Molecular basis of metabolic pathologies and associated to membrane transporters

General Topic: Basis for obesity, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes

Specific Topics:

1. Role of neuregulin and ErbB receptors on insulin sensitivity
2. Role of Caveolin / Caveolae in insulin signaling and GLUT4 traffick in white adipose tissue.
3. New molecular knowledge about phospholipid homeostasis between mitochondria and the endoplasmic reticulum

Brief summary of the research: Our research is addressed to insulin sensitive tissues (skeletal muscle, liver and adipose tissue) searching for the mechanisms relevant to sustain insulin responsiveness and the metabolic causes of the insulin resistance involved in obesity, NAFLD and type 2 diabetes mellitus (T2D). To this end, we are characterizing the multiple roles of the epidermal growth factor (EGF) subfamily, Neuregulin, which binds to tyrosine kinase ErbB receptors, and acts as a myogenic and neurotrophic factor that mediates muscle contraction-depending effects on glucose utilization, enhances cell oxidative capacity and insulin sensitivity in muscle cells and fibers. Acute intraperitoneal administration of neuregulin-1 to rodents rapidly enhances the response to a glucose tolerance test by increasing liver glucose utilization, in an insulin-independent manner, in control and, to a larger extend, in diabetic animals. Neuregulin 4 has been recently described as an adipokine which induces angiogenesis, prevents inflammation, and preserves insulin sensitivity in liver and white adipose tissue (WAT). Another line of interest focuses on the role of Caveolin and caveolae, which have been described as essential to sustain intracellular GLUT4 content and the insulin responsiveness in adipocytes. Recently, we started a new research line focusing on the alterations in lipid metabolism associated to T2D. In this regard, there is clinical evidence for the association between phospholipids (PL) membranes composition and insulin sensitivity. Metabolomic analysis of newly developed type 2 diabetics versus normoglycemic subjects suggested that an abnormal composition of phosphatidylcholine (PC) may contribute to develop insulin resistance. Besides, alterations in mitochondrial dynamics, defined as the processes of mitochondrial fusion and fission, have been observed in T2D. The main proteins involved in mitochondrial fusion are Mitofusins (Mfn1 and Mfn2) and Optic atrophy 1 (OPA1). There are evidence connecting the loss of mitochondrial fusion proteins with defects in insulin sensitivity. In this sense, a deficiency in Mfn2, a protein that tethers endoplasmic reticulum (ER) to mitochondria, causes a reduction in PC synthesis, leading to ER stress and insulin resistance in the liver. Our aim is to demonstrate that mitochondrial fusion proteins are involved in the intracellular phospholipid homeostasis, and in turn, to search for a novel therapeutic target for chronic diseases associated to insulin resistance.