A new study from Joslin Diabetes Center may shed light on why some people can eat excessive amounts of food and not gain weight or develop type 2 diabetes, while others are more likely to develop obesity and this most common form of diabetes on any diet. The study, which used two strains of mice with differing tendencies to gain weight and develop diabetes on a high-fat diet, identified genetic and cellular mechanisms that may prevent certain mice on a calorie-dense diet from gaining weight and developing metabolic syndrome.
"Although this study was done with mice, it points out new mechanisms that may underlie the ability of genetically different mice -- and perhaps genetically different people -- to not gain much weight on high caloric diets," said lead investigator C. Ronald Kahn, M.D., an internationally recognized researcher who is Head of Joslin's Section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.
The study, published in the online edition of the Proceedings of the National Academy of Sciences on Feb. 5-9, builds upon years of research at Joslin and elsewhere on energy metabolism and the genetics of fat cells.
It has long been known that people significantly differ in their tendency to gain weight and develop metabolic syndrome, a group of conditions including hypertension, abdominal obesity, high triglycerides and glucose intolerance that can lead to type 2 diabetes. More than 60 million Americans either are obese or have metabolic syndrome, putting them at risk for type 2 diabetes and its frequent complications, including cardiovascular disease and other serious conditions. Currently 21 million Americans have diabetes and approximately one-third of them do not even know they have the disease. Formerly known as adult-onset diabetes, type 2 diabetes is occurring more frequently in young adults and even children.
Previous studies at Joslin and elsewhere have uncovered the differing functions of the two types of body fat--white and brown. White fat, the more familiar form of fat that accumulates in the abdomen, thighs, buttocks and under the skin, stores energy for future needs, whereas brown fat or brown adipose tissue (BAT) burns energy and generates heat.
White fat, which is packed with large lipid droplets, is deposited under the skin, around internal organs and as visceral fat -- one of the most harmful forms of abdominal fat. Brown fat, on the other hand, contains small lipid droplets tucked behind tiny energy factories called mitochondria. These cells are most prevalent in the necks of infants and between the shoulder blades in mice to help their bodies generate heat, but tend to mostly disappear by adulthood. A 2005 Joslin study by Dr. Kahn and his colleagues discovered genes that control the creation of the precursor cells that give rise to brown fat cells. This latest study shows that brown fat may not disappear in all adult animals and that little collections of brown fat may account for why some mice are protected from obesity and diabetes and others are not.
This study began by exploring differences in basal energy expenditure (the amount of energy required to maintain the body's normal metabolic activity, such as respiration and maintenance of body temperature) and its role in the development of obesity and metabolic syndrome in two different genetic strains of mice: the B6 mouse and the 129 mouse. The B6 mouse is one of the most commonly used strains in metabolic research and an established model for diet-induced obesity.
When placed on a high-fat diet, the B6 mouse develops severe obesity, high blood glucose and insulin resistance with extremely high insulin levels. By contrast, the 129 mouse gains on average 30 to 50 percent less weight on either a high-or low-fat diet than the B6 mouse and has been considered resistant to dietary induced obesity and glucose intolerance. In the new study, Dr. Kahn and his colleagues showed that this difference is due to the higher basal energy expenditure in the 129 mouse. When searching for the source of the energy expenditure, the researchers found unexpected clusters of brown fat cells stuck between bundles of muscle fibers in the leg of the mouse. In this case, the 129 mouse had over 100 times more brown fat in muscle than the B6 mouse.
"This site of brown fat was previously unrecognized and is certainly one of the reasons for the differences in energy expenditure between strains of mice. Now we need to see if the same is true for humans and if this could account for why some people gain weight easily and others seem to be protected against weight gain and metabolic syndrome that can lead to type 2 diabetes," Dr. Kahn said. "Finding drugs that stimulate the amount or activity of this brown fat could also lead to a new therapy for obesity and prevention of diabetes."
Other researchers participating in the study include: lead author Katrine Almind, Ph.D., formerly of Joslin and now of Novo Nordisk, Denmark; Monia Manieri and Saverio Cinti, M.D., Institute of Normal Human Morphology-Anatomy, University of Ancona, Italy; and William I. Sivitz, Ph.D., Department of Internal Medicine, University of Iowa, Iowa City.
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