¯week levels of medium chain fatty acids and C2, C4-OH and C 6:1, but higher values of C3 and C5:1 acyl-carnitines derived from essential amino acids. In contrast energy and fat intake were only weakly related to changes in fatty acyl-carnitines. A decease or smaller rise in 8â¯week medium chain acyl-carnitines was associated with an increase in sleeping energy expenditure (Pâ¯=â¯0.0004), and fat free mass (Pâ¯<â¯0.0001) and a decrease in free fatty acid concentrations (FFA) (Pâ¯=â¯0.0067). In contrast changes in short-chain fatty acyl-carnitines were related to changes in resting energy expenditure (Pâ¯=â¯0.0026), and fat free mass (Pâ¯=â¯0.0007), and C4-OH was positively related to FFA (Pâ¯=â¯0006). CONCLUSION: Protein intake was the major factor influencing changes in fatty acyl carnitines during overfeeding with higher values of most acyl-fatty acids on the low protein diet. The association of dietary protein and fat intake may explain the changes in energy expenditure and metabolic variables resulting in the observed patterns of fatty acyl carnitines.
Subject(s)
Body Composition/physiology , Carnitine/analogs & derivatives , Carnitine/blood , Energy Metabolism/physiology , Fatty Acids/blood , Hyperphagia/blood , Hyperphagia/metabolism , Adolescent , Adult , Diet , Energy Intake , Female , Humans , Male , Young AdultSubject(s)
Acute Kidney Injury/etiology , Feeding Behavior/psychology , Gastric Outlet Obstruction/etiology , Hyperphagia/complications , Pancreatitis/etiology , Abdominal Pain/blood , Abdominal Pain/diagnostic imaging , Abdominal Pain/etiology , Acidosis/blood , Acute Kidney Injury/blood , Acute Kidney Injury/diagnostic imaging , Acute Kidney Injury/therapy , Adult , Competitive Behavior , Duodenum/diagnostic imaging , Gastric Lavage , Gastric Outlet Obstruction/blood , Gastric Outlet Obstruction/diagnostic imaging , Gastric Outlet Obstruction/therapy , Humans , Hyperphagia/blood , Hyperphagia/diagnostic imaging , Pancreatitis/blood , Pancreatitis/diagnostic imaging , Pancreatitis/therapy , Stomach/diagnostic imaging , Tomography, X-Ray Computed , Vomiting/blood , Vomiting/diagnostic imaging , Vomiting/etiologyABSTRACT
BACKGROUND: Obesity and type 2 diabetes (T2D) increase fracture risk; however, the association between obesity/T2D may be confounded by consumption of a diet high in fat, sucrose, and cholesterol (HFSC). OBJECTIVE: The study objective was to determine the main and interactive effects of obesity/T2D and a HFSC diet on bone outcomes using hyperphagic Otuska Long Evans Tokushima Fatty (OLETF) rats and normophagic Long Evans Tokushima Otsuka (LETO) controls. METHODS: At 8weeks of age, male OLETF and LETO rats were randomized to either a control (CON, 10 en% from fat as soybean oil) or HFSC (45 en% from fat as soybean oil/lard, 17 en% sucrose, and 1wt%) diet, resulting in four treatment groups. At 32weeks, total body bone mineral content (BMC) and density (BMD) and body composition were measured by dual-energy X-ray absorptiometry, followed by euthanasia and collection of blood and tibiae. Bone turnover markers and sclerostin were measured using ELISA. Trabecular microarchitecture of the proximal tibia and geometry of the tibia mid-diaphysis were measured using microcomputed tomography; whole-bone and tissue-level biomechanical properties were evaluated using torsional loading of the tibia. Two-factor ANOVA was used to determine main and interactive effects of diet (CON vs. HFSC) and obesity/T2D (OLETF vs. LETO) on bone outcomes. RESULTS: Hyperphagic OLEFT rats had greater final body mass, body fat, and fasting glucose than normophagic LETO, with no effect of diet. Total body BMC and serum markers of bone formation were decreased, and bone resorption and sclerostin were increased in obese/T2D OLETF rats. Trabecular bone volume and microarchitecture were adversely affected by obesity/T2D, but not diet. Whole-bone and tissue-level biomechanical properties of the tibia were not affected by obesity/T2D; the HFSC diet improved biomechanical properties only in LETO rats. CONCLUSIONS: Obesity/T2D, regardless of diet, negatively impacted the balance between bone formation and resorption and trabecular bone volume and microarchitecture in OLETF rats.
