Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
Autor: | Kalyani Mondal, Geoffrey Horner, Manuel E. Lopez, Mark J. Solloway, Chen M, Laird T, Gao Z, Raj Haldankar, Andre White, Yao J, Wang M, Tang J, Avantika Kekatpure, Hugo Matern, Bernard B. Allan, Chan J, Alice Chen Y, Dina A. Ayupova, Higbee Jared Martin, Damodharan Lakshminarasimhan, Li B, Tian H, To C, Hsu Jy, Alan Kutach, Tom Parsons, Wang Sp, Shen Wd, Suzanne Christine Crawley, Joo W, Junming Yie, Darrin A. Lindhout, cEntee M, Fu D |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Glial Cell Line-Derived Neurotrophic Factor Receptors Growth Differentiation Factor 15 Biology Body weight Amygdala Eating Mice 03 medical and health sciences 0302 clinical medicine Weight loss Neurotrophic factors Internal medicine medicine Glial cell line-derived neurotrophic factor Animals Homeostasis Receptor Insulin-like growth factor 1 receptor Mice Knockout Neurons Multidisciplinary Body Weight Central Amygdaloid Nucleus Area postrema Feeding Behavior Parabrachial Nucleus 030104 developmental biology medicine.anatomical_structure Endocrinology Hypothalamus biology.protein Female Brainstem GDF15 medicine.symptom Energy Metabolism Neuroscience Stress Psychological 030217 neurology & neurosurgery Brain Stem |
Zdroj: | Nature. 550:255-259 |
ISSN: | 1476-4687 0028-0836 |
Popis: | 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. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions, 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. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. 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. |
Databáze: | OpenAIRE |
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