Body-weight and fertility have long been known to be related to each other and now a master switch has been found in the brain of mice that controls both, reports Nature Medicine. The findings suggest that variations in the gene responsible for this master switch – known as TORC1 – could contribute a genetic component to obesity and infertility, and might be regulated by pharmaceuticals.
“This gene is crucial to the daisy chain of signals that run between body fat and the brain,” says the Salk Institute’s Marc Montminy, who led the study. “It likely plays a pivotal role in how much we, as humans, eat and whether we have offspring.”
The primary hormone that regulates appetite is leptin, which travels through the bloodstream to the hypothalamus in the brain (the appetite center), keeping the brain aware of the body’s nutritional status. The hormone also is known to play a role in reproduction – although, until this study, no one understood what is was. “Controlling appetite and reproduction together provides a big evolutionary advantage,” Montminy explained. “If there is no food, the brain believes the body should not reproduce because without body fat, a baby’s growth in the womb could be stunted, and without food to replenish the body’s energy reserves, there will be nothing to feed the offspring.”
In this new study, the researchers looked at the function of TORC1 by creating mice that lacked copies of the TORC1 gene – the first such “knock-out” mice to be developed. Mice born without TORC1 looked fine at birth, but at about eight weeks, they began to gain weight and became persistently obese in adulthood, with two to three times as much adipose fat as normal mice, and they also became insulin resistant. “Their hormones and blood sugar resembled that seen in humans with these disorders,” Montminy said.
The team discovered that TORC1, which is found within nerve cells, responds to signals from leptin, which binds to receptors on the outside of the same cells. TORC1 then turns on a spate of genes, two of which are well known. One is the CART (Cocaine and Amphetamine Regulated Transcript) gene that is known to stifle appetite. The other, KISS1 (named by its discoverers at the Penn State Hershey Medical Center) is required for reproduction; mutations in the gene produce human infertility.
So when leptin binds with its receptor on brain cells, it turns on TORC1, which, in turns activates CART to suppress appetite, because more food is not needed, and KISS1, signaling reproduction can now commence in this well-fed body. Conversely, when leptin is not activating brain receptors, TORC1 is turned off, as are CART and KISS1. Tweaking mutated and inefficient TORC genes may be possible through drug therapy, suggests Montminy. “TORC1 is regulated by phosphate handling enzymes called kinases, and kinases often make for very good drug targets.”