The role of hepatic fgf21 (fibroblast growth factor 21) in the maintenance of metabolic homeostasis during metabolic stress
- Autores: Úrsula Monserrat Martínez Garza
- Directores de la Tesis: Diego Haro Bautista (dir. tes.), Joana Relat Pardo (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Juan José Moreno Aznarez (presid.), Carles Lerín Martínez (secret.), Ana Luisa De Sousa Coelho (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
The excessive consumption of calorie-rich foods, together with a sedentary lifestyle, drive the actual global obesity pandemic. Obesity is the leading cause of several other metabolic disorders, such as diabetes, cardiovascular diseases, cancer, and non-alcoholic fatty liver disease (NAFLD).
Fibroblast growth factor 21 (FGF21) has been described as an anti-obesity and antidiabetic hormone because of its potent effects over glucose and lipid metabolism [1]. Also, recent publications suggest that FGF21 effects on the liver lead to a reduction in liver fat content and decrease fibrosis and inflammation [2,3]. For these reasons, FGF21 is considered as a candidate to treat obesity-related metabolic disorders.
Some of our previous results show that mice fed with a low protein diet (5% of protein intake) for seven days increased Fgf21 expression in the liver. Protein restriction mediated by hepatic FGF21 promoted weight loss and induced browning in subcutaneous white adipose tissue (scWAT) by an increase of uncoupling protein 1 (UCP1) expression [4].
The global aim of this project is to understand the role of hepatic FGF21 in the maintenance of metabolic homeostasis during high metabolic stress. This project's specific objectives are: 1) To study the effects of hepatic FGF21 on lipid homeostasis due to excessive acute fat storage caused by tunicamycin. 2) To analyze the effects of protein restriction on protecting against and counteracting the effects of a high lipid intake. 3) To understand the role of FGF21 in the metabolic response to fasting.
6 week-old male C57BL/6J mice were randomly divided into: 1.- a HFD group or a high-fat lowprotein diet HFD-LP group for 10 weeks; 2.- 17h fasting or ad libitum feeding with chow diet; 3.- Injected with Tunicamycin, drug that induce ER stress and TG storage in the liver, or with a control.
Body weight and food intake were recorded twice a week. All diets were formulated and produced by ResearchDiets and were designed to be isocaloric by equally varying protein and carbohydrate content while keeping fat constant. Glucose sensitivity was evaluated during the nutritional intervention and the metabolic profile was analyzed after the sacrifice. Gene expression analysis of the main genes involved in lipid and glucose homeostasis were studied.
Protein restriction in obese mice counteract the effects of diet-induced obesity in part by the effects of hepatic FGF21. It prevents liver weight gain and reduces the expression of genes involved in fatty acid transport and lipid droplet formation in the liver. 17h fasting induces hepatic FGF21, and it contributes to energetic homeostasis maintenance during fasting by activating gluconeogenic genes expression. Hepatic FGF21 is a key factor involved in the metabolic homeostasis during metabolic stress.