Subject(s)
Bone and Bones/pathology , Cholesterol/adverse effects , Diabetes Mellitus, Type 2/complications , Diet, High-Fat , Hyperphagia/complications , Obesity/complications , Sucrose/adverse effects , Animals , Biomarkers/blood , Biomechanical Phenomena , Body Weight , Bone Remodeling , Bone and Bones/diagnostic imaging , Bone and Bones/physiopathology , Cancellous Bone/pathology , Collagen/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/pathology , Diaphyses/pathology , Diaphyses/physiopathology , Glycation End Products, Advanced/metabolism , Hyperphagia/blood , Hyperphagia/pathology , Minerals/metabolism , Obesity/blood , Obesity/pathology , Rats, Inbred OLETF , Tibia/pathology , Tibia/physiopathology , X-Ray MicrotomographyABSTRACT
The effect of gestational hypoxia on the neonatal leptin surge, development of hypothalamic arcuate nuclei (ARH) projections and appetite that could contribute to the programming of offspring obesity is lacking. We examined the effect of 12% O2 from gestational days 15-19 in the Sprague-Dawley rat on post-weaning appetite, fat deposition by MRI, adipose tissue cytokine expression, the neonatal leptin surge, ARH response to exogenous leptin, and αMSH projections to the paraventricular nucleus (PVN) in response to a high fat (HFD) or control diet (CD) in male offspring. Normoxia (NMX) and Hypoxia (HPX) offspring exhibited increased food intake when fed a HFD from 5-8 weeks post-birth; HPX offspring on the CD had increased food intake from weeks 5-7 vs. NMX offspring on a CD. HPX offspring on a HFD remained hyperphagic through 23 weeks. Body weight were the same between offspring from HPX vs. NMX dams from 4-12 weeks of age fed a CD or HFD. By 14-23 weeks of age, HPX offspring fed the CD or HFD as well as male NMX offspring fed the HFD were heavier vs. NMX offspring fed the CD. HPX offspring fed a CD exhibited increased abdominal adiposity (MRI) that was amplified by a HFD. HPX offspring fed a HFD exhibited the highest abdominal fat cytokine expression. HPX male offspring had higher plasma leptin from postnatal day (PN) 6 through 14 vs. NMX pups. HPX offspring exhibited increased basal c-Fos labeled cells in the ARH vs. NMX pups on PN16. Leptin increased c-Fos staining in the ARH in NMX but not HPX offspring at PN16. HPX offspring had fewer αMSH fibers in the PVN vs. NMX offspring on PN16. In conclusion, gestational hypoxia impacts the developing ARH resulting in hyperphagia contributing to adult obesity on a control diet and exacerbated by a HFD.
