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Subtract A Gene And Feasting Mice Add No Fat

Date:
August 13, 2002
Source:
University Of Wisconsin-Madison
Summary:
By subtracting a single gene from the genome of a mouse, scientists have created an animal that can eat a rich, high-fat diet without adding weight or risking the complications of diabetes, according to a new study published this week.

MADISON - By subtracting a single gene from the genome of a mouse, scientists have created an animal that can eat a rich, high-fat diet without adding weight or risking the complications of diabetes, according to a new study published this week.

Writing in the online editions of the Proceedings of the National Academy of Sciences (PNAS), James M. Ntambi, a professor of biochemistry and of nutritional sciences at the University of Wisconsin-Madison and colleagues report that mice lacking a gene known as SCD-1 can eat a rich high-fat diet and avoid the consequences of fat deposition and excess sugar in the blood, the hallmark of type II diabetes.

The new finding, says Ntambi, provides insight into the central genetic mechanisms that underpin diet and metabolism, and suggests it may one day be possible to devise drugs to effectively protect against obesity and diabetes. The gene SCD-1 produces an enzyme known as SCD that is required for the body to make the major fatty acids that reside in fat tissue.

Ntambi, who collaborated in the study with Alan Attie a professor of biochemistry at UW-Madison and Jeffrey M. Friedman, a Howard Hughes Medical Institute investigator at Rockefeller University, says the mice lacking the SCD-1 gene defied every attempt to make them fat.

"The idea was to make them fat," Ntambi says, "but the mice lacking the SCD-1 gene never got up there despite a diet that contained nearly 15 percent fat. What we found is that when you feed these animals a high-fat diet for several weeks, they fail to accumulate fat over time."

The effect, according to the PNAS report, seems to be systemic. In the mice lacking the SCD-1 gene, fat does not accumulate in the liver or other tissues where, under normal circumstances, it would gather and contribute to health problems typically associated with diet and obesity, says Ntambi.

Instead, the excess fat seems to be metabolized: "We have biochemical evidence that the mice burn the excess fat," says Ntambi. "The protection from obesity involves increased energy expenditure and increased oxygen consumption."

Attie says that while the surface effects of removing the SCD-1 gene are not entirely unique, it is notable that the model provides a glimpse of the metabolic mechanisms that underpin those effects: "The fact that you're increasing metabolic rate as a result (of knocking out the gene and its enzyme products) is really interesting."

He notes that while the mice are more insulin sensitive, further tests will be needed to see if they are indeed protected from diabetes. But the absence of the SCD-1 gene does keep glucose levels in the blood low. Diabetes is characterized by a deficiency of insulin and high levels of sugar in the blood.

"These animals are more insulin sensitive and don't become diabetic," Ntambi says. "After eating, glucose levels rise, but within a very short time the glucose goes down and stays down."

Control animals with the SCD-1 gene, fed the same rich diet, have higher blood glucose levels for longer periods of time.

"All of this goes hand in hand," says Ntambi. "Most people who are diabetic have the condition due to the amount of fat. That's what causes insulin resistance and keeps glucose levels in the bloodstream high."

Drugs to prevent obesity would be of significant importance in terms of public health as the U.S. Centers for Disease Control and Prevention estimates that 20 percent of Americans suffer from obesity. Diabetes, as well, is a significant health problem in the U.S. and elsewhere with an estimated 17 million Americans suffering from the disease.

The mouse SCD-1 gene was found and cloned by Ntambi and colleagues in 1988 when he was a post-doctoral fellow with Daniel M. Lane at the Johns Hopkins University Medical School in Baltimore. He developed the knockout mouse model in 2000 while on the Wisconsin faculty. The human equivalent of SCD-1 was recently found and Ntambi's group is studying that gene's function in tissue culture.

In mice, the elimination of the SCD-1 gene does have side effects, Ntambi and co-author Makoto Miyazaki a biochemist at UW-Madison acknowledged, notably skin and eye problems as the animals age. However, in separate studies Ntambi and Miyazaki have shown that mutant mice with half the level of the enzyme appear normal. In these mice, the side effects observed in mice lacking the SCD-1 gene are absent. This suggests, says Ntambi, that it may be possible to develop drugs to suppress the fatty acids produced by SCD-1 and confer protection against obesity and perhaps diabetes while minimizing or eliminating side effects.

In addition to Ntambi, Attie, Friedman and Miyazaki, co-authors of the PNAS paper include Jonathan P. Stoehr, Hong Lan, Christina M. Kendziorski, Brian S. Yandell and Yang Song, all of UW-Madison. Paul Cohen is a co-author from the Joint Tri-institutional M.D.-Ph.D. Program of Rockefeller University, Weill Medical College of Cornell University and Sloan-Kettering Institute.


Story Source:

The above story is based on materials provided by University Of Wisconsin-Madison. Note: Materials may be edited for content and length.


Cite This Page:

University Of Wisconsin-Madison. "Subtract A Gene And Feasting Mice Add No Fat." ScienceDaily. ScienceDaily, 13 August 2002. <www.sciencedaily.com/releases/2002/08/020813072402.htm>.
University Of Wisconsin-Madison. (2002, August 13). Subtract A Gene And Feasting Mice Add No Fat. ScienceDaily. Retrieved September 30, 2014 from www.sciencedaily.com/releases/2002/08/020813072402.htm
University Of Wisconsin-Madison. "Subtract A Gene And Feasting Mice Add No Fat." ScienceDaily. www.sciencedaily.com/releases/2002/08/020813072402.htm (accessed September 30, 2014).

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