Venue: Neurocentre Magendie conference room
Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance
Thesis supervisor:
Daniela Cota, MD, HDR
Summary: Bile acids (BA) are cholesterol-derived molecules mostly known for participating in the digestion of lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, BA can also act as signaling molecules to reduce body weight, increase energy expenditure and improve glycaemia. These outcomes imply an anti-obesity function for TGR5. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, specifically under diet-induced obesity.
Our results show that TGR5 and BAs transporters are expressed in the mediobasal hypothalamus (MBH), and that obese mice have decreased circulating and hypothalamic BA levels. Acute intracerebroventricular (ICV) or intra-MBH administration of TGR5 agonists reduced food intake and body weight in obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality (30°C) or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require the engagement of the sympathetic nervous system. Conversely, by using genetic animal models, we observed that the deletion of TGR5 in the MBH rapidly increased food intake, body weight and adiposity, while blunting the sympathetic response to a cold challenge (4h at 4°C), hence worsening obesity.
Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. These results expose a new mechanism of action for potential anti-obesity therapies.
Keywords: Bile acids, TGR5, diet-induced obesity, mediobasal hypothalamus, energy balance, sympathetic activity, thermogenesis.
SCIENTIFIC OUTPUT
Published research articles:
- André C, Guzman-Quevedo O, Rey C, Rémus-Borel J, Clark S, Castellanos-Jankiewicz A, Ladeveze E, Leste-Lasserre T, Nadjar A, Abrous DN, Laye S, Cota D. Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation. Diabetes. 2017 Apr;66(4):908-919.
- Rodríguez-Peredo SM, Castellanos-Jankiewicz AK, Imaz-Rosshandler I, Espinoza-Camacho MA, Rangel Escareño C, Muñoz-Sánchez JL, Melendez-Zajgla J, Tejero ME, Carbó R, Maldonado V, del Bosque-Plata L. Modulation of the lung RNAome in a metabolic syndrome rat model. Int J Clin Exp Pathol 2017;10(5):5379-5392.
- Castellanos Jankiewicz AK, Rodríguez Peredo SM, Cardoso Saldaña G, Díaz Díaz E, Tejero Barrera ME, del Bosque Plata L, Carbó Zabala R. Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model. Nutr Hosp 2015;31(6):2546-53. doi: 10.3305/nh.2015.31.6.8935.
- Castellanos-Jankiewicz A, Del Bosque-Plata L, Tejero ME. Combined effect of plant sterols and dietary fiber for the treatment of hypercholesterolemia. Plant Foods Hum Nutr 2014;69(2):93-100. doi: 10.1007/s11130-014-0419-8.
- Guevara-Cruz M, Torres N, Tovar AR, Tejero ME, Castellanos-Jankiewicz A, del Bosque-Plata L. A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio. Nutr Hosp 2014;30(3):671-677.
Articles in progress:
- Castellanos-Jankiewicz A*, Guzman-Quevedo O*, Fenelon V, Zizzari P, Clark S, Dupuy N, Leste-Lasserre T, Muhr-Tailleux A, Staels B, Shoonjans K, Cota D. Brain bile acid-TGR5 signaling protects from obesity.
- Perino A, Velazquez Villegas LA, Castellanos-Jankiewicz A, Guzman-Quevedo O, Fenelon V, Cota D, Shoonjans K. Melanocortin-dependent effects determine the action of neuronal TGR5 signaling on feeding behavior.
- Soty M, Vily J, Castellanos-Jankiewicz A, Guzman-Quevedo O, Raffin M, Clark S, Vulin F, Silva M, Gautier-Stein A, Cota D, Mithieux G. Brain circuit by which glucose sensing in the portal vein controls energy homeostasis.
Book chapters:
- González-Franco L.R., Castellanos Jankiewicz A. (2019). Riesgos nutricionales y cuidado nutricional en el paciente con enfermedad de Parkinson (1st Ed.). In Entendiendo al paciente con enfermedad de Parkinson (pp. 219-228). México: Minaya Editorial. ISBN: 978-1-5323-9476-8.
Science communication articles:
- Castellanos Jankiewicz A., Guzmán Quevedo O., Cota D. El origen de la obesidad: ¿está todo en la cabeza? Revista Ciencia (ACM).
https://www.revistaciencia.amc.edu.mx/index.php/ediciones-anteriores/articulos-fuera-de-los-volumenes-publicados-online/482-el-origen-de-la-obesidad-esta-todo-en-el-cerebro - Castellanos Jankiewicz A. (2018 Octubre-Diciembre). Neurobiología del comportamiento alimentario. Revista Ciencia (ACM), vol. 69(4), pp. 56-61.
https://www.revistaciencia.amc.edu.mx/index.php/ediciones-anteriores?id=282
Jury members:
- M. Guillaume Ferreira, Directeur de Recherche, INRA UMR 1286, Université de Bordeaux, France. (Président)
- M. Luc Penicaud, Directeur de Recherche, CNRS Genopole Toulouse, Université de Toulouse III, Toulouse, France. (Rapporteur)
- M. Christophe Magnan, Professeur des Universités, Université Paris Diderot, Paris, France. (Rapporteur)
- M. Gilles Mithieux, Directeur de Recherche, INSERM U1213, Lyon, France. (Examinateur)
- Mme. Daniela Cota, Directrice de Recherche, INSERM U1215, Université de Bordeaux, France. (Directrice de thèse, examinatrice)