Navigation Links
Chewing up a key regulator of fat synthesis keeps mice lean despite a high-fat diet

Scientists at the Salk Institute for Biological Studies have identified a novel pathway that regulates the body's ability to store or burn fat, a discovery that suggests new ways to reduce obesity, diabetes and other fat-related human diseases.

Genetically engineered mice, in which the pathway was constantly revved up, were protected from the ravages of a high-fat diet, the Salk team led by Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology reports in this week's issue of Science.

"These mice were able to deal with a high-fat diet much better than their normal counterparts," Montminy says. "They stayed lean and were much more sensitive to insulin, although they ate more," he adds.

In humans, a high-fat diet ?one heavy on red and processed meats like hot dogs and sausages, refined grains, fried foods and sweets ?increases the risk of fatty liver disease, which may eventually lead to type 2 diabetes, especially in people who are overweight and out of shape.

The engineered mice consumed an equally high-fat diet but did not gain weight, indicating that fat storage pathways can be tweaked. "Maybe the most amazing finding is that these mice are protected from fatty liver disease, a serious problem in obese individuals with insulin resistance," says Montminy.

Our body's ability to store fat requires the activity of the enzyme acetyl-coenzyme A carboxylase, or ACC. When we fast, the body starts to burn fat while simultaneously shutting down ACC through a chemical modification called phosphorylation.

The Salk researchers found that a critical protein called TRB3 orchestrates a second chemical modification of ACC, known as ubiquitination, which gets rid of the enzyme altogether. "In this parallel pathway, TRB3 serves as a go-between for an enzyme that marks ACC for degradation," says Jose Heredia, a graduate student in Montminy's lab.

TRB3 levels in adipose tissue usually rise only during fasting, when ACC should be turned off. Heredia and co-first author Ling Qi, Ph.D., reasoned that keeping the TRB3 pathway artificially "on" during both fasting and feeding might melt away fat depots.

And that's exactly what happened. Mice genetically engineered to express permanently elevated levels of TRB3 protein in fat tissue were 10-20 percent skinnier than normal mice. "Even when we put them on a high-fat diet, these mice just didn't gain any weight," says Qi. "Their physical activity was the same, but they were constantly burning fat."

All this is good news for the fight against obesity and the disorders characterized by insulin-resistance known as "metabolic syndrome." Most people with insulin resistance will develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight--about 10 to 15 pounds for someone weighing 200 pounds. Defining how molecules regulating fat storage interact could lead to novel measures to curb obesity.

Further evidence linking TRB3 to disease comes from recent findings from a team of Italian scientists who report that mutations in the human TRB3 gene are associated with several insulin resistance-related health problems, such as high insulin levels, high cholesterol, and cardiovascular disease.

Achieving a desired physiological outcome by manipulating basic biochemistry was clearly satisfying for Montminy. "What really made this an interesting story is that the molecular mechanism and the biology intersected since we were able to explain how TRB3 made the mice lean," he reflects. "That doesn't happen very often."

Additional contributors to this study included assistant professor Robert Screaton, Ph.D., formerly at the Salk, now at Children's Hospital of Eastern Ontario; Judith Y. Altarejos, Ph.D., Naomi Goebel, Michael Nelson, Ph.D., professor Ronald M. Evans, Ph.D., all at the Salk Institute; Sherry Niessen, Ian X. MacLeod, and Professor John Yates, P h. D., from the Scripps Research Institute in La Jolla, California; Chong Wee Liew, Ph.D., and assistant professor Rohit Kulkarni, Ph.D., both at the Joslin Diabetes Center in Boston, Massachusetts; and James Bain, Ph.D., and professor Christopher Newgard, Ph.D., both at the Sarah W. Stedman Nutrition and Metabolism Center in Durham, North Carolina.


'"/>

Source:Salk Institute


Related biology news :

1. White blood cell waste disposal system plays critical regulatory role
2. Researchers rein in regulatory RNAs
3. OneWorld Health drug receives Orphan designation from U.S. and European regulatory agencies
4. Researchers use RNAi libraries to identify regulators of apoptosis and chemoresistance
5. New technique helps identify multiple DNA regulatory sites
6. An essential regulator of body weight revealed
7. Master regulatory gene found that guides fate of blood-producing stem cells
8. Smoking damages key regulatory enzyme in the lung
9. Key brain regulatory gene shows evolution in humans
10. New methods offer insight into regulatory DNA
11. Research reveals control of potent immune regulator
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:5/20/2016)... MINNEAPOLIS , May 20, 2016  VoiceIt ... technology partnership with VoicePass. By working ... user experience.  Because VoiceIt and VoicePass take slightly ... two engines increases both security and usability. ... expressed excitement about this new partnership. ...
(Date:4/28/2016)... India , April 28, 2016 ... Infosys (NYSE: INFY ), and Samsung SDS, a ... that will provide end customers with a more secure, ... services.      (Logo: http://photos.prnewswire.com/prnh/20130122/589162 ) , ... services, but it also plays a fundamental part in enabling ...
(Date:4/15/2016)... , April 15, 2016  A new ... make more accurate underwriting decisions in a fraction ... timely, competitively priced and high-value life insurance policies ... screenings. With Force Diagnostics, rapid testing ... lifestyle data readings (blood pressure, weight, pulse, BMI, ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... 24, 2016 Epic Sciences unveiled a ... susceptible to PARP inhibitors by targeting homologous recombination ... The new test has already been incorporated into ... cancer types. Over 230 clinical trials ... pathways, including PARP, ATM, ATR, DNA-PK and WEE-1. ...
(Date:6/23/2016)... , June 23, 2016   Boston Biomedical ... novel compounds designed to target cancer stemness pathways, ... been granted Orphan Drug Designation from the U.S. ... of gastric cancer, including gastroesophageal junction (GEJ) cancer. ... designed to inhibit cancer stemness pathways by targeting ...
(Date:6/23/2016)... Prostate Cancer Foundation (PCF) is pleased to announce 24 new Young Investigator ... Members of the Class of 2016 were selected from a pool of 128 ... About the Class of 2016 PCF Young Investigators ... ... ...
(Date:6/23/2016)... ... June 23, 2016 , ... In a new case report published today in ... patient who developed lymphedema after being treated for breast cancer benefitted from an injection ... for dealing with this debilitating, frequent side effect of cancer treatment. , ...
Breaking Biology Technology: