Fat-free may be all the rage in packaged foods, but mice genetically engineered to lack fat cells get diabetes with symptoms even more severe than those of obese mice. The findings, reported in two papers in last week's issue of Genes and Development, may yield clues to the enigma of adult-onset diabetes, also called type 2 diabetes or diabetes mellitus.
Obesity can lead to type 2 diabetes, which afflicts at least 18 million Americans. But people born with a rare disorder that eliminates nearly all fat cells also get diabetic symptoms. To explore this link, Marc Reitman and Charles Vinson's group at the National Institutes of Health in Bethesda, Maryland, inactivated the genes for two families of transcription factors that normally help fat cells grow and develop. (Transcription factors are proteins that turn genes on or off.) A similar approach was taken by Nobel laureates Michael Brown and Joseph Goldstein and their colleagues at the University of Texas Southwestern Medical Center in Dallas.
In both experiments, the mice were born with little or no white fat. Many of the animals died before reaching adulthood, but those that survived developed symptoms of adult-onset diabetes in humans: high blood sugar, high insulin levels, and a ferocious thirst and appetite. And like human diabetics, the animals also had high levels of triglycerides and other fat building blocks in their circulation, and their livers became engorged with triglycerides. "These animals are really sick," Reitman says. "But they clearly don't get diabetes in the same way as normal type 2 diabetics," where excess body fat plays a role.
Reitman and Vinson may be able to explain why both obesity and a complete lack of fat can lead to diabetic symptoms. They propose that excess fatty acids and triglycerides in the circulation and liver might somehow trigger the disease. The compounds might end up in the circulation either because they spill from stuffed fat cells, in the case of obesity, or because there are no fat cells to store them, as in the fatless mice.