Dissertação
Peripheral molecular targets for adiposity control EVALUATED
Obesity is a metabolic disorder with unmet medical need for which a pharmacotherapy is urgently required. Obesity lab has recently discovered that sympathetic nervous system’s (SNS) fibers establish neuro-adipose junctions to mediate lipolysis in white adipose tissue (WAT), via local norepinephrine (NE) signalling. Hence, direct and targeted activation of sympathetic inputs to adipose tissues could represent a new strategy for the induction of fat loss. Sympathomimetic drugs are thought to reduce weight via central action in the brain. Contrary to this established idea, here we demonstrate that the anti-obesity effect of such sympathomimetics (DRUG CS) require an intact SNS, being independent of anorexia and hyperkinesia. Further, we modified DRUG CS to prevent its access to the brain, thus acting as a peripheral sympathomimetic (DRUG PS). DRUG PS protects mice from diet-induced obesity (DIO), without affecting daily food intake nor locomotion. The ameliorating of state-of-art rodent technologies, such as Translating Ribosome Affinity Purification (TRAP), towards the identification of specific molecular neuro-excitatory drug targets in sympathetic inputs to adipose tissues, is a work in progress. Finally, obesity copulates with an inflammatory state in predisposing for development or exacerbating of several related complications. RNA-seq data of the sympathetic neuron-associated macrophages (SAMs) were used to qualify, by means of differential screening, the marcksl1 or egr1 genes as novel potential targets to counteract obesity, via NE transport and degradation machineries shut down. We put forward peripheral sympathomimetics as a new generation of anti-obesity medications.
novembro 12, 2018, 11:30
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Orientação
ORIENTADOR
Pedro Tiago Gonçalves Monteiro
Departamento de Engenharia Informática (DEI)
Professor Auxiliar
