Marfella, Brenda (2025) Endocannabinoids and Endocannabinoid-like Molecules Restore Synaptic Homeostasis and Cognitive Functions in Mouse Model of Obesity. [Tesi di dottorato]

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Abstract

The endocannabinoid system and its extended network, defined as the endocannabinoidome, constitute critical regulators of neuronal signaling, energy homeostasis, and the interplay between metabolism and brain function. Alterations in this system have been associated with the development of obesity and cognitive dysfunctions, suggesting a pivotal role of the endocannabinoidome as an interface between metabolic signals, gut microbiota, and the central nervous system. This thesis investigates the role of endocannabinoids and endocannabinoid-like molecules in the modulation of neuronal circuits involved in the control of food intake, energy balance, and cognitive functions. The results demonstrate that olive oil-derived endocannabinoid-like mediators can attenuate the reward associated with the consumption of highly palatable foods and reduce susceptibility to diet-induced obesity, suggesting the existence of a functional axis linking diet, the endocannabinoidome, and gut microbiota. Moreover, a mechanism is described through which acetate, a metabolite produced by the gut microbiota, modulates the activity of orexinergic neurons in the lateral hypothalamus, connecting microbial metabolism to the regulation of feeding behavior and energy homeostasis. The findings also reveal the presence of a blue-light-sensitive pathway in the retinohypothalamic tract capable of modulating orexinergic neurons via endocannabinoid-dependent mechanisms. Finally, preliminary data suggest that metabolic stress associated with obesity may contribute to alterations in hippocampal plasticity and memory processes through modifications of specific lipid mediators and mechanisms involving microglial dysfunction and synaptic alterations. Overall, these results underscore the role of the endocannabinoidome as a central hub in the integration of metabolic signals, gut microbiota, and neuronal circuits regulating both metabolism and cognitive function.

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