Subject(s)
Hyperphagia/blood , Hyperphagia/complications , Hypoxia/blood , Hypoxia/complications , Leptin/blood , Obesity/blood , Obesity/complications , Adipose Tissue/metabolism , Animals , Animals, Newborn , Anxiety/blood , Anxiety/complications , Arcuate Nucleus of Hypothalamus/metabolism , Behavior, Animal , Diet , Fear , Feeding Behavior , Female , Fetal Weight , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Magnetic Resonance Imaging , Male , Maternal Nutritional Physiological Phenomena , Maze Learning , Motor Activity , Pregnancy , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Water , Weaning , alpha-MSH/metabolismABSTRACT
PURPOSE: Children from smoking mothers have a higher risk of developing obesity and associated comorbidities later in life. Different experimental models have been used to assess the mechanisms involved with this increased risk. Using a rat model of neonatal nicotine exposure via implantation of osmotic minipumps in lactating dams, we have previously shown marked sexual dimorphisms regarding metabolic and endocrine outcomes in the adult progeny. Considering that more than four thousand substances are found in tobacco smoke besides nicotine, we then studied a rat model of neonatal tobacco smoke exposure: adult male offspring had hyperphagia, obesity, hyperglycemia, hypertriglyceridemia, secondary hyperthyroidism and lower adrenal hormones. Since litters were culled to include only males and since sexual dimorphisms had already been identified in the nicotine exposure model, here we also evaluated the effects of tobacco smoke exposure during lactation on females. METHODS: Wistar rat dams and their pups were separated into two groups of 8 litters each: SMOKE (4 cigarettes per day, from postnatal day 3 to 21) and CONTROL (filtered air). Offspring of both sexes were euthanized at PN21 and PN180. RESULTS: Changes in male offspring corroborated previous data. At weaning, females showed lower body mass gain and serum triglycerides, but no alterations in visceral fat and hormones. At adulthood, females had higher body mass, hyperphagia, central obesity, hyperleptinemia, hypercholesterolemia, hypercorticosteronemia, but no change in serum TSH and T3, and adrenal catecholamine CONCLUSIONS: Sexual dimorphisms were observed in several parameters, thus indicating that metabolic and hormonal changes due to smoke exposure during development are sex-dependent.
Subject(s)
Adiposity/drug effects , Eating/drug effects , Hyperphagia/chemically induced , Tobacco Smoke Pollution/adverse effects , Triglycerides/blood , Animals , Animals, Newborn , Female , Hyperphagia/blood , Lactation , Rats , Rats, WistarABSTRACT
Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.
Subject(s)
Appetite Regulation/drug effects , Corticosterone/pharmacology , Hypothalamus/drug effects , Leptin/agonists , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Appetite Depressants/chemistry , Appetite Depressants/pharmacology , Appetite Stimulants/administration & dosage , Appetite Stimulants/agonists , Appetite Stimulants/antagonists & inhibitors , Appetite Stimulants/pharmacology , Behavior, Animal/drug effects , Corticosterone/administration & dosage , Corticosterone/agonists , Corticosterone/antagonists & inhibitors , Dose-Response Relationship, Drug , Energy Intake/drug effects , Hyperphagia/blood , Hyperphagia/chemically induced , Hyperphagia/metabolism , Hyperphagia/pathology , Hypothalamus/metabolism , Hypothalamus/pathology , Leptin/antagonists & inhibitors , Leptin/blood , Leptin/metabolism , Mice, Inbred ICR , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Neurons/metabolism , Neurons/pathology , Organ Specificity , Piperazines/antagonists & inhibitors , Piperazines/pharmacology , Proto-Oncogene Proteins c-fos/agonists , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Spiro Compounds/pharmacology , Sulfonamides/pharmacology , Up-Regulation/drug effectsABSTRACT
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 µg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11ß-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
Subject(s)
Glucocorticoids/metabolism , Hyperphagia/etiology , Hypothalamus/drug effects , Hypothalamus/metabolism , Obesity/etiology , Animals , Body Weight/drug effects , Chromatography, Liquid , Eating/drug effects , Glucocorticoids/blood , Glucocorticoids/pharmacology , Hyperphagia/blood , In Situ Hybridization , Male , Mice , Mice, Inbred C57BL , Obesity/blood , Real-Time Polymerase Chain Reaction , Tandem Mass Spectrometry , Time FactorsABSTRACT
