November 17, 2021

A BRAIN NETWORK THAT CURBS THE URGE TO EAT

Scintillon Institute researchers uncover an evolutionarily conserved brain region that puts a “brake” on food intake which may advance therapeutics for obesity and related disorders with excessive eating such as Prader-Willi syndrome.

Do you ever wonder why you stop eating even when there are appealing foods available?

The cerebellum compares hunger state with after-eating nutritional status in the gut to regulate dopamine reward signals in the striatum to control meal size.

A multi-institution collaboration led by Associate Professor Albert I. Chen at the Scintillon Institute, Assistant Professor J. Nicholas Betley and Postdoctoral Fellow Aloysius Low at the University of Pennsylvania searched for brain regions that might provide a stop signal for feeding and identified the cerebellum, a brain region outside of the conventional feeding network, as an important regulator of meal size. Neural activity of this region directs the suppression of food intake in mice, and this activity is abolished in human subjects with insatiable appetite. Their findings were published in the journal Nature on November 17, 2021.

This project began when the Chen and Betley labs made a surprising observation that the activation of a brain region in mice – the cerebellum, conventionally known to coordinate movement – strongly reduces food intake. Together with Drs. Roscoe Brady (Beth Israel Deaconess Medical Center), Mark Halko (McLean Hospital) and Laura Holsen (Brigham and Women’s Hospital), the team used functional magnetic resonance imaging (fMRI) to examine the brain activity of patients with Prader-Willi syndrome (PWS), a genetic disorder characterized by excessive eating that leads to obesity and related comorbidities. Analysis of the fMRI data revealed that the region most significantly disrupted in PWS patients is in fact the same as the region with the ability to terminate food intake in mice, suggesting the identification of an important brain center that controls food intake.

Guided by the human imaging studies, the team spearheaded by Dr. Low examined the identity of brain cells in this region and how they interact with the rest of the brain in mice. They found that a specific population of cells in the cerebellum responds to food and nutrients, and suppresses food intake through regulation of dopamine level in reward centers of the brain. Activity of this distinct cell population robustly inhibits food intake without compensation in energy expenditure. These results highlight a novel role for the cerebellum in signaling fullness to reduce food intake before overeating occurs.

Thus, the cerebellum represents a novel target for advancing therapeutics for obesity and related disorders with excessive eating such as PWS. In collaboration with Drs. Brady, Halko and Holsen, the team is planning to use non-invasive neuromodulation such as transcranial magnetic stimulation (TMS) to manipulate this circuit in humans. The finding that cerebellar activity has the ability to reduce eating without subsequent compensation either in food intake or energy expenditure is a major breakthrough – as manipulation of other known brain feeding centers have not achieved this feat.

This work titled “Reverse-translational identification of a cerebellar satiation network” was published in Nature on November 17th, 2021. DOI: 10.1038/s41586-021-04143-5. https://www.nature.com/articles/s41586-021-04143-5

Additional authors on the paper are: Nitsan Goldstein, Jamie R.E. Carty, Ju Y. Choi, Alekso M. Miller, and Clara Lenherr (University of Pennsylvania); Jessica R. Gaunt, Norliyana Zainolabidin, Helen S. T. Ho, Alaric K.K. Yip, and Toh Hean Ch’ng (Nanyang Technological University); Kuei-Pin Huang and Amber L. Alhadeff (Monell Chemical Senses Center); Nicholas Baltar and Eiman Azim (Salk Institute for Biological Studies); October M. Sessions (National University of Singapore); Amanda S. Bruce and Laura E. Martin (University of Kansas Medical Center).

The research was supported by the American Diabetes Association (118IBS116), American Heart Association (857082, 17SDG33400158), National Institutes of Health (NS105555, NS111479, NS112959, MH111868, MH125995, MH116170, DK104772, DK119574, DK114104, DK124801), National Science Foundation (1845298), Klingenstein Simons Fellowship Award, McKnight Foundation, Pew Charitable Trusts, Searle Scholars Program, Singapore Ministry of Education (MOE2018-T2-1-065, MOE2017-T3-1-002), Warwick-NTU Neuroscience Programme, and the Whitehall Foundation.