Proteins Link Obesity, Diabetes; May Underlie Systemic 'Metabolic Syndrome'

Mice lacking two related fatty acid binding proteins (FABPs), aP2 and mal1, exhibited striking changes in their lipid profiles and strong resistance to diet-induced obesity, insulin resistance, type 2 diabetes, and fatty liver disease, report Gökhan Hotamisligil and his colleagues at the Harvard School of Public Health. Earlier studies examining each of the proteins in isolation had missed their systemic effects because the two FABPs tend to compensate for one another, he explained.

Mice deficient for both proteins gained less weight than normal mice when fed a high-fat diet due to an increase in energy expenditure and resulting 25 percent reduction in total body fat, they found. Mice lacking the FABPs also exhibited significant shifts in the distribution of fatty acids in fat, muscle, and liver.

Mutant animals on the high-fat diet had significantly lower blood glucose and insulin levels than normal mice on the same diet. Rising blood glucose and insulin concentrations in overweight animals are an indicator of obesity-induced insulin resistance and type 2 diabetes. Examination of livers from the mutant mice also revealed a striking reduction in the infiltration of fat, in comparison to the livers of normal mice.

The cascade of cellular effects the researchers observed in fat cells, as well as cells of the muscle and liver, point to a sophisticated network of regulatory factors--including some yet to be identified--that mediate energy balance at the systemic level, Hotamisligil said.

The current findings--together with the team's earlier discovery of the proteins' role in atherosclerosis--suggest that the FABPs have a robust impact on multiple components of metabolic syndrome by integrating metabolic and inflammatory responses in mice. The researchers further propose that the proteins may serve as a powerful target for the treatment of obesity, diabetes, and cardiovascular disease.

"The incidence and impact of metabolic syndrome have risen to alarming proportions and there is great need for therapeutic and preventive measures against these major health threats," Hotamisligil said. "Fatty acid binding proteins appear to bridge metabolic and inflammatory responses underlying the syndrome, and might therefore offer a means to unlink these debilitating diseases."

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Kazuhisa Maeda, Haiming Cao, Keita Kono, Cem Z. Gorgun, Masato Furuhashi, Kadir T. Uysal, Qiong Cao, Genichi Atsumi, Harry Malone, Bala Krishnan, Yasuhiko Minokoshi, Barbara B. Kahn, Rex A. Parker, and Gökhan S. Hotamisligil: "Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes"

The researchers include Kazuhisa Maeda at Osaka University Hospital; Haiming Cao, Keita Kono, Cem Z. Gorgun, Masato Furuhashi, Kadir T. Uysal, Qiong Cao, and Gökhan S. Hotamisligil of Harvard School of Public Health; Genichi Atsumi of Teikyo University; Harry Malone, Bala Krishnan, and Rex A. Parker of Bristol-Myers Squibb Pharmaceutical Research Institute; and Yasuhiko Minokoshi and Barbara B. Kahn of Beth Israel Deaconess Medical Center and Harvard Medical School. This work was supported in part by grants from NIH and Pew and American Diabetes Foundations.

Publishing in Cell Metabolism, Volume 1, Number 2, February 2005, pages 107-119. www.cellmetabolism.org