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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/102801
Assessing metabolic plasticity in diet-induced obese mice upon lifestyle intervention. An integrative approach
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[eng] Type 2 Diabetes Mellitus (T2DM) is the metabolic disorder that accounts for the presence of hyperglycemia within insulin resistance (IR). The International Diabetes Federation estimated in 2013 that 382 million people (8.3% of world society ) had diabetes and that this number is set to rise beyond 592 million people in the next 22 years. T2DM accounts for 90% of people with diabetes (WHO 1999). Obesity is considered a major risk factor for developing T2DM over time. The World Health Organization (WHO) stated in 2014 that more than 1.9 billion adults were overweight and of these, over 600 million were obese (body mass index (BMI) > 30 kg/m2). Besides healthcare costs, WHO projects that diabetes will be the 7th leading cause of death in 2030 (Mathers & Loncar 2006). Once T2DM is diagnosed, the first therapeutic approach is by lifestyle counselling consisting of an increase in physical activity and changes in the patient dietary habits. The aim of this project is to study and integrate the metabolic responses that regulate systemic glucose homeostasis. We are not aware of other works describing in a holistic way the different metabolic processes regulating glucose homeostasis in different tissues that play an important role during the development and onset of diet-induced T2DM. With this approach, we will gain more insight and a better knowledge of the metabolic alterations taking place during an obese state induced by high-fat diet, as well as assess the degree of reversibility that can be reached by undergoing a lifestyle intervention, known as “metabolic plasticity”. For this purpose a diet-induced obese animal model of T2DM is used. To achieve the presented aims, a phenotypical and funcional study is performed at systemic level in order to complete a more experimental and detailed approach afterwards in each of the studied tissues: pancreas, white adipose tissue, liver, oxidative and glycolytic skeletal muscle, and hypothalamus. This experimental approach encompasses tissue-specific-functional analysis, gene expression studies, protein content determination and signalling, metabolomics and RNAseq. Likewise, systems biology tools have been developed and have allowed to measure several correlations as well as perform different types of multivariant analysis with the studied parameters. Three experimental groups are defined representing the metabolic stages of interest: control group (Ctrl); pathologic group (HFD, that mimic diet-induced T2DM after 16 wks on HFD; and in which animals showed overweight, and fasting hyperglycemia and hyperinsulinemia); and a third group (Int) that follows a lifestyle intervention consisting of caloric restriction, modification of the fatty acid source and carbohydrates in the diet, and the performance of an exercise training programme. The diet-induced obese experimental group (HFD group) reported the typical physiological features of the pathological state: overweight, fasting hyperglycemia, hyperinsulinemia and hyperleptinemia, increase in fat mass and volume, increase of white adipose tissue, liver and pancreas weight, increase of liver and oxidative skeletal muscle triglycerice levels, glucose intolerance, insulin resistance, increase in beta-cell mass along with hypertrophic enlarged islets and dysfunction in glucose-stimulated insulin secretion in vivo and in vitro, and a diminishment in oxygen consumption, heat production and scapular temperature. Lifestyle intervention was enough to revert most of the disruptions reported in the pathological group. However, certain irreversibility degree was still observed in particular studied parameters: (1) alteration in fasting glucose and glucose-stimulated insulin secretion in vivo, (2) increment in pancreatic beta-cell area, (3) affectation in the epididymal white adipose tissue with inflammation and immune cell infiltration, as well as (4) mitochondria dysfunction, already observed in the pathological state. Taken all this together, we can conclude that the pathological state left a certain degree of metabolic irreversibility does not allow a total recovery of the phenotype across the different tissues studied, at least with this type of intervention and timings. The development and application of systems biology tools have allowed the study the irreversibility degree in an integrative mode, the correlations among certain parameters at a multiorganic level, the gene expression patterns of complexes described from a protein-protein interaction (PPI) network. These strategies and computational approaches have led to the identification of most of the altered tissues and metabòlic pathways in the different states under study.
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GONZÁLEZ FRANQUESA, Alba. Assessing metabolic plasticity in diet-induced obese mice upon lifestyle intervention. An integrative approach. [consulta: 2 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/102801]