Within the brain, a cluster of cells serves as appetite-control central. And within these cells, a gene called Pomc—short for proopiomelanocortin—is responsible for emitting appetite-suppressing signals. The Pomc gene, however, is sometimes absent or dysfunctional, with serious consequences. When the brain stops sending “stop eating” signals, the body can grow dangerously obese. And even if brain cells contain perfectly fine Pomc genes, proper signaling isn’t a given. The Pomc gene needs helpers.

As it turns out, the Pomc gene has several helpers, and they can back each other up to some extent. This finding emerged from studies led by Malcolm Low, M.D., Ph.D., of the University of Michigan Medical School and Marcelo Rubinstein, Ph.D., of the University of Buenos Aires in Argentina. According to these scientists, a protein called a transcription factor and two small stretches of DNA called enhancers act as triggers for the Pomc gene. All three regulate how often and when the POMC cells use the gene to create the signal molecules that then go out to the body.

The transcription factor, called Islet 1, also plays a key role in helping POMC cells form correctly during the earliest stages of the brain's development, before birth. The enhancers are called nPE1 and nPE2. They specifically regulate the Pomc gene only in the brain. Mice born without both of them became obese—as if their Pomc gene had been deactivated. Meanwhile, mice that just lacked nPE2 grew normally, as the presence of nPE1 compensated.

The transcription factor described March 31 in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled, “Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood.” The work on the enhancers was reported February 11 in PLoS Genetics, in an article entitled, “Partially redundant enhancers cooperatively maintain mammalian Pomc expression above a critical functional threshold.”

In the PNAS article, the authors wrote: “[We] combined molecular neuroanatomical and biochemical analyses with functional genetic studies in transgenic mice and zebrafish and discovered that the transcription factor Islet 1 determines the identity of central melanocortin neurons during early brain development and is critical for melanocortin-induced satiety and normal adiposity throughout the entire lifetime.”

In the PLoS Genetics article, they wrote: “Since Pomc expression from its intact locus exceeds the sum of the individual enhancer contributions to Pomc mRNA levels in embryonic mice, we infer a synergistic action between the enhancers during development. In contrast, the interaction between the enhancers is additive in adult mice. Deletion of both enhancers simultaneously almost completely abolished Pomc expression and the mutant mice displayed extreme obesity and metabolic dysfunction, while deletion of the individual enhancers had a modest or no phenotypic effect.”

Studying the impact of a total loss of Islet 1 or one or both of the two Pomc gene enhancers in animals showed the importance of these triggers, Dr. Low noted. But looking to see if the same factors do the same thing in humans will be more complex—and there may be other enhancers and transcription factors involved.

So far, genome-wide studies of humans have not shown any relationship between obesity and changes in the Isl1 gene. Brain imaging that tracks the binding of signals to and from POMC cells could reveal further clues. And in theory, it could be possible to find drugs to increase the production of Pomc gene products, or to grow replacement cells for malfunctioning POMC cells.

“For humans, Pomc regulation may be part of the equation of weight control,” said Dr. Low. “We don't know, but we think it likely, that it may be similar to the mouse model, where its role is like a dial, with a linear relationship between the amount of Pomc expression and the degree of obesity. This research opens up our overall understanding of how the brain works to regulate feeding.”

Drs. Low and Rubinstein hope to look for other transcription factors and to examine the roles of leptin and estrogen in stimulating POMC cells. They also hope to use neurons grown from induced pluripotent stem cells to study genetic activity during POMC cell development. And they will study POMC activity in mice that are pregnant or nursing, when POMC expression goes down and feeding increases.

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