Research published today in the journal Nature has identified a new molecule which could be a key player in obesity and metabolic disease. This molecule is a protein known as PGRMC2 which is short for “progesterone receptor membrane component 2”. It had been detected in the uterus, liver and several areas of the body. Interestingly, PGRMC2 is most abundant in fat tissue, particularly in brown fat, which turns food into heat to maintain body temperature which led the scientists at Scripps Research Institute to investigate its role in fat tissue and what it was doing there?

PGRMC2 is a haem chaperone

PGRMC2 binds to and releases an essential molecule called haem. It is well known that haem is a central co-factor for many proteins and is critical signalling molecule in several physiological processes. However, free haem can be highly cytotoxic so it needs a protective chaperone for shuttling around in the cells. That is where PGRMC2 comes in. The researchers for the first time discovered that PGRMC2 is a “chaperone” of haem, encapsulating the molecule and transporting it from the cell’s mitochondria, where haem is created, to the nucleus, where it helps carry out important functions. This a critical because without a protective chaperone, haem would react with and potentially destroy everything in its path.

PGRMC2 as a target for obesity?

The novelty of this study is that the scientists have identified PGRMC2 as the first intracellular haem chaperone to be described in mammals. They also investigated what happens in the body if this protein doesn’t exist to transport haem. Lo and behold without PGRMC2 present in their fat tissues, mice that were fed a high-fat diet became glucose intolerant and insensitive to insulin which are the hallmark signs of diabetes and other metabolic diseases.

Brown fat, which is normally the highest in haem content, is often considered the “good fat”. One of the key roles of brown fat is to generate heat by thermogenesis to maintain body temperature. In mice without PGRMC2 in their fat tissues, temperatures dropped quickly when placed in a cold environment. Although the brain was sending the right signals in these mice to generate heat the body was unable to do so, indicating the relevance of PGRMC2 in metabolism.

On the other hand, the scientists also observed that obese-diabetic mice that were treated with a small molecule to activate PGRMC2 function, showed a substantial improvement of symptoms associated with diabetes. They observed mice becoming more glucose tolerant and less resistant to insulin.

This research suggests that modulating PGRMC2 activity in fat tissue may be a useful pharmacological approach for reverting some of the serious health effects of obesity and metabolic syndrome.

Take Home: Unexpected discovery of a protein that’s highly expressed in fat tissue, might have opened doors to critical new understandings about obesity and metabolism. The discovery could lead to new approaches for addressing obesity and potentially many other diseases.