Buildup of "Toxic Fat" Metabolite Could be to Blame
For years, scientists have known that someone who is thin could still end up with 糖尿病. Yet an obese person may be surprisingly healthy.
Now, new research led by scientists at the 大发娱乐, and carried out with an international team of scientsts, points to an answer to that riddle: accumulation of a toxic class of fat metabolites, 被称为神经酰胺, may make people more prone to type 2 糖尿病.
Among patients in Singapore receiving gastric bypass surgery, ceramide levels predicted who had 糖尿病 better than obesity did. Even though all of the patients were obese, those who did not have type 2 糖尿病 had less ceramide in their adipose tissue than those who were diagnosed with the condition.
"Ceramides impact the way the body handles nutrients," says the study's senior author 斯科特·萨默斯博士.D., also chairman of the University of Utah Department of Nutrition and Integrative Physiology. "They impair the way the body responds to insulin, and also how it burns calories."
这项研究发表于11月11日. 3 in 细胞代谢 在线, the researchers also show that a buildup of ceramides prevents the normal function of fat (adipose) tissue in mice.
When people overeat, they produce an excess of fatty acids. Those can be stored in the body as triglycerides or burned for energy. However in some people, fatty acids are turned into ceramides.
"It's like a tipping point," Summers said.
在这一点上, 当神经酰胺积累时, the adipose tissue stops working appropriately, and fat spills out into the vasculature or heart and does damage to other peripheral tissues. Until now, scientists didn't know how ceramides were damaging the body.
The three-year project found that adding excess ceramides to human fat cells or mice caused them to become unresponsive to insulin and develop impairments in their ability to burn calories. The mice were also more suceptible to 糖尿病, as well as fatty liver disease.
相反, they also found that mice with fewer ceramides in their adipose tissue were less susceptible to insulin resistance, 这是糖尿病的第一个征兆. 利用基因工程, researchers had deleted the gene that converts saturated fats into ceramides.
The findings indicate that high ceramides levels may increase 糖尿病 risk and low levels could protect against the disease.
The scientists think this could mean that some people are more likely to convert calories into ceramides than others. "That suggests some skinny people will get 糖尿病 or fatty liver disease if something such as genetics triggers ceramide accumulation,Bhagirath Chaurasia说, Ph.D., assistant professor at the University of Utah and the lead author of the study.
作为一项新研究的结果, the scientists are now searching for genetic mutations that lead to people's predisposition to accumulating ceramides, developing obesity and type 2 糖尿病.
Summers notes that some Asian countries have a higher 糖尿病 rate than the United States even though the obesity rate is relatively low. "Some people are just not made to deal with dietary fat," says Summers. “这不仅仅是你吃了多少, because some people can eat a lot and they just store all the fat effectively and remain healthy."
Adipose tissue exists as three types. White adipose tissue is considered the "bad" kind, because it predominately stores fat. Brown adipose tissue burns fat to generate heat. Beige adipose tissue is a variety of white fat that can change to brown when the body needs to produce heat or create energy.
根据他们的研究, the scientists propose that as ceramides build up, the tissue loses the characteristics of brown fat, 有效地变得更白. This sets off a sequence of events that can lead to disease.
Summers previously published research in 2007 proving that the inhibition of ceramide synthesis in rodents prevented the development of fatty liver disease and 糖尿病. He is now working to develop drugs to target that issue.
“通过阻断神经酰胺的产生, we might be able to prevent the development of type 2 糖尿病 or other metabolic conditions, 至少对某些人来说是这样,查拉西亚说. Knowing how problematic ceramide accumulation is inside adipose tissue will help researchers focus on that specific problem.
引用: Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism; 细胞代谢 在线11月. 3, 2016
资助: 国家医学研究委员会, Singapore; Victorian State Government OIS scheme, Australia; University of Utah Diabetes and Metabolism Center; 大发娱乐.
合作机构: 大发娱乐; Baker IDI Heart and Diabetes Institute, Australia; Singapore Bioimaging Consortium; Duke-NUS Graduate Medical School, Singapore; National University of Singapore; Tata Institute of Fundamental 研究, India; University of Brunei Darussalam; Yong Loo Lin School of Medicine; University of Michigan; RIKEN Brain Science Institute, 日本.
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