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Oleoylethanolamide in the Homeostatic and Non- Homeostatic Control of Eating

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Oleoylethanolamide in the Homeostatic and Non- Homeostatic Control of Eating Oleoylethanolamide in the homeostatic and non- homeostatic control of eating A Dissertation in Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Pharmacology and Toxicology Cristina Anna Gallelli Department of Physiology and Pharmacology “Vittorio Erspamer” Sapienza University of Rome Director of the Ph.D Program: Thesis Committee: Prof. Maura Palmery Prof. Paola Casolini Thesis Advisor: Prof. Grazia Graziani Prof. Silvana Gaetani Prof. Luigia Trabace ACADEMIC YEAR 2017-2018 Index 1. Chapter I: General Introduction 1.1. Obesity and eating-related disorders ………………………………………………………..2 1.1.1. The binge eating disorder (BED) …………………………………………………….3 1.2. Neurobiological mechanisms regulating energy homeostasis ………………………………4 1.2.1. Hormonal Signals …………………………………………………………………….9 1.2.2. Neuropeptidergic system …………………………………………………………...13 1.2.2.1. Oxytocinergic system ……………………………………………………….15 1.2.3. Neurotransmitter systems …………………………………………………………...17 1.3. Neurobiological mechanisms regulating stress ……………………………………………23 1.4. Neurobiological mechanisms regulating food addiction …………………………………..25 1.5. Pharmacological treatment for obesity and BED ………………………………………….27 1.6. Oleoylethanolamide and N-acylethanolamides as lipid mediators ………………………..32 1.6.1. Synthesis and metabolism …………………………………………………………..33 1.6.2. Receptors ……………………………………………………………………………35 1.6.3. OEA and the control of food intake ………………………………………………...36 1.6.4. OEA effects in the central nervous system …………………………………………37 1.7. Aim of the thesis …………………………………………………………………………..40 1.8. References …………………………………………………………………………………43 2. Chapter II: Role of the area postrema in the hypophagic effects of oleoylethanolamide Abstract …………………………………………………………………………………………66 2.1. Introduction ………………………………………………………………………………..67 2.2. Materials and Methods …………………………………………………………………….69 2.2.1. Animals and housing ………………………………………………………………..69 2.2.2. Area postrema lesion surgery ……………………………………………………….70 2.2.3. Drugs and treatments ……………………………………………………………….71 2.2.4. Food intake experiment ……………………………………………………………..72 2.2.5. Terminal experiment ………………………………………………………………..72 2.2.6. Immunohistochemistry study ……………………………………………………….72 2.2.7. Brain section analyses ………………………………………………………………74 2.2.8. Statistical analyses ………………………………………………………………….75 2.3. Results ……………………………………………………………………………………..75 2.3.1. APX prevents the hypophagic effect of OEA ………………………………………75 2.3.2. OEA induces Fos in DBH neurons of the AP ………………………………………77 2.3.3. APX prevents OEA-induced DBH and Fos expression in the NST ………………..79 2.3.4. APX prevents OEA induced Fos in the PVN and TMN ……………………………82 2.3.5. APX prevents OEA-induced DBH and OXY expression in the PVN ……………...84 2.3.6. PPAR-alpha receptors are expressed at AP level …………………………………..86 2.4. Discussion …………………………………………………………………………………87 2.5. Conclusions ………………………………………………………………………………..91 2.6. References …………………………………………………………………………………92 3. Chapter III: Evaluation of the brain distribution of oleoylethanolamide and its analogues after acute systemic administration in rats Abstract ………………………………………………………………………………………..97 3.1. Introduction ………………………………………………………………………………98 3.2. Materials and Methods …………………………………………………………………..100 3.2.1. Animals and housing ……………………………………………………………...100 3.2.2. Drugs and treatments ……………………………………………………………...100 3.2.3. Tissue collection …………………………………………………………………..100 3.2.4. N-acylethanolamides extraction …………………………………………………...101 3.2.5. UPLC-MS/MS analyses …………………………………………………………...101 3.2.6. Statistical analyses ………………………………………………………………...103 3.3. Results ……………………………………………………………………………………103 3.3.1. Effects of OEA systemic administration on the levels of OEA and its analogues in selected brain areas ………………………………………………………………….103 3.3.2. Effects of OEA systemic administration on the levels of OEA and its analogues in the plasma …………………………………………………………………………...109 3.4. Discussion ………………………………………………………………………………..111 3.5. References ………………………………………………………………………………..118 4. Chapter IV: Satiety factor oleoylethanolamide prevents binge-like palatable food consumption induced by stress in female rats with a history of food restriction Abstract ………………………………………………………………………………………..123 4.1. Introduction ………………………………………………………………………………125 4.2. Materials and Methods …………………………………………………………………...128 4.2.1. Experimental procedure for Binge-eating induction ………………………………128 4.2.2. Experiment 1: Effects of OEA on stress-induced binge-eating …………………...129 4.2.3. Experiment 2: Effects of OEA on the pattern of c-fos expression and on monoamine turnover in selected brain areas ……………………………………………………...131 4.2.4. Experiment 3: Effects