Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight
| Autor: | Xinyu Yue, Jeremy F. Reiter, Yi Wang, Sumei Zhang, Adelaide Bernard, Christian Vaisse, Fanny Comblain, Christophe Paillart |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mice Transgenic Biology Ciliopathies Energy homeostasis Adenylyl cyclase Eating Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Cilia Neurons Cilium Body Weight digestive oral and skin physiology Brain General Medicine Cell biology Melanocortin 4 receptor 030104 developmental biology medicine.anatomical_structure chemistry Hypothalamus 030220 oncology & carcinogenesis Receptor Melanocortin Type 4 Neuron Melanocortin Energy Metabolism Signal Transduction Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | The melanocortin 4 receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis, and mutations in the MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R-expressing neurons are unknown. We recently reported that the MC4R localizes to the primary cilium, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether the MC4R functions in this organelle. Here, using mouse genetic approaches, we found that cilia were required specifically on MC4R-expressing neurons for the control of energy homeostasis. Moreover, these cilia were critical for pharmacological activators of the MC4R to exert an anorexigenic effect. The MC4R is expressed in multiple brain regions. Using targeted deletion of primary cilia, we found that cilia in the paraventricular nucleus of the hypothalamus (PVN) were essential to restrict food intake. MC4R activation increased adenylyl cyclase (AC) activity. As with the removal of cilia, inhibition of AC activity in the cilia of MC4R-expressing neurons of the PVN caused hyperphagia and obesity. Thus, the MC4R signaled via PVN neuron cilia to control food intake and body weight. We propose that defects in ciliary localization of the MC4R cause obesity in human inherited obesity syndromes and ciliopathies. |
| Databáze: | OpenAIRE |
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