Scientists Identify Genetic Switch in the Brain That Regulates Body Weight and Fertility

by Rajashri on Sep 1 2008 5:00 PM

A master switch in the mice brain that controls both body weight and fertility has been identified in experiments on mice conducted at the Salk Institute for Biological Studies.

The researchers believe that a similar switch may work the same way in humans.

In their study report, the team suggest that variations in the gene that produces the master switch, TORC1, may contribute a genetic component to obesity and infertility, and may be regulated with a novel drug.

"This gene is crucial to the daisy chain of signals that run between body fat and the brain. It likely plays a pivotal role in how much we, as humans, eat and whether we have offspring," Nature magazine quoted Dr. Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology, who led the study, as saying.

Montminy says that it is as important as leptin, the well-known star regulator of appetite, because leptin turns on TORC1, which in turn activates a number of genes known to help control feeding and fertility.

The researchers looked at the signals that travel from body fat to the brain and inform the brain of how well fed the body is, a function that is primarily performed by the hormone leptin.

They say that the hormone also is known to play a role in reproduction, though no one understood what it was until this study.

"Controlling appetite and reproduction together provides a big evolutionary advantage. 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," Montminy says.

"Leptin works remarkably well to give the brain a good indication of how much food has been eaten; 99.9 percent of the time it balances food intake with energy use. The problem is that no machine works 100 percent of the time, and that slight bit of inefficiency can lead to extra body weight," he adds.

During the study, the researchers created mice that lacked one or both copies of the TORC1 gene.

Though the animals born without the gene looked fine at birth, they began to gain weight and became persistently obese in adulthood, with two to three times as much adipose fat as normal mice.

Such mice also became insulin resistant.

"Their hormones and blood sugar resembled that seen in humans with these disorders," Montminy says.

He reveals that the mice of both sexes were infertile: the uteri and ovaries in female mice were anatomically dysfunctional, for example.

"We don't study infertility, but we put two and two together. We knew leptin is the critical hormone for regulating body weight, and that it is also very important for regulating reproduction," he says.

Judith Altarejos, first author on this study, says that her study showed that TORC1, which is found within nerve cells, responds to signals from leptin.

She has also found that when mice inherit only one TORC1 gene, fertility is restored but the mice gain more weight than normal mice.

"This suggests that half of the dose of TORC switch is enough to cause problems in leptin signalling in the brain, and it may be that subtle mutations in TORC1 in humans could be responsible for an inheritable risk factor for gaining weight," Montminy says.

Modifying mutated and inefficient TORC genes may be possible through drug therapy, he adds.

"TORC1 is regulated by phosphate handling enzymes called kinases, and kinases often make for very good drug targets," he says.