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Cellular Stress Appears to Link Obesity, Diabetes
The link between obesity and diabetes is so clear that a new word has been coined to describe it: diabesity. But researchers cannot say how, exactly, eating too many calories causes the insulin resistance that often leads to diabetes.
Diagnosing the source of insulin resistance in the ER. The overloaded endoplasmic reticula (ERs) inside fat and liver cells of overweight mice cope with stress by sending out the molecule XBP-1, a transcriptional regulator. This molecule temporarily reduces the number of proteins entering the ER for processing and increases the number of ER helper molecules that fold client proteins and degrade misfolded proteins. If this is not enough for the ER to catch up with its metabolic duties, the stress-induced IRE1 activates JNK, which impairs insulin signaling via IRS-1. (Image by Jeff Cleary)
Scientists have come to view fat as surprisingly active, sending out inflammatory molecules, fatty acids, and hormones that conspire with other tissues, especially the liver, to sabotage insulin's job of escorting glucose into cells. Still, the question remains, what is happening in the fat cells?
HSPH researchers may have found a pivotal mechanism inside fat and liver cells that connects obesity to insulin signaling. In mice and rats, these cells appear to respond to extra fat with a stress response that unleashes insulin saboteurs. It all begins in the endoplasmic reticulum (ER), a membranous network enclosing the nucleus. The ER's normal daily chores include making and folding proteins destined to join cellular membranes or to be secreted outside the cell.
| "These findings demonstrate that ER stress is a central player in metabolic deterioration in obesity by triggering peripheral insulin resistance." |
"It is a novel implication of a well-known biological process," said Christopher Newgard, director of the Stedman Nutrition and Metabolism Center at Duke University Medical Center. "The new insight will influence the entire field about where we look for the initiating factors." One of the questions now becomes how, exactly, does obesity distress the ER, wrote Newgard and his co-author in an accompanying Science commentary.
An Emergency Response
The study began when the HSPH researchers noticed that some of the things that stress the ER are aspects of obesity, such as chronic lipid overload and increased synthesis of secretory proteins. The ER copes by activating a mechanism called the unfolded protein response. This reaction temporarily slows down the number of client proteins coming into the ER and increases the number of helper molecules that fold client proteins and degrade misfolded ones. Sustained ER stress paired with an insufficient coping response can result in apoptosis.Working with animal models and people with rare mutations, other researchers have implicated ER stress in the death of pancreatic beta cells. Hotamisligil speculates that ER stress is involved in the islet cell collapse at the end stage of type 2 diabetes. As the body becomes more insulin resistant, the beta cells exhaust themselves trying to churn out more and more insulin until many collapse under the strain. With insufficient insulin, dangerously high levels of glucose build up in the blood.
The disease process may begin, Hotamisligil and his colleagues now report, in fat and liver cells with stressed ERs. The researchers found elevated markers of ER stress in the fat and liver tissue but not in the muscle of mice made obese by genetics or a high-fat diet, compared with their lean counterparts.
Umut Ozcan (left) and Qiong Cao (right), postdoctoral fellows in the lab of Gökhan Hotamisligil (center), have found that obesity may tip the scales toward disease in the endoplasmic reticulum, whose stress may be the source of insulin resistance and chronic low-grade inflammation that often leads to diabetes.
In the next experiments, chemically induced ER stress in rat liver cells interfered with insulin receptor signaling and activated the JNK enzyme. JNK is a crucial component of the biochemical pathway responsible for obesity-induced insulin resistance in animals, Hotamisligil and his colleagues reported two years ago (see Focus, November 22, 2002).
Clinching the case, the researchers used a knockout-mouse cell culture to show that a specific ER stress sensor molecule, IRE1, works through JNK to block the insulin signaling pathway. In mice, fatty acids in the blood and cytokines released by bloated fat cells also activate JNK, which turns up production of more cytokines in a vicious cycle. The latest paper suggests that the same JNK inflammatory signaling loop traces its origins to obesity-related ER stress.
Testing the Tie
Once they established the link between ER stress and insulin resistance in cells, the researchers tweaked the coping response to see how it would affect relative susceptibility to insulin resistance. Mouse cells armed with extra ammunition for coping with ER stress were much less prone to insulin resistance. The opposite was also true. The researchers found marked insulin resistance in cells missing the function of a coping molecule, XBP-1.Using partial XBP-1 knockout mice from the neighboring lab of HSPH immunologist and co-author Laurie Glimcher, the scientists showed that XBP-1-deficiency combined with a high fat diet increased ER stress, impaired insulin receptor signaling, and led to insulin resistance and diabetes in a mouse strain that is typically resistant to type 2 diabetes.
"The really clever and most exciting part of the paper is that it provides a plausible mechanism by which the extra ER stress of obesity can get transduced into increased insulin resistance," said cell biologist and endocrinologist David Ron of New York University Medical Center, who provided the ER stress sensor IRE1-knockout cells.
The provocative findings may leave scientists puzzling over the larger conceptual framework. But for Hotamisligil, it provides a compelling possible source of the chronic low-grade inflammation that he and others have found in obesity and diabetes.
--Carol Cruzan Morton