Old genetic discoveries may reveal ‘new tricks’ for treating obesity
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Genetic modifiers — many discovered in the late 1990s — can be “harnessed” to better understand the processes and mechanisms behind weight gain and one day even regulate appetite, according to a speaker.
“For some people, because of their genetic makeup, it will always be more difficult to ‘say no’ to food,” Giles Yeo, PhD, a principal research associate at the MRC Metabolic Diseases Unit at the University of Cambridge, U.K., told Healio. “As a result, they end up eating more, which is why there are people that are small, medium and large in today’s food environment.”
Studying the genetics of body weight means understanding the genetics of how the brain controls food intake, Yeo said during an online key lecture at ObesityWeek Interactive. The human brain needs two pieces of information to control food intake: long-term energy stores, or how much fat one has, and short-term energy stores, or what someone is currently eating or has just eaten.
“Your brain senses these signals of long-term energy stores and signals of short-term energy stores, and then responds, translates and then influences your next interaction with a menu, a refrigerator or a supermarket,” Yeo said. “Most people are surprised at how conserved, through evolution, the pathways and circuits that control food intake and body weight actually are.”
‘Harnessing’ old, new gene discoveries
By leveraging genetic modifiers, researchers now understand that one of the key pathways in the brain that influences food intake is the central leptin melanocortin signaling pathway — what Yeo called one of the “old dogs.”
The leptin melanocortin pathway is central to controlling appetitive behavior in monogenic, or severe, obesity and influencing where individuals “sit” on the normal distribution of body weight, Yeo said. Leptin is an adipocyte hormone and one of the key signals coming from fat and signaling the hypothalamus. There, leptin influences expression of pro-opiomelanocortin (POMC), which is processed into several peptides that influence food intake and body weight.
“We know this pathway is important, because if you disrupt every single portion of this pathway, whether or not you have whiskers and a tail, it results in severe obesity,” Yeo said.
Not all POMC neurons are the same; research now demonstrates they are a highly heterogeneous population with at least four identifiable subclasses, Yeo said.
“We do tend to think of these neurons in the brain as big, homogeneous lumps of neurons, when that clearly is not the case,” Yeo said. “For example, we have known for a long time that there are two broad POMC classes of neurons, those that are insulin responsive, and those that are leptin responsive. They are separate neurons.”
Better understanding of these differences in detail is important to safely target pathways, Yeo said.
Risk vs. predictability
Severe mutations in the leptin melanocortin pathway are relatively rare; the causes behind most common obesity conditions are polygenic, Yeo said.
Genetic analyses show that where a person stores fat has to do with adipocyte biology, whereas how much fat one has — their BMI — has to do with genes, like FTO, expressed exclusively within the brain and influencing food intake, Yeo said.
“If you have severe mutations in the leptin melanocortin pathway, you end up with severe obesity,” Yeo said. “But if you have very mild polymorphisms within the pathway, it then influences where you sit on the normal distribution of body weight.”
Based on this and other genetic research, there is a growing trend of companies offering individuals a “polygenic risk score,” or the estimated effect of many genetic variants on an individual's phenotype. The higher the polygenic risk score, the more likely a person is to become obese.
“Does that mean we can predict obesity in order to target treatments? The short answer is, no,” Yeo said. “That doesn’t stop people from doing it, like 23andMe and other DNA screening companies. They all fall for the same problem, and that is a fundamental misunderstanding of population-level risk vs. personal predictability. You get data from hundreds of thousands of people and try and make a prediction of whether an individual will become obese given a certain genetic makeup. We are just not there with that kind of prediction. The data does not allow us to do that. The data is sound, but it is a misinterpretation of the data.”
Yeo cautioned that “mice or flies are not humans,” and the study of the human hypothalamus should reveal many more “new tricks” with time.
“We need to understand how we can utilize our genetic knowledge to improve treatment of obesity,” Yeo told Healio.
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Yeo G. The genetics of obesity: Can an old dog teach us new tricks? Presented at: ObesityWeek Interactive; Nov. 2, 2020 (virtual meeting).
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