CNC.IBILI

Metab3 | Main Goals

Portugal has not been spared from the worldwide surge in obesity and Diabetes and its demographics are accelerating towards an ageing population. Thus, in common with other European nations, a considerable portion of the population will be both elderly and obese and it will be important to understand how these factors interact to create metabolic and tissue dysfunction. By integrating a “bottom up” approach of metabolic phenotyping via metabonomic and metabolic flux profiling analyses with a “top down” analysis of putative control factors such as insulin/glucagon levels and insulin signaling pathway status, our group is well positioned to resolve the contributions of age and obesity to complications such as steatosis, cardiovascular disease, impaired wound healing, sperm dysfunction, and muscle degeneration. We will focus on the following paradigm and technology developments:

1. We will seek to understand the synergy of aging and obesity in the development of nonalcoholic fatty liver disease and insulin resistance – key early milestones in the development of Type 2 diabetes and/or severe hepatic complications such as cirrhosis and hepatocellular carcinoma. We will also test the hypothesis that “young obese” and “elderly obese” have distinctive metabolic phenotypes and therefore respond differently to nutritional or pharmacological interventions designed to restore metabolic homeostasis.

2. The lower amount of births, increase in reproductive age and infertility in Western countries has resulted in government sponsored Assisted Reproduction initiatives that tend to involve patients with increasing obesity and diabetes–related complications, thought to further hamper reproductive success. We plan to investigate how previous data acquired so far in normal patients may be used to metabolically characterize gametes, and improve the success rates with this increasing group of patients. Furthermore, it has recently been established that nutrition and metabolism-based disorders may have consequences for future generations, as different aspects may be epigenetically transmitted via modified gametes with improper DNA methylation patterns, or histone modifications. Given the expertise gathered in the group we are uniquely positioned to be able to address epigenetic modifications in human sperm in metabolic-related conditions.

3. The unintentional loss of lean body mass is clinically ominous for elderly subjects and for diabetic subjects of all ages. However, it is difficult to diagnose, and for obese subjects that are undergoing weight loss by diet or by bariatric surgery, loss of lean body mass may be difficult to differentiate from loss of adipose fat mass. Through development of novel metabolite tracer assays and plasma hormone, cytokine and metabolite profiles, we will aim to identify early markers of lean body mass loss.

4. We will evaluate the impact of dysfunctional epicardial adipose tissue on cardiomyocytes in heart failure, in patients with or without diabetes. We will evaluate the alterations in the insulin-stimulated glucose uptake and in lipolysis, the endoplasmic reticulum stress, autophagy, angiogenesis and cardiac damage, in isolated adipocyte tissue.

5. The use of immunosuppressive agents leads to changes in the metabolism. We will evaluate the effect of cyclosporin A and rapamycinon insulin action and the insulin signaling pathway, on oxidative phosphorylation and mitochondrial respiration, in white and brown adipose tissue.

6. We will determine the skin insulin resistance and map effects of systemic versus topical insulin treatment on skin or wound insulin bioavailability, insulin signaling, glycemia and inflammation in diabetic animal models. In addition we will develop novel gel formulations for topical insulin delivery to chronic diabetic wounds and evaluate the wound healing progression.