Enhancing Satiation Signaling to Reduce Overeating and Obesity in Prader-Willi Syndrome

Funding Summary

Lack of satiety, or feeling 'full', is a hallmark characteristic of PWS. Satiety mechanisms are not well understood, and it is not clear how the stomach signals the brain to stop eating. It is believed, however, that the vagus nerve to hind brain connection (NTS) may be a key part of this mechanism. In this project, Dr. Edward Fox will artificially enhance NTS satiety signaling to see if we can increase satiety and reduce meal size in PWS mice. This knowledge could be very helpful in figuring out the satiety circuit and potentially develop treatments for the lack of satiety in people with PWS.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.  

Watch the full webinar describing the 8 research projects funded in this grant cycle here. 

Lay Abstract

Extreme overeating that leads to life-threatening obesity is a hallmark of Prader-Willi Syndrome (PWS). This obesity results in cardiorespiratory diseases that lead to early morbidity and mortality. Thus, controlling food intake in PWS can greatly extend lifespan, improve self-esteem and quality of life with better weight control, and minimize the decrease in IQ with age. Therefore, developing an effective means to control the dramatic overeating of PWS is essential.

People with PWS require much larger and much longer duration meals than healthy people to feel full and after eating and they feel hungry much sooner. This suggests their overeating results from a severe deficit in the ability of food consumed to reduce hunger and stop eating (satiety). Thus, finding a way to enhance satiety is a promising route to stop overeating in PWS.

Food in the stomach activates satiety signals that travel along the vagus nerve to the hindbrain where they excite brain cells in the nucleus tractus solitarius (NTS). In turn, NTS brain cells transmit these signals to many other brain areas. Surprisingly, we do not know how this brain circuit stops eating. The satiety brain circuit and expression of genes associated with PWS hyperphagia and obesity overlap, suggesting the overlapping brain areas may be affected by PWS mutations. One such area, the NTS, is pivotal as it is the major source of satiety information for the rest of the brain.

We hypothesize PWS mutations compromise satiety signaling by the NTS to contribute to increased meal size and overeating. As a first step, we propose to test this hypothesis in mice that have PWS mutations and a satiety deficit. We will determine whether satiety signals in the NTS are reduced by PWS mutations. The outcome will help design future experiments that test whether artificially enhancing satiety signaling in the NTS, using novel, innovative approaches can reduce meal size and overeating. If successful, we could isolate the NTS brain cells involved and identify genes active only in these cells. We can then test whether any of these genes have the right properties for developing pharmacological or gene therapy treatments that enhance satiation signals in the NTS to help control eating in people with PWS. In parallel, the ability to selectively excite NTS brain cells involved in satiety could help dissect the entire satiety circuit to figure out how it stops eating. Such basic knowledge could also be useful for developing treatments for PWS.

Research Outcomes: Public Summary

Snord116 null mice, like people with PWS, are thought to overeat mainly because of a satiety deficit. Satiety signaling from the gut enters the brain in the caudal solitary tract nucleus (cNTS). The cNTS receives information directly from the stomach and upper intestine about the amount of food consumed during a meal. As we have shown previously in other mouse strains, during consumption of a meal, this information from the upper gut excites many neurons in the cNTS, which leads to inhibition of eating and thus ends a meal. In the present experiment, as expected, both Snord116 null and wild-type mice exhibited an increase in the number of neurons excited in the cNTS in FED as compared with NONFED mice (excitation of these neurons was assessed by counting c-Fos stained neurons in the 3 brain regions examined). Our hypothesized reduction in the number of excited neurons in the cNTS of FED Snord mutants compared to FED wild types, however, was not observed; these numbers were similar in Snord116 null and wild-type mice. This suggests excitation of cNTS neurons during a meal is normal in snord116 null mice. This further suggests the satiety deficit in Snord116 null mice is not due to faulty signaling by the cNTS to other brain areas. Thus, the deficit in satiety signaling may be in brain regions that receive the satiety information from the cNTS. My future work includes plans to pursue this possibility by trying to identify the locus of the signaling deficit in the snord116 null mice. Identification of the locus of the deficit in satiety signaling, if it were similar to PWS in people, could be a starting point to identify possible treatments for PWS.