Novas abordagens terapêuticas para a obesidade baseadas nos mecanismos neuroendócrinos do tecido adiposo

The main objective is to develop pharmacological strategies for weight loss and prevention of adipose tissue dysfunction and insulin resistance (IR), which will effectively prevent the metabolic and vascular sequelae of obesity. THINNER 2.0 will use peripheral dopaminergic signalling as a therapeutic target and combine known dopamine agonists with modulators of the melanocortin system, which regulates energy expenditure mechanisms both in the brain and in the adipose tissue. THINNER 2.0 has two main outputs: 1) implement a new therapeutic strategy based on the peripheral crosstalk of dopamine with the melanocortin system, an important neuroendocrine mechanism of energy balance, in modulating WAT lipid and glucose metabolism in animal models of obesity and diabetes; 2) validate the new therapeutic strategy for the prevention of cardiovascular diseases, one of the major complications of metabolic diseases. We will also evaluate the WAT vascular function given its relevance in WAT plasticity and function. THINNER 2.0 will build upon robust preliminary data and combine dopaminergic modulation with melanocortin receptor agonists in animal models of obesity towards sustained weight loss and the prevention of metabolic and cardiovascular risks of obesity. THINNER 2.0 will build upon previous data and the results of the exploratory project THINNER and will be disruptive in creating a new therapeutic strategy for obesity, a field where specific therapeutic options are still insufficient. THINNER has two specific objectives: 1) Taking advantage of adipocyte cell lines, human WAT explants and animal models, we will determine the crosstalk between dopamine and MC4R agonists in modulating WAT metabolic activity. We will disclose the role of dopaminergic signalling in the regulation of melanocortin receptors levels both in vitro in cell cultures and in vivo in animal models. The metabolic response of WAT to MC4R agonists upon dopaminergic modulation will be assessed in vitro in adipocyte cultures and WAT explants and in vivo in animal models by magnetic resonance proton spectroscopy using pharmacoimaging experiments. Moreover, THINNER 2.0 will implement a therapeutic approach based on dopamine and melanocortin agonists in animal models of obesity (induced by a high-caloric diet) and type 2 diabetes (GK rats fed a high-caloric diet) and study their metabolic health, and white and adipose tissue and liver metabolic function pathways. 2) The same therapeutic strategy will be evaluated for its effects in preventing vascular complications in animal models of obesity and diabetes. In animal models of obesity, we will evaluate the vascular function of adipose tissue using MRI, an important determinant of WAT function. In animal models of obesity and diabetes, we will study the macrovascular function in the aorta to evaluate the effects of the therapeutic strategy in preventing endothelial dysfunction and vascular complications. THINNER 2.0 ambition: THINNER 2.0 will identify novel mechanisms of crosstalk between dopamine and melanocortin to regulate the energy balance/expenditure in the WAT. Taking advantage of PI’s previous data partially obtained in the previous exploratory project, THINNER 2.0 will employ a therapeutic strategy simultaneously targeting dopaminergic and melanocortin signalling to achieve sustained weight loss, prevent metabolic complications of obesity and spare the need for metabolic surgery.