Posted on Nov 21, 2019, 3 p.m.
Scripps Research has revealed new and unexpected findings about a protein that is highly expressed in fat tissue in a study that is published in the journal Nature which may lead to new understandings about obesity and metabolism as well as in developing new approaches for addressing obesity and possibly other diseases.
PGRMC2 is a signalling protein which is not extensively studied, this is short for progesterone receptor membrane component 2 which has been detected in the uterus, liver, and several other areas of the body, but it is most abundant in fat tissue-particularly in brown fat.
PGRMC2 binds and releases heme, an essential molecule, and it has gained recent attention for providing flavor to some plant based foods. PGRMC2 is an iron containing molecule that travels within cells to enable important life processes including cell proliferation, cellular respiration, cell death, and circadian rhythms.
Biochemical techniques and advanced assays in cells were used to find that PGRMC2 is a chaperone of heme encapsulating the molecule and transporting it from the mitochondria where heme is created to the nucleus where it helps to carry out function; without the chaperone as protection heme would react with and destroy everything in its path.
"Heme's significance to many cellular processes has been known for a long time," says Saez, associate professor in the Department of Molecular Medicine. "But we also knew that heme is toxic to the cellular materials around it and would need some sort of shuttling pathway. Until now, there were many hypotheses, but the proteins that traffic heme had not been identified."
PGRMC2 was established as the first intracellular heme chaperone to be described in mammals via mice studies. When taking the study further to investigate what happens without the chaperone the researchers discovered without PGRMC2 present in fat tissues mice on high fat diets became intolerant to glucose and insensitive to insulin, which are hallmark symptoms of diabetes and other metabolic diseases; and obese-diabeteic mice that were treated with a drug to activate PGRMC2 functions were observed to display substantial improvements of symptoms associated with diabetes.
"We saw the mice get better, becoming more glucose tolerant and less resistant to insulin," Saez says. "Our findings suggest that modulating PGRMC2 activity in fat tissue may be a useful pharmacological approach for reverting some of the serious health effects of obesity."
"The first surprise finding was that the brown fat looked white," the study's lead author, Andrea Galmozzi, Ph.D.
Brown fat typically high in heme content is considered to be the good fat, one role is to generate heat to maintain body temperature. Mice that were not able to produce PGRMC2 in fat tissues when placed in cold environments were found to have their body temperatures drop rapidly.
"Even though their brain was sending the right signals to turn on the heat, the mice were unable to defend their body temperature," Galmozzi says. "Without heme, you get mitochondrial dysfunction and the cell has no means to burn energy to generate heat."
Activating PGRMC2 in other organs such as the liver where a large amount of heme is made may help to mitigate the effects of other metabolic disorders such as non-alcoholic steatohepatitis, which is a major cause of liver transplantation.
"We're curious to know whether this protein performs the same role in other tissues where we see defects in heme that result in disease," Saez says.
"PGRMC2 is an intracellular haem chaperone critical for adipocyte function," write the authors.
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