Discovery in Nature may hold key to alleviating metabolic disease

Familial partial lipodystrophy type 2 (FPLD2) is a rare disorder that causes diabetes, loss of fat in the extremities, and excessive muscle development, but the defective protein (lamin a) is present in all cells

Scientists at the University of Edinburgh found that mice lacking the protein Tmem120a, which is mainly found in fat cells, developed symptoms similar to FPLD2

Tmem120a belongs to a group of proteins called NETs that help ensure that genetic material within the cell's command center -- the nucleus -- is organized and read correctly

They found that Tmem120a plays a key role in normal adipose tissue development and healthy metabolism by boosting the expression of adipose genes and turning off muscle genes in adipose tissue

These effects appear to be due to Tmem120a's ability to release parts of the genome that control fat metabolism from the nuclear edge while simultaneously recruiting muscle genes to the nucleus

When genes are located at the edge of the nucleus, they tend to be turned off, and the scientists found that mislocalization of the gene in mice lacking Tmem120a also occurred in human patients with FPLD2

The study's authors propose that because Tmem120a is predominantly found in adipose tissue, it mediates the adipose-specific defect caused by the defective lamin A previously associated with FPLD2

Studies of genetic defects that cause metabolic diseases have shown that these defects are associated with many genes; thus, Tmem120a may be analogous to this by affecting the localization of many genes

The finding could have broader implications for other metabolic diseases, such as diabetes, insulin resistance, glucose intolerance, obesity, as well as muscle disorders and fitness

These symptoms, which were only seen in mice fed a high-calorie diet, were consistent with symptoms of FPLD2, which typically appears later in life and requires careful diet control

This mechanism could explain why some diseases, such as diabetes, are only detected when the body is under stress—such as feeding a high-calorie diet to mice lacking the Tmem120a gene

Defects in the function of other NET proteins are associated with many human diseases, such as muscular dystrophy, cardiomyopathy, blood and bone disorders, cancer and progeria syndrome

Other complex diseases may have similar mechanisms, where NETs affect gene localization, causing small changes in the expression of multiple genes, so that pathways are still functioning, but with diminished function, and thus only produce symptoms in some cases

Dr Rafal Czapiewski, lead author and postdoctoral researcher at the Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, said:

"For me, the most interesting part is the discovery of the new mechanism of muscle growth observed in lipodystrophy, which opens up new potential avenues for increasing muscle mass, such as the muscle mass that astronauts lose during space travel , muscular dystrophy or muscle loss from injury

The research, published in Nature Communications, was funded by Wellcome, the Medical Research Council and Muscular Dystrophy UK

Journal Reference :

1. Czapiewski, R.