Epigenetic modulation of eating disorders and obesity: searching for new pharmacotherapies

Research project

Description

Obesity, and eating disorders (ED) are urgent public health problems, potentially affecting emotional and physical health, with a relevant mortality rate and a high burden of disease for our societies. Core symptoms of these extremely heterogeneous diseases are disturbance of eating habits and inhability to control body weight. In recent years several approaches have been investigated to treat such disorders but, despite some medication have been proved useful, their efficacy is still matter of debate. Clearly, the development of more efficacies pharmatherapeutic approaches is a medical priority
Efforts should be made to determine the causes that render individuals more vulnerable to the development of obesity or ED to provide information about alleviating or even preventing the conditions from occurring.
Environment and heritability factors certainly contribute to individual vulnerability, although, the mechanisms at the basis of the interaction between these two factors in the development of ED and obesity are still largely unexplored. Recently, molecular research has paved the basis for understand how these factors may interact to facilitate diseases progression pointing at the role of epigenetic mechanisms.

In fact if to one hand genetic determinants may play a pivotal role in innate vulnerability to develop ED and obesity to the other it has been recognized that environmental and developmental risk factors (i.e. dieting, psychosocial stress) may activate epigenetic mechanisms able to further influence disease progression.

It is well known that these mechanisms, that include histone modifications (e.g. acetylation, phosphorylation, methylation, ubiquitination, and ADP-ribosylation) and
DNA methylation can evoke transient changes (although how long they actually last is unclear) in gene expression, involving chemical modifications of DNA not affecting the actual DNA sequence of the organism.

Understanding the nature of genetic and epigenetic (gene x environment) interaction in regulating individual risk of developing an ED and obesity represents a major challenge in this research area and may provide invaluable help for the development of preventive strategies or new more effective pharmacological targets.

In the search of new targets, one emerging compound is the anandamide monounsatured analogue, oleoylethanolamide (OEA). Like anandamide, OEA is produced by cells in a stimulus dependent manner, from membrane phospholipid precursors, such as the N-oleoylphosphatidylethanolamine (NOPE), and is eliminated through intracellular uptake and enzymatic hydrolysis, the latter being catalyzed mostly by two enzymes, the fatty acid amide hydrolase (FAAH) and the N-acylethanolamine-hydrolyzing acid amidase (NAAA).
A growing body of evidence suggests a role of OEA in the pathophysiology of ED and provides robust preclinical evidence of the anti-obesity potential of this compound when administered as drug. Physiologically, OEA acts a mediator of satiety, released from the enterocytes upon the intake of dietary fats and under the control of the sympathetic nervous system. As a drug, it decreases food intake and body weight gain in lean and obese rats and mice through the activation of peripheral peroxisome-proliferator-activated receptor-alpha.

In this study we aim to investigate whether OEA administration might control ED and whether its might modulate epigenetic mechanisms in obesity and ED.

Moreover, to gain novel insights on OEA mechanism of action we will also evaluate the neuronal pathways involved in its effects on food intake and body weight, as well as we will test also other OEA related compounds. These will include the OEA precursor NOPE, and novel NAAA inhibitors (NAAAI) that can increase OEA peripheral endogenous levels. Furthermore, based on the availability of NOPE in the market as a phosphobioflavonic complex with epigallocatechin gallate (NOPE-EGCG) for anti-obesity treatment in humans, we will evaluate the effects of NOPE-EGCG in obesity and ED both in preclinical models and in humans.

These objectives will be achieved through a collaboration of four Research Units, each of which is coordinated by a young researcher with distinct scientific background.

This will warrant the possibility to approach this complex program at multidisciplinary level through the use of genetic cellular and molecular biology techniques (RU_UNITE), pharmacology and animal behavior (RU_UNIROMA, RU_UNICAM). In addition, RU_UNIMI will provide us with genetic material from large cohorts of ED and obese patients also eventually undertake proof-of-concept-clinical studies on selected treatments. In this way, we thus plan to undertake a translational approach aimed at evaluating to whether genetic and epigenetic regulations occurring in our animal models have parallels in humans.

Therefore, in this proposal we intent to study:

1) The significance of epigenetic mechanisms in the progression of ED and obesity in both animal models and humans. The following animal models will be adopted: activity based anorexia (ABA) model; binge eating (BE) model based on cycles of food restrictions/refeeding and stress; a model of yohimbine-induced relapse of high fat food seeking; a model of diet induced obesity. Moreover, large cohorts of ED patients (patients diagnosed with anorexia nervosa, bulimia nervosa and binge eating disorder based on DSM-IV-R) and also patients with essential obesity will be recruited. By studying different animal models in parallel and by analyzing blood samples from human subjects suffering from ED or obesity, we plan to shed light on how genetic predisposing factors and epigenetic mechanisms interacts to further shaping individual vulnerability to develop the different diseases and related behaviors;
2) To identify how, where and which epigenetic modifications may take place and may account for diseases progression in the different animal models and in human samples;
3) To provide essential neurobiological information on the role of oleoylethanolamine (OEA) and of its related compounds in the regulation of epigenetic mechanisms associated to ED and obesity;
4) To evaluate the effects of medications already available in clinic that have DNA methyltransferases (DNMTs) and/or histone acetyltransferases (HATs) inhibition activities and that could be tested for their ability to control ED and body weight gain in animal models. Both of these enzymatic properties characterize epigallocatechin gallate (EGCG), which complexed with NOPE is already commercially available as dietary supplement for anti-obesity treatment. This approach is taken to identify new medication with potential in the treatment of ED and obesity and that could be rapidly moved into clinic.
StatusActive
Effective start/end date1/1/12 → …

Funding

  • MIUR - FIRB

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Eating Disorders
Epigenomics
Obesity
Drug Therapy
Body Weight
Disease Progression
Eating
Methylation
Weight Gain
Pharmacology
Food
Acids
DNA
Binge-Eating Disorder
Histone Acetyltransferases
PPAR alpha
Obese Mice
Gene-Environment Interaction
Bulimia Nervosa
Animal Behavior