A gene earlier found to underlie lipodystrophy--a disorder characterized by a severe deficiency of fat--can also spur obesity, according to new research published in the premier issue of Cell Metabolism. The gene, which alters fat storage and metabolism, is the first found to adjust body fat content up or down, depending on its expression level in fat and muscle, according to the researchers.
The gene might therefore represent a novel peripheral target for the treatment of obesity and lipodystrophy, they said. The finding further suggests that differences in lipin might contribute to the natural range of fat levels found among people.
The group, led by Karen Reue of the David Geffen School of Medicine and the University of California, Los Angeles found that excess levels of lipin, in either the fat tissue or skeletal muscle of mice, promote obesity. The protein operates through diverse mechanisms to affect body weight, they show. While lipin in fat influences the storage capacity of fat cells, in muscle the protein determines whole-body energy expenditure and the rate at which the body burns fat.
"Lipodystrophy and obesity represent extreme and opposite ends of the adiposity spectrum and have typically been attributed to alterations in the expression or function of distinct sets of genes," Reue said. "Lipin represents the first gene with the capacity to go both ways on the scale, modulating body fat content from one extreme to the other."
Lipin is normally found in metabolically active tissues such as fat and skeletal muscle. Mice lacking lipin exhibit lipodystrophy, with symptoms including a severe deficiency of adipose tissue and insulin resistance. A deficiency of lipin prevents both diet-induced and genetic obesity and is required for the normal development of mature fat cells, Reue's team reported last year.
To further elucidate lipin's role, the researchers generated transgenic mice with enhanced expression of the gene in either mature fat cells or skeletal muscle. When fed a high-fat diet for a period of six weeks, mice with elevated lipin in fat or muscle showed accelerated weight gain, with a 20 percent greater increase in body weight than normal mice. Mice with excess fat lipin also exhibited an increase in the expression of other genes involved in lipid synthesis and storage, they found.
Mice with extra lipin in skeletal muscle consumed 10 to 15 percent less oxygen than normal and exhibited a decline in body temperature, indicating that the gene in muscle determines energy expenditure, the team reported. The researchers further found that mice with excess muscle lipin exhibit a shift in metabolism, characterized by the preferential use of glucose over fatty acids.
Based on the results, the human lipin gene might be a candidate gene for disorders associated not only with decreased but also with increased adipose tissue mass, the researchers said. Subtle variations in lipin expression levels may also contribute to the range of adiposity in human populations, they added.
Jack Phan and Karen Reue: "Lipin, a lipodystrophy and obesity gene"
The members of the research team include Jack Phan and Karen Reue of the David Geffen School of Medicine and Molecular Biology Institute, University of California, Los Angeles and VA Greater Los Angeles Healthcare System. This work was supported by National Institutes of Health grant and a UCLA Medical Scientist Training Program grant.
The context and implications of this work are discussed in a Preview by Marc L. Reitman.
Publishing in Cell Metabolism, Volume 1, Number 1, January 2005, pages 73-83. www.cellmetabolism.org