Unraveling the Biocircuitry of Obesity

Posted on January 17th, 2018 by Dr. Francis Collins

Obesity involves the complex interplay of diet, lifestyle, genetics, and even the bacteria living in the gut. But there are other less-appreciated factors that are likely involved, and a new NIH-supported study suggests one that you probably never would have imagined: antenna-like sensory projections on brain cells.

The study in mice, published in the journal Nature Genetics [1], suggests these neuronal projections, called primary cilia, are a key part of a known “hunger circuit,” which receives signals from other parts of the body to control appetite. The researchers add important evidence in mouse studies showing that changes in the primary cilia can produce a short circuit, impairing the brain’s ability to regulate appetite and leading to overeating and obesity.

The new findings come from an interesting convergence between two NIH-funded labs at the University of California San Francisco (UCSF). One lab, led by Christian Vaisse, has been on a quest to identify the many genetic factors that can contribute to obesity. The quest has led them to a key stretch of the hunger circuit wired into the brain’s hypothalamus. There, specific neurons constantly sense levels of leptin, which is a hormone secreted by fat cells that offers a surrogate measure of how much fat is stored in the body.

Leptin-sensing neurons then relay their readings to another part of the circuit, where other nerve cells can inform the rest of the brain to adjust appetite up or down. Studies by Vaisse’s team recently revealed that MC4R, a protein receptor on the surface of this second group of nerve cells, is a key component in forwarding appetite-regulating information. When MC4R is defective, the forwarded signal doesn’t work properly, and appetite gets locked in the “on” position. In fact, mutations in the MC4R gene are the most common genetic cause of extreme childhood obesity in people [2].

The other UCSF lab, led by Jeremy Reiter, has been studying primary cilia. Interestingly, primary cilia in the brain had once been dismissed as an obsolete cellular organelle, a mere biological relic that served no purpose. It’s now clear that’s not correct. Primary cilia defects contribute to a wide range of genetic syndromes collectively known as ciliopathies. Ciliopathies often include a wide range of features, such as polydactyly (extra fingers and toes), retinal defects, lung disorders, and kidney diseases [3]. But there was one thing that remained much less clear: why people with certain ciliopathies, including Bardet-Biedl and Alström syndromes, are almost always extremely obese.

The new study helps to fit all these pieces together. Tagging the MC4R protein and visualizing its location for the first time in the mouse brain, the researchers discovered that it is located on the primary cilia. What’s more, MC4R is specifically found on the neurons that communicate with the rest of the brain to adjust appetite.

Researchers also examined a second protein, called ADCY3, known to be expressed specifically on the primary cilia of neurons. While ADCY3 had already been tied to obesity, two studies, also published in Nature Genetics, provide further data from the United States, Pakistan, and Greenland that ADCY3 mutations are indeed a cause of obesity and diabetes in people [4, 5].

Vaisse’s team suspected that MC4R and ADCY3 might function together on the primary cilia. To find out, the researcher blocked the function of ADCY3 specifically at the primary cilia in the MC4R-expressing neurons of mice. As predicted, those animals began eating more and packing on weight.

Together, the data suggest that these two proteins, located on the primary cilia of neurons, work together to regulate the brain’s hunger circuit. While obesity-causing MC4R mutations are relatively rare in the general population—occurring in 3 to 5 percent of all severe obesity cases—more common variations in dozens, if not hundreds, of genes can make people more likely to become obese. Vaisse now thinks many of those genes could turn out to have a role in the brain’s primary cilia. If correct, it could offer a potentially important “unifying theory” for the genetics of obesity.

References:

[1] Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Siljee JE, Wang Y, Bernard AA, Ersoy BA, Zhang S, Marley A, Von Zastrow M, Reiter JF, Vaisse C. Nat Genet. 2018 Jan 8.

[2] 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. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C. J Clin Endocrinol Metab. 2006 May;91(5):1811-8.

[3] Genes and molecular pathways underpinning ciliopathies. Reiter JF, Leroux MR. Nat Rev Mol Cell Biol. 2017 Sep;18(9):533-547.

[4] Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, Din SM, Gaitan J, Milochau A, Durand E, Vaillant E, Haseeb A, De Graeve F, Rabearivelo I, Sand O, Queniat G, Boutry R, Schott DA, Ayesha H, Ali M, Khan WI, Butt TA, Rinne T, Stumpel C, Abderrahmani A, Lang J, Arslan M, Froguel P. Nat Genet. 2018 Jan 8.

[5] Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Grarup N, Moltke I, Andersen MK, Dalby M, Vitting-Seerup K, Kern T, Mahendran Y, Jørsboe E, Larsen CVL, Dahl-Petersen IK, Gilly A, Suveges D, Dedoussis G, Zeggini E, Pedersen O, Andersson R, Bjerregaard P, Jørgensen ME, Albrechtsen A, Hansen T. Nat Genet. 2018 Jan 8.

Links:

Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Christian Vaisse (University of California San Francisco)

Reiter Lab (UCSF)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of General Medical Sciences; National Institute on Drug Abuse