Resumen de Cerebral Regulation of Global Energy Balance in health and disease as detected by functional Diffusion Weighted MRI
Regulation of the global energy metabolism is a vital cerebral function, which balances energy expenditure and food intake. However, this regulation is disrupted in different pathologies such as obesity or cancer, with the underlying physiological mechanisms that cause or potentiate these pathologies being still under study. In this line, magnetic resonance imaging (MRI) methods are excellent tools to assed, in vivo and non-invasively, the anatomical and functional alterations of the brain under different physiological and pathological conditions. In this thesis, I will present a set of physiological results in different animal models of diseases that alter the cerebral appetite regulation, as well as the role of a specific brain water channel, by using magnetic resonance imaging, particularly diffusion sequences, and ex vivo spectroscopy methods. Chapter 1. introduces the physiological mechanisms that participate in the appetite regulation as well as the neuroimaging techniques used for its evaluation. This chapter also presents the basic concepts of the magnetic resonance phenomenon, emphasizing the methodologies used throughout the thesis. Chapter 2. describes the development of a diet induced obesity mouse model to assess the alterations in endocrine blood levels, phenotypic characteristics, diffusion parameters and metabolic profiles linked to the diet and feeding status, as well as to identify the association among them. Chapter 3. presents the evaluation of the cerebral response to a fasting condition in a model of cancer cachexia developed in glioblastoma bearing mice. To that, structural and functional MRI methods under different feeding conditions were performed, as well as phenotypic assessment and ex vivo metabolomic analysis by acquiring magnetic resonance spectra. In Chapter 4. diffusion studies and manganese enhanced MRI were tested and compared as functional magnetic resonances approaches to evaluate the cerebral response to diverse feeding conditions in an advanced stage glioblastoma in rat cohorts. Chapter 5. presents the evaluation of the role of aquaporine-4 (AQP4) in the cell volume response to a glucose bolus administration in order to assess the contribution of this channel in the functional diffusion studies. To that, an AQP4 inhibitor was employed and the diffusion coefficients related with the swelling-shrinking cellular processed, were evaluated. Chapter 6. introduces the general concepts of the in vivo magnetic resonance spectroscopy (MRS), and specifically the use of labeled 13C substances to enhance the 13C MRS signal allowing the study of metabolic pathways. In this chapter, it is also described the use of in vivo 1H MRS to evaluate the glutamatergic neurotransmission in the hypothalamic region of high fat diet feeding mice after the administration of memantine. Besides, by using 13C MRS acquisitions in combination with the infusion of [2-13C]acetate, it was assessed the in vivo metabolism of the hypothalamus and modeled the pathways involved considering different two-cellular compartment models