of OEA on dopamine transmission in the AcbSh …………133 4.2.5. Experiment 4: effects of OEA on frustration stress exposure ……………………..134 4.2.6. Statistical Analyses ………………………………………………………………..135 4.3. Results ……………………………………………………………………………………136 4.3.1. The combination of caloric restriction and stress exposure induced BED ………..136 4.3.2. OEA treatment selectively prevented binge-like eating in a dose dependent manner………………………………………………………………………………..137 4.3.3. OEA treatment affected the brain pattern of c-Fos expression in bingeing rats …..138 4.3.4. OEA treatment dampened AcbSh DA release induced by stress exposure or amphetamine challenge ……………………………………………………………...142 4.3.5. OEA treatment affected monoaminergic system in bingeing rats ………………...143 4.3.6. OEA treatment affected CRF mRNA level in the AMY and oxy expression in the PVN of bingeing rats ………………………………………………………………...147 4.4. Discussion ………………………………………………………………………………..150 4.5. Conclusions ………………………………………………………………………………156 4.6. References ………………………………………………………………………………..157 5. Chapter V: Conclusions 5.1. Conclusions ………………………………………………………………………………165 5.2. References ………………………………………………………………………………..167 Chapter I General introduction 1 1.1. Obesity and eating-related disorders Obesity and overweight, defined as abnormal or excessive fat accumulation, are currently considered as major worldwide public health issues 1. According to the World Health Organization (WHO), obesity is recognized as a global epidemic that has been spreading all over the world contributing to the higher incidence of major health problems, thus increasing mortality. The high levels of intra-abdominal or visceral fat that are associated with this clinical condition are the most responsible for the development of the main obesity comorbidities such as hypertension, dyslipidemia, type 2 diabetes, osteoarthritis, and changes in the reproductive system 2. Obesity is a multifactorial disease and among the several conditions that predispose to the weight gain and consequently to obesity, it is well known that genetic, environmental and physiologic factors play a key role 3. Moreover, some medications can contribute to the development of this complex disease by increasing appetite, reducing the basal metabolic rate and by stimulating adipose cells proliferation as well. Among the pharmacological classes that might be more commonly involved in this process there are antidepressants and corticosteroids 4,5. More rarely obesity is the consequence of other medical conditions including Prader Willi 6 and Cushing syndrome 7, hypothyroidism or hypothalamic dysfunctions 8. The current most commonly used method for classifying obesity is the body mass index (BMI), calculated as weight (kg) divided by the square of the height (m2), which ranges between 25 and 29.9 in overweight individuals whereas it is equal to or more than 30 in obese-classified patients 9,10. Furthermore, waist circumference, another marker of excess body fat, has becoming discriminating as a measure of overweight/obesity 11. The WHO estimated that in 2016 more than 1.9 billion adults, over the age of 18 years old, were overweight, of these over 650 million were obese 12. Since over the past 40 years it has been registered a huge increase in the percentage of overweight and obese individuals worldwide, it has been estimated that by 2030 the 38% of the world’s adult population will be overweight and another 20% will be obese 13. Moreover, changes in body weight are frequently accompanied by psychological and psychosocial problems thus leading to persistent disrupted eating behaviours, which are defined as eating disorders (EDs). 2 EDs are currently considered, likewise obesity, major health problems worldwide and they are characterized by altered dietary habits and impaired physical health. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) recognizes three different EDs: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) 14. The latter will be abundantly discussed in the following paragraph since it is one of the main topic of this experimental dissertation. Although EDs can occur in adults or young individuals indiscriminately, adolescence represents the most vulnerable period for the onset of these diseases 15. The main criteria for classifying an individual affected by AN are represented by: a persistent caloric restriction followed by a considerable body weight loss with a BMI of 17.5 or even less 16; a strong fear to gain weight along with a distorted body image perception 14. AN occurs more commonly among women than men (80-90% of patients with AN are female) and it reaches a peak incidence in adolescents between 14 and 17 years 15. Moreover, AN is often linked with depressive disorder 17, obsessive compulsive disorder and autism spectrum disorder 18, counting the highest mortality of any
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