Oral Presentation ANZOS-ASLM-ICCR 2019

The primary cilium is required for MC4R control of food intake and body weight (#87)

Adelaide Bernard 1 2 , Yi Wang 1 , Fanny Comblain 1 , Chritophe Paillart 1 , Sumei Zhang 1 , Christian Vaisse 1
  1. Diabetes Center , University of California San Francisco , San Francisco, CA, USA
  2. Nutritional Sciences and Toxicology , University of California Berkeley, Berkeley, CA, USA

The Melanocortin 4 receptor (MC4R) is a GPCR that plays an essential role in human body weight regulation, as common variation at the MC4R locus are strongly associated with weight gain, and rare mutations in the MC4R coding sequence cause severe human obesity1,2. MC4R expression in neurons of the paraventricular nucleus of the hypothalamus (PVN) has been shown to be both necessary and sufficient for the control of food intake and body weight3,4, and we have recently demonstrated that MC4R localizes at the primary cilia of these neurons5. The primary cilium is a solitary hair-like organelle on the cell surface that serves as an antenna sensing environmental conditions. Mutations that disrupt the function of primary cilia in humans cause ciliopathies, pleiotropic diseases of many of which obesity is a cardinal manifestation6–8. How ciliary dysfunction leads to obesity is unclear, but is thought to involve disruption of neuronal signaling pathways that regulate energy homeostasis9.

We therefore hypothesized that primary cilia are required for MC4R control of food intake and body weight. First, we demonstrated that developmental deletion of primary cilia in MC4R-expressing cells leads to increased body weight. We showed that whole-body deletion, as well as PVN-specific deletion of primary cilia in adult mice lead to hyperphagia and obesity, as well as a blunted response to an MC4R agonist. We further demonstrated that blocking adenylate cyclase signaling specifically at the primary cilium of MC4R neurons in the PVN of adult mice leads to hyperphagia and obesity.

Together, these results provide a direct link between the primary cilium and MC4R-regulated energy homeostasis. Hence, mislocalization of MC4R to the primary cilium may be causing the obesity phenotype encountered in some ciliopathies, suggesting that genes that are necessary for the localization and function of MC4R at the cilium are candidate genes for obesity.

  1. Lubrano-Berthelier, C. et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J. Clin. Endocrinol. Metab. 91, 1811–1818 (2006).
  2. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114 (1998).
  3. Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).
  4. Shah, B. P. et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc. Natl. Acad. Sci. U. S. A. 111, 13193–13198 (2014).
  5. Siljee, J. E. et al. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat. Genet. 50, 180 (2018).
  6. Green, J. A. & Mykytyn, K. Neuronal ciliary signaling in homeostasis and disease. Cell Mol Life Sci 67, 3287–97 (2010).
  7. Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N Engl J Med 364, 1533–43 (2011).
  8. Reiter, J. F. & Leroux, M. R. Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18, 533–547 (2017).
  9. Davenport, J. et al. Disruption of Intraflagellar Transport in Adult Mice Leads to Obesity and Slow-Onset Cystic Kidney Disease. Curr. Biol. 17, 1586–1594 (2007).