LI 1: Identification of mediators and molecular mechanisms in the intra- and extrahepatic interactome in insulin resistance (IR) associated with obesity.

• Coordinator: HEPIR
• Participants: GESTOBES, METABOALL, and DIABEHEART-DIABEMAC

Objectives:

1. Study the effect of short-chain fatty acids (SCFAs) derived from intestinal bacterial metabolism on the production and composition of EVs by colon epithelial cells under physiological and proinflammatory conditions (in vitro studies).


2. Study the effect of EVs of intestinal origin on the function and survival of pancreatic β cells (in vitro studies).


3. In vivo effects of EVs of intestinal origin on the function and survival of pancreatic β cells: approaches in two murine models of diet-induced IR or insulin receptor deletion in the liver.

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LI 2: Identification of new molecules in cardiac dysfunction in insulin resistance situations and associated molecular mechanisms.

• Coordinator: DIABEHEART-DIABEMAC
• Participants: GESTOBES, METABOALL, and HEPIR

Objectives:

1. Study the functional impact of RXR in the adult heart: phenotypic evaluation of the cardio-specific RXR-deficient mouse model.


2. Characterize the molecular mechanism by which RXR controls the metabolic homeostasis of the adult heart.


3. Investigate the impact of RXR on mitochondrial dysfunction as an underlying mechanism of diabetic cardiomyopathy.

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LI 3: Identification of new molecules in renal dysfunction in IR situations: associated molecular mechanisms.

• Coordinator: LIPOBETA
• Participants: GESTOBES, METABOALL, and HEPIR

Objectives:

1. Investigate the role of TGFβ3 in the development of fibrosis associated with the imbalance between de novo lipogenesis and fatty acid oxidation leading to cellular apoptosis.


2. Investigate the role of TGFβ3 in the development of fibrosis associated with inflammation processes.


3. Investigate the role of TGFβ3 in the development of fibrosis associated with ER stress and oxidative stress.

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LI 4: Cardiovascular complications associated with insulin resistance: role of nuclear receptors in diabetic cardiomyopathy.

• Coordinator: GESTOBES
• Participants: LIPOBETA, METABOALL, and HEPIR

Objectives:

1. Study the involvement of PTN in adipose tissue inflammation associated with IR in obesity.


2. Molecular characterization of the PTN-mediated signaling pathway and its possible counterregulation by midkine in adipose tissue inflammation associated with IR in this endocrine organ.

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LI 1: Study of communication mechanisms of the entero-insular axis in states of insulin resistance.

• Coordinator: ENTEROBETA
• Participants: LIPOBETA, METABOALL, and DIABEHEART

Objectives:

1. Study the involvement of PTN in adipose tissue inflammation associated with IR in obesity.


2. Molecular characterization of the PTN-mediated signaling pathway and its possible counterregulation by midkine in adipose tissue inflammation associated with IR in this endocrine organ.

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LI 2: Neuro-insular-adipose axis: implication of pleiotrophin in the connection of peripheral metainflammation associated with obesity with neuroinflammation.

• Coordinator: GESTOBES
• Participants: ENTEROBETA, METABOALL, and HEPIR

Objectives:

1. Study the role of PTN in insulin signaling and central nervous system metabolism in obese mice.


2. Analyze the circulating secretome in a diet-induced obesity model in mice.


3. Study the effects of PTN on the secretome of adipocytes, pancreatic beta cells, and neurons.

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LI 3. Study of communication mechanisms of the adipose-renal axis: effect of adipose tissue secretome on obesity and IR-associated chronic kidney disease.

• Coordinator: LIPOBETA
• Participants: ENTEROBETA, METABOALL, and DIABEHEART-DIABEMAC

Objectives:

1. Evaluate the secretory structure and function of adipose tissue in TGFβ3+/male and female mice under normal and high-fat diet conditions.


2. Study the gene/protein profile of adipokine and estrogen receptors in the kidney of TGFβ3+ mice.


3. Study the interaction of adipokines, miRNAs contained in EVs, and steroid sex hormones in the TGFβ3 signaling pathway and its role in obesity-associated kidney fibrosis.

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LI 1: Identification of new biomarkers in obesity-associated chronic kidney disease.

• Coordinator: LIPOBETA
• Participants: ENTEROBETA, METABOALL, and HEPIR

Objectives:

1. Identify EV miRNAs, metabolites, lipids, and proteins in serum and urine samples as biomarkers for the development of nephropathy during the progression of obesity-associated IR.


2. Characterize the newly identified biomarkers and study their involvement in the development of obesity-associated nephropathy and the effect of potential treatments (bariatric surgery and an anti-obesity drug).


3. Validation in a line of human podocytes of the functional role of lipidomic, metabolic, and proteomic networks, as well as the identified miRNAs in obese patients with chronic kidney disease.

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LI 2: Impact of plasma EVs from individuals with NAFLD on the liver-pancreas axis.

• Coordinator: HEPIR
• Participants: ENTEROBETA and METABOALL

Objectives:

1. Isolate and characterize circulating EVs from a cohort of individuals with different stages of NAFLD (from fatty liver to fibrosis).


2. Investigate whether the lipotoxic/inflammatory cargo of circulating EVs from individuals with NAFLD has a deleterious impact per se on a healthy liver.


3. Understand the effect of EVs from individuals with NAFLD on the pancreas.

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LI 3: Search for early biomarkers of gestational diabetes.

• Coordinator: GESTOBES
• Participants: DIABETEHEART-DIABEMAC and METABOALL

Objectives:

1. Validation of the rs10830963 and rs1387153 polymorphisms of the MTNR1B gene in a cohort of pregnant women to complete the semiological study of these potential early biomarkers of gestational diabetes.


2. Identification of other biomarkers of gestational diabetes (EV miRNAs, and metabolites, in serum samples).