'World's Fattest Mice' Immune To Diabetes

DALLAS, Aug. 23 -- An over-abundance of a key hormone protects the "world's fattest mice" from the metabolic effects of their excess fat, researchers said.

Animals genetically engineered to lack the hormone leptin start getting morbidly obese at a young age, and they develop all the symptoms of the metabolic syndrome, culminating in diabetes, according to Philipp Scherer, Ph.D., of the University of Texas Southwestern Medical Center here.

But if they also have an over-abundance of the hormone adiponectin, they have normal insulin sensitivity and lipid metabolism, even though they still gain weight -- and even outdo their leptin-lacking cousins in that regard, Dr. Scherer and colleagues reported online in the Journal of Clinical Investigation.

The extra adiponectin, the researchers said, causes fat to be stored subcutaneously, rather than in liver, heart, and muscle tissue. Because of the changed fat distribution, the animals remain physiologically skinny, even though they are actually fatter than the obese mice that lack leptin.

"The continual firing of adiponectin generated a 'starvation signal' from fat that says it is ready to store more energy," Dr. Scherer said. "The mice became what may be the world's fattest mice, but they have normal fasting glucose levels and glucose tolerance."

The findings may help explain why some people are obese but have normal lipid metabolism, the researchers said.

Adiponectin is secreted by fat cells, but circulating levels decline as a person accumulates more fat, said Dr. Scherer, who discovered the hormone in 1994.

That may be because people who have low levels of the hormone have fat cells that don't send the signal that they're ready to accept fat, Dr. Scherer said. Instead, the excess fat is stored in liver, heart and muscle tissues where it can cause inflammation and lead to disease.

"The inability to appropriately expand fat mass in times of overeating may be an underlying cause of insulin resistance, diabetes, and cardiovascular disease," he said.

The researchers began with mice that do not have the gene for leptin, an appetite-suppressing hormone. Then they added a transgene that triggered an increase in circulating concentrations of adiponectin by a factor of two or three.

The over-expression of adiponectin was "relatively modest" and led to levels comparable to what's seen when the leptin-deficient mice are treated with thiazolidinediones, such as rosiglitazone (Avandia), the researchers said.

But the effect was associated with "dramatic improvements" in the metabolic parameters of the mice, compared with baseline values. Specifically:

• Fasting glucose, in milligrams per deciliter, was 313.8 in leptin-deficient mice, 100.6 in the mice with adiponectin, and 92.4 in wild-type mice. The differences between leptin-deficient mice and both the adiponectin and wild-type mice were statistically significant, at P<0.01.
• Insulin, in nanograms per milliliter, was 7.85 in leptin-deficient mice, 2.33 in the mice with adiponectin, and 1.83 in wild-type mice. The differences between leptin-deficient mice and both the adiponectin and wild-type mice were statistically significant, at P<0.05.
• Triglycerides, in milligrams per deciliter, were 300.37 in leptin-deficient mice, 93.5 in the mice with adiponectin, and 147.2 in wild-type mice. The differences between leptin-deficient mice and both the adiponectin and wild-type mice were statistically significant, at P<0.01 and P<0.05, respectively.

At the same time, the adiponectin mice -- while still overeating compared to wild-type animals -- ate less than their leptin-deficient cousins, but gained more weight, almost all of it stored as subcutaneous fat, the researchers reported.

They also had reduced energy expenditure, compared to wild-type and leptin-deficient animals.

The observations suggest that "adiponectin is a central player antagonizing the metabolic axis of evil involving obesity, hepatic lipid deposition, and local inflammation, leading ultimately to systemic insulin resistance," the researchers concluded.