WP1. STUDY OF THE MOLECULAR BASES OF INSULIN RESISTANCE AND ITS PHYSIOPATHOLOGICAL COMPLICATIONS.
RL 1: Study of inflammation and adipose tissue plasticity in conditions of insulin resistance: aging, obesity and nutritional disorders.
Objetivos:
1. To study the role of PTN in white and brown adipose tissue plasticity as modulator of metainflammation and insulin resistance: characterization in an aging and in a diet-induced obesity mouse models.
2. To unravel the role of RPTP beta/zeta in adipose tissue plasticity: pilot study as a new therapeutic target.
3. To study the role of undernutrition and refeeding as modulators of WAT metainflammation and plasticity in a rat model.
4. To study the impact of hypothalamic-pituitary-adrenal axis in WAT in undernourished/refeed rats.
Coordinator: MP. Ramos (GESTOBES).
Participants: F. Escrivá (ENMEPER).
RL 2: Molecular mechanisms associated to inflammation-mediated insulin resistance in the liver: progression of non-alcoholic fatty liver disease (NAFLD).
Objetivos:
1. To investigate the dual role of the protein tyrosine phosphatase 1B (PTP1B) during the progression and regression of NAFLD, particularly in the NASH stage.
2. To decipher the molecular interplay between non-parenchymal cells (NPCs) and hepatocytes within the liver in wild-type (PTP1B+/+) and PTP1B-deficient (PTP1B-/-) mice.
3. To study the molecular interplay between macrophages and hepatocytes in the liver in wild-type and myeloid-RXRa/b-deficient mice.
Coordinator: AM. Valverde (HEPIR).
Participants: M. Ricote (DIABEHEART).
RL 3: Effects of undernutrition and refeeding on the Central Nervous System (CNS).
Objetivos:
1. To study the effect of early undernutrition and subsequent refeeding on ghrelin and central leptin signaling.
2. To study the impact of the dietary patterns on neuroendocrine peptides and neurotransmitters.
3. To evaluate the effects of nutritional status on M6a, that regulates hypothalamic fibbers projections.
4. To investigate the effects of nutritional conditions on amylin and its receptors in different brain regions.
Coordinator: F. Escrivá (ENMEPER).
Participants: M. Benito (BETABRAIN).
RL 4: Cardiovascular complications associated with insulin resistance: role of nuclear receptors in the diabetic cardiomyopathy.
Objetivos:
1. To investigate the molecular mechanism of lipid-induced cardiac dysfunction in diabetes: role of RXR.
2. To elucidate the mechanisms of inflammation in development in diabetes-induced cardiac dysfunction: role of RXR.
3. To decipher the metabolic communication between the heart and other tissues (WAT, liver, pancreas and muscle).
Coordinator: M. Ricote (DIABEHEART).
Participants: G. Medina-Gomez (LIPOBETA).
RL 5: New molecular mechanisms involved in lipotoxicity-induced renal failure in obesity and DM2: role of RXR.
Objetivos:
1. To investigate the role of RXR on inappropriate balance between lipogenesis "de novo" and oxidation of fatty acids leading to apoptosis in podocytes.
2. To investigate the role of RXR on inflammation-associated IR in podocyte failure.
3. To investigate the role of RXR on increased ER and oxidative stress in kidney failure.
Coordinator: G. Medina-Gomez (LIPOBETA).
Participants: M. Ricote (DIABEHEART); AM. Valverde (HEPIR).
WP2. INTERTISULAR COMMUNICATION BETWEEN TISSUES AND SYSTEMS IN THE CONTEXT OF INSULIN RESISTANCE.
RL 6: The adipose-pancreatic-cerebral axis in type 2 diabetes: amylin and pleiotrophin.
Objetivos:
1. To study the role of autophagic flux blockade in exosome production (bearing human amylin).
2. To unravel the molecular link between pancreatic beta cells and neurons in vitro and in vivo in mice model of T2DM with an overexpression of hIAPP (iLIRKO/Tg hIAPP).
3. To study the potential role of inflammation in the production of exosomes.
4. To analyze the role of pleiotrophin (PTN) as a novel regulator of inflammatory processes in the CNS associated with insulin resistance: cross- talk adipose tissue-pancreas-brain.
Coordinator: M. Benito (BETABRAIN).
Participants: MP. Ramos (GESTOBES).
RL 7: Deciphering regulatory circuits for myocardial and renal metabolism associated with insulin resistance: role of nuclear receptors.
Objetivos:
1. To identify the molecular mechanism of inflammation and lipid homeostasis in the fatty heart and fatty kidney.
2. To elucidate the molecular mechanism underlying the association between obesity-associated insulin resistance and cardiac hypertrophy on kidney dysfunction).
3. To elucidate the molecular mechanism underlying the crosstalk between the heart and kidney in T2DM.
Coordinator: M. Ricote (DIABEHEART).
Participants: G. Medina-Gomez (LIPOBETA).
RL 8: Communication of the gut with liver and pancreas.
Objetivos:
1. To perform an appropriate follow-up study on gut microbiota and intestinal function in rats submitted to maternal undernutrition and refed a high-fat diet after weaning.
2. To determine the role of lipopolysaccharides (LPS) on pancreatic beta-cell function and viability, as well as in the regulation of the expression and action of the glycoprotein osteopontin.
3. To study the role of PTP1B in the disruption of the gut barrier permeability during the progression of NAFLD.
4. To study the endotoxemia responsible of the inflammation in the gut as an early event in the progression of NAFLD towards NASH wild-type and PTP1B-deficient (PTP1B-/-) mice.
Coordinator: F. Escrivá (ENMEPER).
Participants: AM. Valverde (HEPIR).
WP3. THERAPEUTIC TARGETS AND BIOMARKERS IDENTIFICATION
RL 9: Comparative effects of a of glucagon receptor (GCGR) and GLP1 receptor (GLP1R) dual agonist versus a single GLP1 receptor agonist in the hepatic inflammation associated to the progression of non-alcoholic fatty liver disease (NAFLD).
Objetivos:
1. To perform a comparative analysis of the effects of a dual agonist of GLP-1 and glucagon receptors (GLP-1R/GCGR) versus a single GLP-1R agonist in the development of NAFLD in a mouse model of diet-induced obesity (DIO).
2. Evaluation of the mechanisms of action (MOA) of the dual GLP-1R/GR co-agonist versus the single GLP1-R agonist by performing in vitro studies in hepatocytes and non-parenchimal cells (NPCs) under conditions that recapitulate the inflammatory milieu of NAFLD.
Coordinator: AM. Valverde (HEPIR).
RL 10: Identification of new biomarkers of insulin resistance associated diseases: studies in gestational diabetes mellitus (GDM) and renal failure.
Objetivos:
1. Identification of early biomarkers human GDM and other pregnancy associated pathologies.
2. To identify biomarkers as prognostic tools to predict the early onset of diabetic complications in GDM women after delivery.
3. To identify miRNAs from exosomes as biomarkers in adipose tissue, serum and urine in the development of nephropathy during the progress of IR state in the metabolic syndrome.
4. Validation in human podocyte line of the functional role of the lipodomic and metabolic networks and miRNAs identified in vivo (mice and humans).
Coordinator: MP. Ramos (GESTOBES).
Participants: G. Medina-Gomez (LIPOBETA).