Genetic Differences in Leptin Regulation May Predispose Some to Obesity
A new study reports that genetic changes in how the hunger-inhibiting hormone leptin is regulated could predispose some people to obesity.
The study, “Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity,” was published in the journal Nature Medicine.
Leptin is one of the best-understood hormones related to obesity. It’s made by fat cells, and essentially helps tell the brain when it’s time to stop eating. Despite thousands of studies investigating this hormone, basic questions about how cells turn the leptin gene on or off remain unanswered.
“We’ve learned a lot about leptin, but we didn’t actually understand the basic biology of what regulates the leptin gene,” Olof Dallner, the study’s first author and a research associate at New York’s Rockefeller University, said in a press release.
As researchers examined the regulatory mechanisms affecting the leptin gene, they found a long non-coding RNA (lncRNA) that seemed closely tied to leptin expression.
“When we studied the lncRNA, we realized it was completely co-regulated with leptin. It’s expressed where leptin is expressed. When leptin is down the lncRNA is down, and vice versa,” Dallner said.
As the name suggests, lncRNAs are long RNA molecules that don’t encode for a protein the way messenger RNAs do. Instead, they’re often involved in regulating how much other genes are expressed, as seems to be the case here. The specific lncRNA found to be associated with leptin is called lncOb.
When researchers fed mice lacking the lncOB gene a high-fat diet, they gained weight just like wild-type (normal) mice fed the diet, which wasn’t surprising. What was odd, though, was that mice lacking lncOB still had comparatively low leptin levels.
Typically, obese mice (and humans) have higher leptin levels, which causes the brain to become less sensitive to the hormone, which in turn can cause a vicious cycle in obesity (as leptin is no longer able to control appetite/hunger signals in the body). Yet, since mice lacking lncOB had low leptin levels, their brains could still be responsive to the hormone, the researchers predicted.
Indeed, when researchers gave those mice injections of leptin, the animals lost weight, effectively “curing” them of their obesity.
“These results show that reduced leptin gene expression can lead to a … leptin-responsive form of obesity,” researchers said.
Furthermore, the team analyzed genetic data from over 46,000 people, and found differences in the lncOB gene that were linked to leptin levels, suggesting that this same mechanism might play a role in a subset of obese patients.
It’s not entirely clear to what extent differences in this gene might account for obesity in people, but the team estimated that as many as 10% of obesity cases might be related to improper regulation of the leptin gene.
“There is a large subset of humans who are obese and still are relatively low in leptin,” Dallner said. “We now think that many of them may have these or similar gene variants that affect the expression of the leptin gene. This gives them less leptin from an early age, making them a little bit hungrier than everyone else.”
Early clinical trials of a leptin therapy, which was approved by the U.S. Food and Drug Administration (FDA) in 2014, have shown that some obese patients with low leptin levels lose a significant amount of weight when treated with the hormone.
It’s still not entirely clear how lncOB regulates leptin, and there are likely many interconnected factors that end up affecting leptin expression. Nonetheless, according to the team, further studies may help clarify these mechanisms, and identify which patients are most likely to respond well to leptin therapy.
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