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A broken calorie sensing pathway: How overeating may lead to more eating

June 15, 2016

(PHILADELPHIA) - Research is finally beginning to shed light on some of the reasons that extra weight is difficult to shed permanently. Now, a new study has uncovered another method by which the gut senses how much food a person eats and relays that to the brain. When the gut senses too many calories, a pathway that promotes the feeling of fullness becomes blocked. The new research was published in the journal Nutrition & Diabetes, published by Nature.

Through earlier studies on colon cancer, Thomas Jefferson University researchers led by Scott Waldman, M.D., Ph.D., Chair of the Department of Pharmacology and Experimental Therapeutics and researcher at the Sidney Kimmel Cancer Center at Jefferson, noticed that a hormone called uroguanylin also appeared to play a role in obesity. Their studies had shown that in non-obese mice, uroguanylin would travel to the brain, where it produced a feeling of fullness. But it was unclear what happened to this signaling in the obese state.

In the current study, the researchers looked at mice who were overfed, and saw that the small intestines of these mice had stopped producing uroguanylin. The receptors for uroguanylin that reside in the brain were intact, and had even increased in number, but hormone itself was no longer being made, suggesting that overeating had caused its production to shut down. However, when the animals were put on a diet, the guanylin production resumed.

"What's interesting," said Dr. Waldman, "is that it didn't matter whether the mice were lean and overfed, or obese and overfed - urogaunylin production stopped in both groups of animals when they got too many calories." This, says Dr. Waldman, is opposite to what's been observed for other obesity-related hormones like insulin and leptin, which are produced in ever greater quantity as weight increases. "Here, it's not the obese state that's causing the problem but rather it's the calories," he added.

To find out how overeating shuts off uroguanylin production, the researchers looked at the cells in the small-intestine that produce the hormone. They suspected that the endoplasmic reticulum (ER) might be involved. The ER is an cellular organelle that serves as the production line for many of the body's proteins and hormones, and can stop functioning when it is stressed. When the researchers applied a chemical, tunicamycin, known to cause ER stress, mice stopped producing uroguanylin, much as they did when they were overfed. Finally when overfed, obese, mice were given a chemical that was known to relieve ER stress, the animals once again began producing uroguanylin, suggesting that overfeeding caused the ER stress that in turn shut down uroguanulin production.

"Taken together, these experiments show that excess calories - either from fat or carbohydrates - stress small intestinal cells so that they stop producing uroguanylin, which helps people feel full after eating," says Dr. Waldman. "What we don't know is how much is too much and what molecular sensor makes that decision."

"Like in cancer, there are many steps on the way to becoming obese that aren't easily reversed. While the uroguanylin hormone pathway appears to be one of those steps, we don't yet know whether it's important early on in the process, or later, and how much of a role in plays," says Dr. Waldman. "But in combination with other approaches, hormone replacement of uroguanylin may become an important component of therapy to reverse obesity."

These studies were supported by grants from the NIH (R01 CA75123, R01 CA95026, RC1 CA146033, P30 CA56036 and R01 CA170533), the Pennsylvania Department of Health (SAP 4100059197 and SAP 4100051723) and Targeted Diagnostics & Therapeutics, Inc. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Other funding sources listed in the paper.

Dr. Waldman is the chair of the Data Safety Monitoring Board for the CHART-1 trial sponsored by Cardio3 Biosciences, a member of the Scientific Advisory Board for Immunovative Therapies, and the chair (uncompensated) of the Scientific Advisory Board of Targeted Diagnostics & Therapeutics, Inc. that provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work. The authors report no other conflicts of interest.
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Article reference: GW Kim et al., "Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity," Nutr Diabetes, doi: 10.1038/nutd.2016.18, 2016.

For more information, contact Edyta Zielinska, 215-955-5291, edyta.zielinska@jefferson.edu.

About Jefferson

Our newly formed organization, Jefferson, encompasses Thomas Jefferson University and Jefferson Health, representing our academic and clinical entities. Together, the people of Jefferson, 19,000 strong, provide the highest-quality, compassionate clinical care for patients, educate the health professionals of tomorrow, and discover new treatments and therapies that will define the future of health care.

Jefferson Health comprises five hospitals, 17 outpatient and urgent care locations, as well as physician practices and everywhere we deliver care throughout the city and suburbs across Philadelphia, Montgomery and Bucks Counties in Pa., and Camden County in New Jersey. Together, these facilities serve nearly 73,000 inpatients, 239,000 emergency patients and 1.7 million outpatient visits annually. Thomas Jefferson University Hospital is the largest freestanding academic medical center in Philadelphia. Abington Hospital is the largest community teaching hospital in Montgomery or Bucks counties. Other hospitals include Jefferson Hospital for Neuroscience in Center City Philadelphia; Methodist Hospital in South Philadelphia; and Abington-Lansdale Hospital in Hatfield Township.

Thomas Jefferson University enrolls more than 3,800 future physicians, scientists, nurses and healthcare professionals in the Sidney Kimmel Medical College (SKMC), Jefferson Colleges of Biomedical Sciences, Health Professions, Nursing, Pharmacy, Population Health and is home of the National Cancer Institute (NCI)-designated Sidney Kimmel Cancer Center.

For more information and a complete listing of Jefferson services and locations, visit http://www.jefferson.edu.

Thomas Jefferson University

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