Physiopathology and Molecular Mechanisms of Obesity and Comorbidities

Insulin resistance is an early event in the development of obesity and related comorbidities, including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). The close relationship between metabolism and the immune system (immunometabolism) plays an essential role in the development of these pathologies. The changes in the intestinal microbiota that occur in obese individuals are the first trigger of the low-grade chronic inflammation that alters the functions of relevant tissues responsible for controlling whole body glucose and lipid homeostasis. Among them, the liver is a target organ for the proinflammatory mediators from the gut (endotoxins) and/or adipose tissue (cytokines, adipokines, free fatty acids and reactive lipid species) and, furthermore, this organ capable of recruiting circulating monocytes that, together with the resident macrophages (Kupffer cells), contribute to exacerbate the intrahepatic inflammatory response. These conditions determine the progression of NAFLD, a disease with a high incidence in the obese and insulin-resistant population that begins with accumulation of fat in the liver (steatosis) and progresses to steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Our laboratories investigate the molecular bases of the development of obesity and comorbidities. To achieve this, we use cellular models (i.e. hepatocytes, Kupffer cells, stellate cells, oval cells), as well as preclinical experimental models that recapitulate the different stages of NAFLD and, in this regard, we are especially interested in the NASH and fibrosis stages. In this context, we are also studying therapeutic approaches with single or dual agonists of the GLP-1 and glucagon receptors to prevent or reverse obesity and NAFLD. Other pharmacological targets of interest are cyclooxygenase 2 (COX2), the protein kinase D family, the BMP protein (bone morphogenetic factors) family, as well as extracellular vesicles. In addition, the group is interested in understanding the regulation of brown adipose tissue (BAT) thermogenic genes that could be related to glucose consumption and lipid metabolism and, therefore, contribute to the regulation of energy balance and body weight.