Obesity Comorbidities: Novel Approaches for Metabolic Inflammation and Binge Eating Behavior

Considering the complex condition of patients living with obesity and the limited attention some aspects of the disease receive when it comes to pharmacological therapies, with the projects of this thesis I focused on new potential treatments to counteract the ongoing inflammatory process and searched for possible new targets to treat BED. The first project of my thesis was focused on new pharmacological approaches to counteract metaflammation. One well-known pathway involved in the establishment of metaflammation is that of COX 2, a frequently used target in numerous pathologies but less studied in the context of obesity due to the side effects its inhibitors carry with them. In the first study, a mice model of diet- induced obesity that efficiently mimics the inflammation typical of the condition with all the associated metabolic derangements was used. During the study two different compounds were administered: the first was etodolac, a selective COX- 2 inhibitor, which was compared to a newly synthesized molecule, called compound A in this thesis (CmpA), with an added effect on TP. This approach addressed the concerns regarding potential cardiovascular complications of selective COX-2 inhibitors; furthermore, TP antagonism might also improve the deranged cardiovascular condition frequently associated with obesity, representing a new opportunity for this field of research. Compound A was synthesized by the medicinal chemistry laboratory of Professor Massimo Bertinaria at the University of Turin by allosteric modulation of the etodolac molecule, an approach that they had previously applied to produce another class of double inhibitors (Bertinaria et al., 2012). This compound was proved in vitro to have efficacy comparable with etodolac in inhibiting COX-2. Etodolac and CmpA were administered in equivalent doses to diet-induced obese mice of which we assessed the condition through the experiment according to numerous aspects of the disease: BW, insulin resistance, glucose intolerance, circulating triglycerides, and liver function. The efficacy of the two compounds in counteracting metaflammation in vivo was investigated together with some markers of cardiovascular dysfunction to see if CmpA had any added benefits compared to etodolac. In the second project of this thesis, I focused my research on finding new possible targets to treat BED, a well-characterized condition that affects numerous patients living with obesity, but that is still lacking proper pharmacological tools. To mimic the disorder an animal model of repeated episodes of BE was used, in this, female rats went through cycles of food restriction and acute stress that led to them eating a disproportioned amount of HPF once exposed to it (Cifani et al., 2009). After the establishment of the BE patterns in the animals, we collected brain samples on which we performed different analyses. The approach was to investigate epigenetic modifications, a field of research understudied when it comes to the BED, to try to find genes, particularly of the ECS, which are modulated after repeated episodes of BE (Hübel et al., 2019). We looked for gene expression, different patterns of DNA methylation, and histone modifications to find possible interesting targets that were modulated in this context.