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.

Mitochondrial function if a cornerstone of metabolic plasticity, allowing the eukaryotic cell to adapt efficiently to changing energetic demands and nutrient availability. Its role in human physiology is well documented and its dysfunction has been associated with an always increasing number of pathologies. In particular, mitochondria as a source of damaging ROS has been extensively investigated. Nevertheless, how mitochondria function or dysfunction contributes to disease development is still a matter of controversy. In healthy individuals, mitochondrial activity is associated with low levels of mitochondrial ROS due to optimized electron transfer activities and the presence of high levels of antioxidants. In disease states, dysfunctional mitochondria produce high levels of ROS that cannot be detoxified efficiently leading to an oxidative stressed state.We investigate the impact on tumor development, its role in the vascular complications of diabetes, in the pathological development of liver steatosis and in the toxicity associated with some pharmacological treatments. All these aspects are investigated at a molecular, cellular and physiological level. We also aim to validate the application of biomarkers based on the evaluation of mitochondrial function in the diagnosis and prognosis of these diseases. The particular contribution of gender is also considered, as well as the impact that the results may have on different social groups in the analysis of the data and on their communication.