Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight
Yi Wang, … , Jeremy F. Reiter, Christian Vaisse
Yi Wang, … , Jeremy F. Reiter, Christian Vaisse
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e142064. https://doi.org/10.1172/JCI142064.
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Research Article Endocrinology Metabolism

Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight

Abstract

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.

Authors

Yi Wang, Adelaide Bernard, Fanny Comblain, Xinyu Yue, Christophe Paillart, Sumei Zhang, Jeremy F. Reiter, Christian Vaisse

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Figure 5

Primary cilia are required in PVN neurons for weight control and sensitivity to MC4R agonists.

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Primary cilia are required in PVN neurons for weight control and sensiti...
(A) Schematic of the experimental protocol. Bilateral stereotaxic injections (coordinates: AP = –0.8, ML = ±0.2, DV = –5.2) of AAV-CreGFP or AAV-nGFP were performed on 20-week-old Ift88fl/fl mice. (B) Schematic representation of the hypothalamic region studied. (C and D) Representative images of PVN sections from AAV-CreGFP- or AAV-nGFP–injected mice showing AAV-infected cells in green and nuclei in blue. Scale bars: 200 μm. Enlarged insets show immunofluorescence images of primary cilia (ADCY3, magenta) in the PVN regions shown in C and D. Arrows indicate cilia. Scale bars: 10 μm. (E) Body weights of Ift88fl/fl mice following bilateral PVN injection of AAV-CreGFP (n = 5) or AAV-nGFP (n = 5). (F) Body weights at the time of AAV injection and 1 month later. Individual mice are indicated by lines. (G) Schematic of the experimental protocol for testing the anorexigenic effects of the MC4R agonist MTII. Three weeks after AAV injection and cannulation, 20-week-old Ift88fl/fl mice were alternately treated with vehicle (aCSF) or MTII by i.c.v. infusion after fasting for 24 hours, with a 4-day recovery between infusions. Food intake during a 4-hour re-feeding period was then averaged for aCSF and MTII (values are shown in I and J). (H) Schematic of bilateral stereotaxic injections (coordinates: AP = –0.8, ML = ±0.2, DV = –5.5) of AAV-CreGFP (n = 9) or AAV-nGFP (n = 6), and placement of an i.c.v. cannula in the lateral ventricle (coordinates: AP = –0.3, ML = +1, DV = –2.5). (I) Four-hour food intake following injection of aCSF or MTII into AAV-CreGFP– and control AAV-nGFP–injected Ift88fl/fl mice (repeated-measures averaged). (J) Percentage of food ingested within 4 hours following i.c.v. administration of MTII normalized to aCSF administration. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by Student’s t test (J) and repeated-measures 2-way ANOVA followed by Sidak’s multiple-comparison test (E, F, and I).