BACKGROUND: Adaptive responses of appetite-mediating hormones to negative energy balance are thought to contribute to a counterregulatory response that drives weight regain, but they have not been studied while controlling for reduced diet volume. OBJECTIVE: In this secondary analysis, we aimed to determine the effects of short-term, severe energy deprivation (ED) on appetite and appetite-mediating hormone concentrations. METHODS: Twenty-one adults with a mean ± SD age of 21 ± 3 y and body mass index of 25 ± 3 kg/m(2) consumed isovolumetric diets provided over separate 48-h periods while increasing habitual energy expenditure by 1683 ± 329 kcal/d through light- and moderate-intensity exercise. Energy intake was matched to energy expenditure to maintain energy balance (EB) (-44 ± 92 kcal/d) or was <10% of energy expenditure to generate a -3696 ± 742-kcal/d energy deficit. Postprandial appetite, glucose, insulin, acyl ghrelin, peptide YY, pancreatic polypeptide (PP), and glucagon-like peptide-1 (GLP-1) responses and ad libitum energy intake were measured as secondary outcomes after both experimental periods. RESULTS: Fasting insulin (-56% ± 42%) and acyl ghrelin (-60% ± 17%) concentrations decreased during ED but not during EB (condition-by-time interaction; P-interaction ≤ 0.01), whereas fasting leptin concentrations decreased more during ED compared with during EB (-47% ± 27% compared with -20% ± 27%; P-interaction = 0.05). Postprandial insulin (57% ± 63%; P < 0.001), GLP-1 (14% ± 28%; P = 0.04), and PP (54% ± 52%; P < 0.001) areas under the curve (AUCs) were higher, whereas the acyl ghrelin AUC was lower (-56% ± 13%; P < 0.001) after ED compared with after EB. After ED, self-rated appetite was greater, and ad libitum energy intake was 811 kcal/36 h (95% CI: 184, 1439 kcal/36 h) higher relative to after EB (P = 0.01). CONCLUSIONS: Short-term, severe ED suppressed acyl ghrelin concentrations and increased postprandial anorexigenic hormone concentrations. These effects preceded compensatory overeating, suggesting that in adults without obesity, altered sensitivity to appetite-mediating hormones may contribute to an adaptive counterregulatory response during the initial stages of negative EB. This trial was registered at clinicaltrials.gov as NCT01603550.
Subject(s)
Appetite , Body Mass Index , Energy Intake , Food Deprivation/physiology , Hormones/blood , Hyperphagia/blood , Satiety Response , Adaptation, Physiological , Adolescent , Adult , Area Under Curve , Blood Glucose/metabolism , Body Weight , Caloric Restriction , Energy Metabolism , Female , Ghrelin/blood , Humans , Hyperphagia/etiology , Male , Postprandial Period , Reference Values , Young AdultABSTRACT
BACKGROUND & AIM: Western diets rich in animal protein and poor in fruit and vegetables increase the body acid load, a predictor of type 2 diabetes risk. The relationships between dietary acid load, mild metabolic acidosis and insulin resistance remain unclear. The objective of this study was to assess the association between dietary acid load, body acid/base markers and peripheral insulin resistance at baseline and following a short-term overfeeding intervention in healthy individuals. METHODS: In a cross-sectional study of 104 men and women, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Plasma lactate, a marker of metabolic acidosis, was assessed and acid load scores (potential renal acid load, PRAL and net endogenous acid production, NEAP) derived from diet diaries. The cohort was grouped into lean and overweight/obese and the latter further classified as insulin-sensitive (Obsen) and insulin-resistant (Obres) based on hyperinsulinemic-euglycemic clamp glucose infusion rate (GIR, top tertile vs. bottom 2 tertiles). A subset of 40 individuals participated in an overfeeding intervention (+1250 kcal/day) for 28 days and studies repeated. RESULTS: Obsen and Obres were matched for adiposity (BMI and fat mass, both P = 1). Fasting plasma lactate was higher in Obres (0.78 [0.63-1.14] mmol/L) compared with both lean (0.71 [0.44-0.90] mmol/L, P = 0.02) and Obsen (0.67 [0.56-0.79] mmol/L, P = 0.04) and not different between lean and Obsen (P = 0.9). Overfeeding was characterized by an increase in dietary acid load scores PRAL (P = 0.003) and NEAP (P = 0.05), a reduction in GIR necessary to maintain euglycemia (P = 0.03) and an increase in fasting plasma lactate (P = 0.02). The change in lactate was inversely associated with the change in GIR (r = -0.36, P = 0.03). CONCLUSIONS: Mild metabolic acidosis, measured by plasma lactate, aligns with insulin resistance independent of obesity and is induced by short-term increases in energy and dietary acid load in healthy humans. Further studies are required to determine whether buffering mild metabolic acidosis improves insulin resistance and reduces diabetes risk.