Summary: Researchers have identified a signaling pathway that appears to be responsible for hunger. Targeting the pathway, researchers say, could be key to finding new treatments to curb obesity.
Source: University of Montreal.
About 64 per cent of Canadian adults are overweight or obese, according to Health Canada. That’s a problem, because obesity promotes the emergence of chronic diseases such as type 2 diabetes, heart disease and some cancers.
To address the issue, researchers are trying to develop a pharmacological solution capable of interfering with the hormones behind weight gain. Those that regulate appetite are prime targets, including ghrelin.
By blocking the binding of ghrelin to its receptor with a drug, one could theoretically reduce a person’s feeling of hunger.
But ghrelin and its receptor also stimulate gastrointestinal motility and secretion of growth hormone, as well as having an impact on mood and behavior – both undesirable side effects.
There is hope however:
With colleagues at the University of Copenhagen, Université de Montréal professor Michel Bouvier and his team at the Institute for Research in Immunology and Cancer have discovered a strategy to specifically tackle hunger.
Find a (path)way
In their study, published in PNAS (Proceedings of the National Academy of Sciences), the researchers 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. Trouble is, this is only partially true.
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, thereby stimulating hunger.
Researchers clearly demonstrated that it is this particular signaling pathway that allows the ghrelin receptor to stimulate hunger, using 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 three times more, on average.
Since it stimulates hunger, the drug YIL781 is unsuitable for treating obesity. However, this molecule has demonstrated that the ghrelin receptor can be partially turned on, providing hope for future research.
Source: Catherine Cardinal – University of Montreal
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to University of Montreal.
Original Research: Abstract for “Translating biased signaling in the ghrelin receptor system into differential in vivo functions” by 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 in PNAS. Published October 9 2018.
[cbtabs][cbtab title=”MLA”]University of Montreal”Targeting a Hunger Hormone to Treat Obesity.” NeuroscienceNews. NeuroscienceNews, 22 October 2018.
<https://neurosciencenews.com/obesity-hunger-hormone-10073/>.[/cbtab][cbtab title=”APA”]University of Montreal(2018, October 22). Targeting a Hunger Hormone to Treat Obesity. NeuroscienceNews. Retrieved October 22, 2018 from https://neurosciencenews.com/obesity-hunger-hormone-10073/[/cbtab][cbtab title=”Chicago”]University of Montreal”Targeting a Hunger Hormone to Treat Obesity.” https://neurosciencenews.com/obesity-hunger-hormone-10073/ (accessed October 22, 2018).[/cbtab][/cbtabs]
Translating biased signaling in the ghrelin receptor system into differential in vivo functions
Biased signaling has been suggested as a means of selectively modulating a limited fraction of the signaling pathways for G-protein–coupled receptor family members. Hence, biased ligands may allow modulation of only the desired physiological functions and not elicit undesired effects associated with pharmacological treatments. The ghrelin receptor is a highly sought antiobesity target, since the gut hormone ghrelin in humans has been shown to increase both food intake and fat accumulation. However, it also modulates mood, behavior, growth hormone secretion, and gastric motility. Thus, blocking all pathways of this receptor may give rise to potential side effects. In the present study, we describe a highly promiscuous signaling capacity for the ghrelin receptor. We tested selected ligands for their ability to regulate the various pathways engaged by the receptor. Among those, a biased ligand, YIL781, was found to activate the Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-arrestin or other G-protein coupling is sufficient to decrease food intake.