Caracterización del papel del succinato y su receptor SUCNR1 en la fisiopatología de la obesidad y la diabetes de tipo 2

Identificador:  TDX:3231

Handle: https://hdl.handle.net/20.500.11797/TDX3231

Autors:  Keiran Fernández, Noelia

Resum:
The succinate-SUCNR1 axis has emerged as relevant molecular pathway implicated in the development of inflammatory chronic conditions, such as obesity and type 2 diabetes (T2D). Elevated amounts of circulating succinate occur in some pathologies related with an increased cardiovascular risk. Activation of SUCNR1 by extracellular succinate has been associated with a broad range of effects, especially in the context of inflammation and immune response. Accordingly, this doctoral thesis focuses on the study of succinate-SUCNR1 signaling pathway in macrophages, and its effect in the development of the inflammatory status underlying obesity and T2D. Furthermore, we propose circulating succinate levels as a biomarker of metabolic status, that could apply in clinical and therapeutic management of these pathologies. For this purpose, we generated mice with myeloid-cell-specific SUCNR1 deficiency and study the metabolic effect of this specific depletion. On the other hand, a prospective single-center, nonblinded, randomized controlled trial including obese patients with T2D, were employed to determine circulating succinate levels, anthropometrical and biochemical parameters, before and 1 year after bariatric surgery. The results were externally validated in a second cohort based on clinical criteria. Our study reveals succinate-SUCNR1 axis as crucial factor to adequately develop chronic and acute inflammatory response, as well as contributing to the resolution of inflammation; we note the relevance of this pathway in the maintenance and function of macrophages; and exposes obesity as a succinate-resistant state with loss of its anti-inflammatory properties. Finally, we highlight the potential of the succinate-SUCNR1 route from a translational point of view in the development of clinical approach focused on metabolic pathology