European Research Network, GDRE EARLY PROGRAMMING OF MODERN DISEASES, EPMD Silvana Gaetani, IT Department of Physiology and Pharmacology “V. Erspamer”

European Research Network, GDRE Assistant Professor in Pharmacology University of Rome “La Sapienza”, Italy In vivo/ex vivo pharmacology: Behavioral experiments: microstructure analysis of feeding behaviour of rats and mice (both pellet diet or liquid diet), to unveil possible alteration of satiety or appetite, using both normal animals or overweight animals (Diet-Induced-Obese or genetically obese). Body dissections of rat and mouse organs and tissues. Neurochemical experiments: brain microdialysis in freely moving rats or mice to analyze in different brain areas the extracellular levels of the several neurotransmitters: dopamine, serotonin, norepinephrine (and their major metabolites), GABA, glutamate, aspartate, glycine. Metabolic experiments: Analysis of selected enzyme activities related to lipid metabolism (i.e. ex vivo lypolisis or lipogenesis, mitochondrial carnitine acyl transferase activity, etc from the homogenates or the subcellular fractions of different tissues, or from rat hepatocyte primary culture); analysis of mitochondrial respiration in mitochondrial preparations from different tissues Others: Brain in situ hybridization, Real time PCR, immunohystochemistry. Department of Physiology and Pharmacology “V. Erspamer”

European Research Network, GDRE Endocannabinoid – Obesity The lipid messenger OEA links dietary fat intake to satiety. Cell Metab Food intake regulates oleoylethanolamide formation and degradation in the proximal small intestine. J Biol Chem Cold exposure stimulates synthesis of the bioactive lipid oleoylethanolamide in rat adipose tissue. J Biol Chem 2006 Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties. J Pharmacol Exp Ther 2006 Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology 2005 Regulation of food intake by oleoylethanolamide CMLS, Cell Mol Life Sci 2005 Oleoylethanolamide inhibits food intake in free-feeding rats after oral administration. Pharmacol Res 2004 Modulation of meal pattern in the rat by the anorexic lipid mediator oleoylethanolamide. Neuropsychopharmacology 2003 Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 2003 Department of Physiology and Pharmacology “V. Erspamer”

European Research Network, GDRE Department of Physiology and Pharmacology “V. Erspamer” Natural epigenetic modulators as potential antiobesity strategy Silvana Gaetani and Anna Moles Nutritional epigenomics have suggested that stable epigenetic alterations are relevant to the development of obesity and type2 diabetes, showing how in most cases these disorders take root in early nutrition, during gestation and lactation. Silencing and unsilencing of genes can occur via changes in DNA methylation, as well as through epigenetic modifications at the level of the histones. These include histone acetylation and deacetylation. Several agents are being sought that might target abnormal patterns of histone modification, they are usually referred as "epigenetic modulators“. A particularly active avenue of research involves inhibitors of histone deacetylase (HDAC), and has expanded into dietary compounds such as butyrate, diallyl disulfide and sulforaphane exhibiting weak HDAC inhibitory activity. Recent evidence demonstrated that in addition to regulating histones, the HDACs directly regulate the activity of several nuclear receptors, including PPARgamma.

European Research Network, GDRE Department of Physiology and Pharmacology “V. Erspamer” We hypothesize that altered patterns of histone/receptor acetylation might be involved in the development of obesity. Thus, dietary epigenetic modulators might represent a possible tool to increase obesity resistance. We aim at exploring such possibilities by following a multidisciplinary (molecular, biochemical and neurofunctional) approach based on two models of obesity in mice: 1.the classical "diet-induced obesity paradigm“ 2.a novel ethological model based on the theory of "comfort food" as a self-medication from the negative effects of psychosocial stress induced by chronic defeat by a dominant conspecific.