Isabelle Wilson, Biological Sciences, Spring 2021
Figure 1: Diagram of the effects of bile acids on decreased food intake. Bile acids from the digestive system bind to TGR-5 receptors on the surface of hypothalamic cells to effectively increase insulin synthesis and decrease food intake (Source: Frontiers).
Obesity has become a worldwide pandemic affecting approximately 13% of the global. population with vast health implications including heart disease and diabetes. Prescription medications, such as Lorcaserin, are effective in promoting weight loss by acting directly on serotonin receptors in the brain to cause earlier satiety. However, these medications are associated with extremely harmful side effects, such as suicidal thoughts, increased occurrence of cancers, and birth defects (Kushner 2014). Additionally, obesity accounts for 80-85% of the risk for developing type 2 diabetes, which is characterized by insulin resistance and inadequate insulin secretion (Diabetes – Symptoms and Causes, 2020). For these reasons, there is a high demand for research into safer medications that can manipulate hunger/satiety pathways to decrease food intake.
The body’s system for regulating food intake is mainly controlled by the hypothalamus, which is responsible for maintaining steady state of systems in the body, called homeostasis. The widely accepted theory as to how the stomach conveys hunger and satiety signals to the brain involves two types of neurons in the hypothalamus: neuropeptide Y (NPY) and agouti-related peptide (AgRP) that produce hunger signals when activated. Low nutrient availability in the stomach causes the release of hormones, such as ghrelin, that can bypass the blood brain barrier through leaky blood vessels in the hypothalamus and bind to NPY and AgRP neurons (Proietto 2015). Recently, however, researchers at Schoonjan’s lab at Ecole Polytechnique Féderale de Lausanne (EPFL) identified a link between bile acids and satiety that could add to our understanding of how nutrient availability information is conveyed.
Bile acids are the most abundant metabolites in the gut that help the body digest food and absorb fat-soluble vitamins. During a meal, the gallbladder deposits bile into the gut to increase lipid surface area, augment absorption, and aid with digestion (Chen, 2021). Bile acids also act as a key relay messenger of nutrient availability. After leaving the digestive tract, bile acids temporarily enter the bloodstream and then accumulate in the hypothalamus where they bind to G-protein-coupled bile receptors (TGR-5) on the surface of AgRP and NPY hypothalamic cells (Ecole Polytechnique Fédérale de Lausanne, 2021). The binding of bile acids to this receptor produces both short-term blocking of AgRP/NPY peptide release and a long-term inhibition of their expression (Ecole Polytechnique Fédérale de Lausanne, 2021). Considering that AgRP and NPY neurons produce hunger signals, the ability of bile acids to inhibit these signals will suppress hunger and consequently may combat obesity.
To demonstrate the efficacy of bile acids as a potential obesity treatment, Schoonjan’s lab induced obesity in mice with high-fat diets and measured the effects of TGR-5 activation. Their study demonstrated the ability of bile acids to activate TGR-5 and successfully attenuate obesity in diet-induced obese mice models (Ecole Polytechnique Fédérale de Lausanne, 2021). Therefore, the bile acid-TGR-5 axis provides a promising future for obesity and type 2 diabetes treatments by inhibiting expression of hunger signals induced by AgRP and NPY neurons.
References
Chen, I. (2021, May 9). Physiology, Bile Acids. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK549765/.
Diabetes – Symptoms and causes. (2020, October 30). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444
Ecole Polytechnique Fédérale de Lausanne. (2021, May 24). Bile acids trigger satiety in the brain. ScienceDaily. Retrieved May 31, 2021 from www.sciencedaily.com/releases/2021/05/210524161743.htm
Guo, C., Chen, W. D., & Wang, Y. D. (2016). TGR5, Not Only a Metabolic Regulator. Frontiers in physiology, 7, 646. https://doi.org/10.3389/fphys.2016.00646
Proietto, J. (2015, September 25). Chemical messengers: How hormones make us feel hungry and full. The Conversation. https://theconversation.com/chemical-messengers-how-hormones-make-us-feel-hungry-and-full-35545#:~:text=Ghrelin%20is%20made%20in%20the,the%20release%20of%20ghrelin%20increases.
Kushner, R. F. (2014). Weight loss strategies for treatment of obesity. Progress in cardiovascular diseases, 56(4), 465-472.
Perino, A., Velázquez-Villegas, L.A., Bresciani, N. et al. Central anorexigenic actions of bile acids are mediated by TGR5. Nat Metab 3, 595–603 (2021). https://doi.org/10.1038/s42255-021-00398-4