January 9, 2004

UCSD, Salk Researchers Define Role of Abnormal
Muscle, Fat & Liver in Common Metabolic Disorder

By Eileen Callahan

Metabolic Syndrome, a cluster of health symptoms including obesity, high blood pressure and insulin resistance, puts one in four Americans at increased risk for diabetes, heart disease and stroke. Although a common disorder affecting upwards of 60 million Americans, the syndrome is not completely understood by scientists.

Now, researchers at the University of California, San Diego (UCSD) School Medicine and the Salk Institute in La Jolla have identified specific tissue sites within the body where abnormal cells lead to Metabolic Syndrome. Their studies offer the potential for future treatment that can be targeted directly to abnormal tissue.

Published in the December 1, 2003 issue of the journal Nature Medicine and the December 23, 2003 issue of Proceedings of the National Academy of Sciences (PNAS), the research was led by Jerrold Olefsky, M.D., UCSD Professor of Medicine and Chief of the Division of Endocrinology and Metabolism, and Ronald M. Evans, Ph.D., March of Dimes Chair in Developmental and Cell Biology at the Salk Institute and an Investigator with the Howard Hughes Medical Institute.

Taken together, the two studies show that a specific deficiency in muscle tissue directly leads to insulin resistance, while an abnormality in a similar molecule found in fat affects the ability of adipose, or fat cells to function properly. The deficient fat cells lead to elevated fatty acids and triglycerides, as well as a fatty liver and insulin resistance in the liver.

Also known as Syndrome X and Insulin Resistance Syndrome, Metabolic Syndrome is characterized by a cluster of conditions, or “warning signs,” including:

• Excessive fat in and around the abdomen,
• High blood pressure,
• High triglycerides (blood lipids, or fats),
• Low HDL (the good cholesterol),
• Insulin resistance and glucose intolerance, where the body can’t property use insulin to transport blood sugar into muscle cells for needed energy.

An individual is considered to have Metabolic Syndrome if three of these conditions are present.

In experiments with mice, the Salk and UCSD research teams determined the specific contributions of abnormal muscle, fat and liver tissue in the development of Metabolic Syndrome. Their studies focused on a protein called peroxisome proliferators-activated receptor (PPAR) gamma, which is known to play a role in glucose and lipid metabolism. Most PPARgamma is found in fat tissue, with only small amounts in muscle and liver.

The researchers also investigated the effects on tissue of an anti-diabetic medication called thiazolidinedione (TZD), which is known to target PPARgamma and increase insulin sensitivity in cells. Because PPARgamma is most prevalent in fat tissue, scientists had hypothesized that TZD was effective in treating diabetes through its actions in fat. This is in spite of the fact that muscle is the primary organ for insulin-stimulated glucose disposal, a bodily mechanism that goes wrong in diabetes.

The following are the findings presented in each of the recent papers:

Nature Medicine

In the study published in Nature Medicine, the researchers determined that abnormal PPARgamma in muscle caused profound insulin resistance in muscle tissue and indirectly affected insulin action in fat and liver tissue.

While PPARgamma was defective in the muscle tissue of mice, it remained normal in fat and liver tissue. Compared to normal mice, the PPARgamma muscle deficient mice were 80 percent less effective than normal mice in utilizing insulin to move glucose into muscle cells. This is the first direct evidence that PPARgamma directly coordinates glucoregulatory responses in skeletal muscle.

The team further determined that while TZD treatment did not increase insulin sensitivity in PPARgamma muscle deficient mice, it did ameliorate liver and fat tissue insulin resistance, indicating that TZD remained fully effective through the normal PPARgamma in these tissues.

TZD treatment also lowered detrimental conditions linked to Metabolic Syndrome, specifically, high levels of free fatty acids, glucose and triglycerides. According to the researchers, this indicates that TZD treatment targeted only to fat tissue and liver may be sufficient to normalize most of the major manifestations of Metabolic Syndrome.

Proceedings of the National Academy of Sciences

In the paper published in PNAS, the investigators focused on the role of PPARgamma and TZD treatment in mice with normal PPARgamma in muscle, but defective PPARgamma in fat tissue.

These mice had normal insulin sensitivity in muscle and normal glucose tolerance. However, they expressed a marked decrease (more than 70 percent) in the number of fat cells and a resulting 30-50 percent increase in the volume of remaining fat cells. According to the researchers, this indicates an essential role for PPARgamma in the normal function of fat cells.

Because past studies with fatless animal models have shown the importance of fat tissue in maintaining muscle insulin sensitivity, the new findings suggest that it is the fat tissue itself, rather than the PPARgamma in fat, that plays an important part in maintaining systemic insulin sensitivity.

Additional defects found in the PPARgamma fat deficient mice included elevated levels of plasma free fatty acids and triglycerides, a fatty liver, insulin resistance in liver, and decreased levels of a protein called leptin that tells the brain how much fat is in the body.

In an additional experiment, the PPARgamma fat deficient mice were fed a high-fat diet, which increased their body weight by more than 30 percent. As a result, insulin levels were two-fold higher than normal mice or normal-weight mice with PPARgamma deficient fat, indicating that PPARgamma in fat tissue is important for insulin sensitivity when the animal has a high-fat diet.

While TZD treatment of the PPARgamma impaired mice failed to improve fat insulin sensitivity, it normalized liver insulin resistance. According to the researchers, this indicates that TZD’s sensitization effects are most likely occurring as a direct activation of PPARgamma within the liver.

The studies were funded by the National Institute for Diabetes, Digestive and Kidney Diseases; the National Heart, Lung and Blood Institute; the Hilblom Foundation; the Howard Hughes Medical Institute; and the Veterans Administration Research Service.

Co-first authors on the Nature Medicine and PNAS papers were Andrea L. Hevener and Weimin He, UCSD, and Yaacov Barak, Jackson Laboratory, Bar Harbor, Maine, and the Salk Institute. Additional authors contributing to the studies were Jamie Le, Gautam Bandyopadhyay, and Jason Wilkes, UCSD; Peter Olson, UCSD and the Salk Institute; and Debbie Liao, Michael Nelson and Estelita Ong, the Salk Institute.

Media Contact: Sue Pondrom (619) 543-6163