Journal Article

Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

Alice Chen, Yu, Lopez, Manuel, Lindhout, Darrin A., Mondal, Kalyani, Yie, Junming, Horner, Geoffrey, Parsons, Thomas, Lakshminarasimhan, Damodharan, Haldankar, Raj, To, Carmen, Solloway, Mark, Ayupova, Dina A., Kutach, Alan, Higbee, Jared, Joo, William, Allan, Bernard B., Shen, Wenyan D., Tian, Hui, Crawley, Suzanne, Chen, Michael, Tang, Jie, Matern, Hugo, Yao, Jun, Laird, Teresa, Chan, Jackie, Hsu, Jer-Yuan, Li, Betty, McEntee, Michele, Fu, Diana, Kekatpure, Avantika, Wang, Marilyn, Wang, Sheng-Ping, White, Andre, Gao, Zhengyu

2017

Overview

GDNF receptor alpha-like is a brainstem-restricted receptor for growth and differentiation factor 15, regulating appetite and body weight in non-homeostatic conditions by activating the emergency circuit response to disease and toxin stresses. Brainstem receptor regulates body mass loss Growth and differentiation factor 15 (GDF15) acts on feeding centres in the brain to cause anorexia, leading to loss of both lean and fat mass and eventually cachexia. GDF15 levels rise in response to tissue stress and injury, and higher levels are associated with weight loss in numerous chronic human diseases, including cancer. Bernard Allan and colleagues now show that glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) is a GDF15 receptor in the brainstem. The structure of GDF15 and its interaction with GFRAL together with biochemical experiments and analysis of Gfral knockout mice demonstrate that regulation of body weight by GFRAL is independent of previously characterized pathways. Unlike hormones from gut and adipose tissue that activate receptors mostly in the hypothalamus, GDF15 increases in response to tissue damage and activates GFRAL-expressing neurons in the brainstem. Gfral knockout mice overate under stressed conditions and were resistant to chemotherapy-induced anorexia and weight loss. These findings provide therapeutic opportunities for disorders with altered energy demands. Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure 1 , 2 . In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand 3 . Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions 4 , 5 , 6 , but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions 7 . GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases 8 , 9 . By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14 / 14/33 / 14/63 / 38 / 38/15 / 38/61 / 60 APPLIED LIFE SCIENCES / 631/443/319/1557 / 631/80/2391 / 64/60 / Amygdala / Animal diseases / Animals / Anorexia / Area postrema / BASIC BIOLOGICAL SCIENCES / Body weight / Body weight loss / Brain / Brain stem / Cell receptors / Chemotherapy / Circuits / Eating disorders / Energy demand / Energy expenditure / Food / Food consumption / Food intake / Gene expression / Glial cell line-derived neurotrophic factor / Homeostasis / Humanities and Social Sciences / Hypothalamus / Kinases / letter / Metabolism / multidisciplinary / Neural networks / Neuronal-glial interactions / Neurons / Parabrachial nucleus / Pharmacology / Physiological aspects / Physiological regulation / Physiological research / Proteins / Receptors / Science / Solitary tract nucleus / Toxins / Weight loss