By Martin Primeau

Researchers from the University of Copenhagen and the team of Michel Bouvier at the IRIC just published a study suggesting a new avenue for developing drugs against obesity. The results of this research were published this week in the journal PNAS.

According to Health Canada, approximately 64% of Canadian adults are currently overweight or obese. The problem is that obesity promotes the emergence of chronic diseases such as type 2 diabetes, heart disease and some cancers.

To address this problem, researchers are currently trying to develop a pharmacological solution capable of interfering with the hormones behind weight gain. Those that regulate appetite, like ghrelin, are prime targets.

This hormone, secreted mainly by the stomach when it is empty, circulates through the blood to the hypothalamus in the brain.

This is where it generates its effect.

Ghrelin attaches to cells via the ghrelin receptors that communicate with both the outside and the inside of the cells. These receptors then activate a series of signaling pathways within each cell. These signals then trigger hunger.

By blocking the binding of ghrelin to its receptor with a drug, one could theoretically reduce the feeling of hunger in an individual.

The reality is unfortunately not so simple.

In addition to stimulating hunger, ghrelin and its receptor also stimulate gastrointestinal motility and secretion of growth hormone, as well as having an impact on mood and behavior. Preventing ghrelin from functioning would therefore have many side effects.

There is hope however: the team of Michel Bouvier and their colleagues have discovered a strategy to specifically tackle hunger.

To find a (path)way

The study in which the IRIC team was involved identified that a particular signaling pathway downstream of the receptor, the one involving the Gαq/11 protein, was responsible for hunger. By specifically blocking this signaling pathway, without interfering with the others, a drug could therefore effectively fight obesity while limiting the side effects.

Researchers have demonstrated this by testing a series of pharmacological compounds that bind to the ghrelin receptor to block its action. In their presence, the receptor is unable to activate the signaling pathways that it normally stimulates.

The researchers have found that his is only partially true however.

The molecule YIL781, for instance, prevents some functions of the receptor, but not all of them. Instead of blocking the signaling pathway involving the Gαq/11 protein, it activates it instead … and therefore stimulates hunger!

Researchers clearly demonstrated that it is this particular signaling pathway that allows the ghrelin receptor to stimulate hunger. To do this, they used an animal model: mice unable to produce the Gαq/11 protein in the cells of their hypothalamus.

The appetite of these mice remained unchanged when administered YIL781. On the other hand, normal mice ate 3 times more on average!

We understand that the drug YIL781 will never treat obesity since it stimulates hunger. However, this molecule has demonstrated that the ghrelin receptor can be partially turned-on, to selectively activate some of the downstream signaling pathways.

This work also specifically linked another signaling pathway, the beta-arrestin pathway, to intestinal motility. These results therefore suggest that side effects related to ghrelin receptor inhibition, including nausea, could be avoided by not blocking beta-arrestin.

The Holy Grail of the fight against obesity: to identify a molecule capable of specifically blocking the signaling pathway of the Gαq/11 protein without harming others remains elusive for now.

No one knows if this will be achieved, but through their work, the IRIC researchers have taken a step further in this direction.

Study cited

Translating biased signaling in the ghrelin receptor system into differential in vivo functions

Franziska Mende, Cecilie Hundahl, Bianca Plouffe, Louise Julie Skov, Bjørn Sivertsen, Andreas Nygaard Madsen, Michael Lückmann, Thi Ai Diep, Stefan Offermanns, Thomas Michael Frimurer, Michel Bouvier, and Birgitte Holst

http://www.pnas.org/content/early/2018/10/08/1804003115

PNAS published ahead of print October 9, 2018 https://doi.org/10.1073/pnas.1804003115