Conference Agenda

Several studies provide evidence of a bidirectional relationship between metabolic disease and cognitive impairments and most recent findings suggest that the low-grade, chronic inflammatory response due to dietary impairments, known as “metaflammation”, exerts a key role as cross-talk mechanism linking the development of metabolic derangements and neurological disorders.

We recently contributed to demonstrate the peculiar impact of the heterogeneous class of diet-derived advanced glycation end products (AGEs) on “metaflammation” and activation of selective inflammatory pathways leading to molecular and functional impairments in both peripheral organs and Central Nervous System. Here we will discuss our findings on the molecular pathways activated by dietary AGEs chronic exposure at both peripheral and central levels, and the potential of treatments that halt or induce regression of AGE accumulation to provide clinical benefits.

Mechanistic insights provided by animal models of dietary manipulations suggest that excess AGEs accumulation compromises the activation of cerebrovascular protective pathways, thus exacerbating either myocardial and cerebral ischemic injuries. Most notably, we demonstrated that approved drugs for the treatment of hyperglycemia, including gliptins, glitazones and insulin, may improve stroke outcomes showing additional effectors behind their efficacy. Here our findings will be presented at the light of most recent literature evidence to critically discuss the cross-talk mechanisms linking pharmacological modulation of metaflammation-related signaling pathways to the improvement in metabolic and cerebrovascular cascades as well as the attractive perspective to identify approved medications potentially suitable for drug repurposing into the treatment of cerebrovascular and cardiometabolic diseases.

Anorexia nervosa (AN) is a severe eating disorder characterized by a reduction in food consumption with the aim to lose body weight. AN occurs in young women and is characterized by an evolution towards the chronicity of the disease, and by an excess of physical activity. Although the pathophysiology of AN is not completely understood, biological variables appear to play a role in its development. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is involved in the development of the peripheral and central nervous systems. ALK deletion has recently been demonstrated to boost energy expenditure and provide resistance to obesity. Because no research has been conducted on the possible involvement of the ALK in the etiology of AN, we investigated the expression of this receptor and the downstream intracellular pathways in animals subjected to the "activity-based anorexia" (ABA) model, which reproduces important features of human AN such as body weight loss and hyperactivity. In these rats’ hypothalamus lysates, we found a decrease in ALK receptor expression, in Akt phosphorylation, and no change in extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. The others experimental groups showed no changes. By virtue of the alterations that have been observed in AN patients in relation to apoptosis, we focused on caspase activation. ABA paradigm failed to cause caspase-3 and poly-(ADP ribose) polymerase (PARP) cleavage. Furthermore, our findings show that ALK receptor protein decrease occurred independently of apoptosis. During the recovery from body weight loss, ALK levels in ABA rats returned to the control baseline values. In the second induction, the reduction in ALK was marked but less than in the first. Overall, this evidence suggests a possible involvement of the ALK receptor in the pathophysiology of AN, that may be implicated in its stabilization, resistance, and/or its exacerbation.

Oleoylethanolamide (OEA), an endogenous N-acylethanolamine acting as a gut-to-brain signal to control food intake and metabolism, has been attracting attention as a target for novel therapies against obesity and eating disorders. Numerous observations suggested that the OEA effects might be peripherally mediated, although they involve central pathways including noradrenergic, histaminergic and oxytocinergic systems of the brainstem and the hypothalamus. Whether these pathways are activated directly by OEA or whether they are downstream of afferent nerves is still highly debated. Some early studies suggested vagal afferent fibers as the main route, but our previous observations have contradicted this idea and led us to consider the blood circulation as an alternative way for OEA’s central actions.

To test this hypothesis, we first investigated the impact of subdiaphragmatic vagal deafferentation (SDA) on the OEA-induced activation of selected brain nuclei. Then, we analyzed the pattern of OEA distribution in plasma and brain at different time points after intraperitoneal administration in addition to measuring food intake.

Confirming and extending our previous findings that subdiaphragmatic vagal afferents are not necessary for the eating-inhibitory effect of exogenous OEA, our present results demonstrate that vagal sensory fibers are also not necessary for the neurochemical effects of OEA. Rather, within a few minutes after intraperitoneal administration, we found an increased concentration of intact OEA in different brain areas, associated with the inhibition of food intake.

Our results support that systemic OEA rapidly reaches the brain via the circulation and inhibits eating by acting directly on selected brain nuclei.

Frequent and recurrent binge eating (BE) episodes and loss of control over eating, characterizing Binge Eating Disorder (BED) and Bulimia Nervosa (BN), are driven by several risk factors, such as impaired decision making and impulsivity, all regulated by distinguishable brain regions and neurocircuitry. Among others, the dopaminergic system has attracted growing attention due to its widely distributed receptors in the neurocircuitry implicated in BE risk factors. We investigated the role of dopaminergic system genes regulation in BE, using both preclinical models and clinical studies. The epigenetic of dopamine transporter (DAT) and dopamine D2 receptor (DRD2) genes were analysed on DNA from saliva samples of patients suffering from BED and BN. Genes hypomethylation resulted relevant for BE behaviour. Moreover, the same genes regulation was evaluated in different brain regions of an animal model showing recurrent episodes of BE. We detected an up-regulation of DRD2 gene expression in the caudate putamen and a reduction of both DAT and DRD2 mRNA levels in the prefrontal cortex and nucleus accumbens in BE rats. In addition, studying Caenorhabditis elegans feeding behaviours as a possible model resembling BE behaviours, it was observed that the altered food intake occurring in wild type nematodes exposed to starvation and stress condition was reverted in worms which have a loss of function mutation in the genes ortholog of human DAT and DRD2 (dat-1 and dop-2, respectively). Finally, in order to better understand the mechanism behind these changes, we are also investigating the role of salivary microbiota in human subjects. Preliminary findings indicate a role for Actinobacteria in the epigenetic alterations observed. These findings highlight an important evolutionarily conserved role of dopaminergic system genes in BE behaviour. Their epigenetic modulation is relevant to suggest possible biomarkers and new targets to treat binge eating behaviour.