GDF15, a novel regulator of the AMPK-mediated antidiabetic actions of PPARβ/δ and metformin
Type 2 diabetes (T2D) is a multifactorial disease that comprises metabolic defects in multiple organs. Several studies have shown that the presence of a chronic low-state inflammatory process induces the development of insulin resistance, a pathology in which the organism fails to respond to the hor...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/673920 |
| Acceso en línea: | http://hdl.handle.net/10803/673920 |
| Access Level: | acceso abierto |
| Palabra clave: | Diabetis Diabetes Metabolisme Metabolismo Metabolism Dianes farmacològiques Dianas terapéuticas Drug targeting Factors de transcripció Factores de transcripción Transcription factors Bioquímica Biochemistry Ciències de la Salut 577 |
| Sumario: | Type 2 diabetes (T2D) is a multifactorial disease that comprises metabolic defects in multiple organs. Several studies have shown that the presence of a chronic low-state inflammatory process induces the development of insulin resistance, a pathology in which the organism fails to respond to the hormone insulin. This condition precedes and predicts the development of T2D. Likewise, the presence of endoplasmic reticulum (ER) stress induced by a lipid overload in obesity states contributes to the development of insulin resistance through multiple processes, including the activation of inflammatory pathways. At present, T2D has become a chronic disease that affects more than 400 million people worldwide, reaching epidemiological rates. In addition to the metabolic defects, T2D progression can lead to further complications, including blindness, cardiovascular disease, kidney failure, or limb amputation. Despite its growing incidence, the current available drugs for the treatment of T2D show a limited efficacy and significant side effects that are not fully controlled. For that reason, there is an urgent need to discover new therapeutic targets that can control the complexity of the disease. In this regard, PPARβ/δ agonists have been proven effective as a therapy against insulin resistance and T2D, by improving lipid-induced ER stress and inflammation, as well as glucose and lipid homeostasis. However, PPARβ/δ agonists are not currently available for clinical therapy. On the other hand, metformin has been the most prescribed oral drug for T2D in the past years. Nevertheless, the molecular mechanisms by which this drug exerts its antidiabetic actions are not fully understood. Interestingly, many of the antidiabetic effects of PPARβ/δ activation and metformin on lipid metabolism, inflammation or insulin signalling rely on AMPK activation, and present similarities with the actions of growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism through different mechanisms. In the present thesis, we show that pharmacological PPARβ/δ activation increases GDF15 levels, which contribute to the antidiabetic effects of PPARβ/δ on glucose intolerance, fatty acid oxidation, ER stress, inflammation and insulin signalling. Additionally, we report that the AMPK-p53 pathway is involved in the PPARβ/δ-mediated increase in GDF15, which in turn is necessary to maintain the activation of AMPK. Similarly, metformin treatment increases GDF15 levels through an AMPK-ATF3 pathway. Interestingly, we report that GDF15 mediates the AMPK- mediated antidiabetic effects of metformin on fatty acid oxidation, inflammation and insulin signalling independently of changes in food intake or body weight. Importantly, one of the most remarkable findings is that GDF15 activates AMPK in skeletal muscle independently of central nervous system or the glial cell line- derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), the neuronal receptor for GDF15. Overall, the results of the present doctoral thesis shed light on the mechanism of action of two well-known antidiabetic agents and indicate that GDF15 may become a new therapeutic target for the potential treatment of metabolic disorders. |
|---|