La fenotipizzazione di modelli murini tramite metodiche di imaging PET e CT rivela l’importanza di nuovi processi patofisiologici alla base della disregolazione metabolica associata ad obesità.

Emerging molecular imaging techniques in small animals allow a non invasive study of animal models of diseases, providing in vivo information on metabolic pathways. The metabolic process can be visualized and quantified by images, avoiding animal sacrifice which is often mandatory with conventional techniques In this work we show how small animals Positron Emission Tomography (PET) and Computed Tomography (CT) usefully provide metabolic and anatomic information respectively, in a non invasive fashion. Toghether with other conventional approaches, these molecular imaging techniques allowed, in the present work, to collect information on the pathofisiological mechanisms underlying energy metabolism and consequently body weight control in obesity. The first project of the PhD focused on the comprehension of the mechanism by which endocannabinoid system is able to control energy balance at different anatomical sites. The endocannabinoid system (ECS) is a physiological system composed by endogenous lipid molecules regulating energy metabolism acting on the cannabinoid receptor type 1 (CB1). This receptor is expressed in different anatomical sites as central and peripheral nervous system, adipose tissue, liver, skeletal muscle. The ECS is pathologically over-activated during obesity and this overactivation is known to contribute to fat mass and body weight accumulation in obese individuals. The mechanisms and the major anatomical sites underlying this control, are, however, not fully elucidated yet. We focused on the role played by CB1 receptor expressed in some neuronal population. To this aim, the phenotype of conditional knockout for CB1 receptor in some neuronal populations was studied, and compared with the phentype of global CB1 receptor knockout mice (mice having a whole body deletion of the receptor). We found that neuronal CB1 receptor has a deep influence in the ability of ECS to control energy balance and the plasma metabolic profile during obesity. This property of neuronal CB1 receptor is strictly linked with a modulation of the peripheral sympathetic tone which finally influences the metabolic activity of peripheral organs. This loop seems to be particularly effective in modulating brown adipose tissue (BAT) activity, which apparently underlyes most of the changes in whole body energy metabolism observed in the conditional mutant mice for neuronal CB1. These results, which show a strict functional relationship between ECS and BAT thermogenic activity, highlight BAT as a key organ able to control fat mass and body weight gain in obese individuals. The second project of this PhD thesis focused on the relationship between BAT, insulin sensitivity and obesity. BAT is an insulin sensitive organ having a very high uptake of glucose per gram of tissue. The role of insulin on glucose uptake in BAT is still poorly understood, and it is not clear whether BAT insulin function is compromised with obesity. Using a small animal PET/CT imaging approach we analysed in vivo glucose uptake in the BAT of lean and diet-induced obese mice in basal condition and after insulin stimulation. All these findings allowed us to demonstrate that diet induced obesity is associated with an altered (reduced) insulin function in the BAT. Recent experimental evidences indicate that BAT is an important organ in insulin induced glucose clearance in humans; thus, the data obtained in this PhD project, which indicate a compromised insulin function in the BAT of obese individuals, highlight this tissue as a new target to control insulin resistance in obesity.