New MC4R Variants Discovered to Protect Against Obesity

[Ygggdrasil]

TL;DR

Variants of the gene MC4R protect against obesity and point to MC4R as a potential target for anti-obesity drugs.

Published this week in the journal Cell, researchers report discovering variants of the human gene MC4R that protect against obesity by helping to make people full. These new findings, combined with previous work on other MC4R variants that contribute to obesity, suggest the potential for new anti-obesity therapies that target MC4R.

In the new study, Dr. Farooqi and her colleagues found that in some thin people, the MC4R gene is always turned on, instead of always off, because of different mutations involving a previously unknown metabolic pathway.

These people continually feel satiated. About 6 percent of the population carries such protective mutations.

“This proves that MC4R is an important, if not the most important, controller of weight,” Dr. Farooqi said. And the new pathway provides an obvious target for drugs to protect against obesity.

Researchers increasingly are finding that appetite and satiety determine who gains excess weight and who does not

https://www.nytimes.com/2019/04/18/health/genetics-weight-obesity.html

Citation to the paper discussed:
Lotta et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 177: 597 (2019)
https://doi.org/10.1016/j.cell.2019.03.044

Abstract:

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing β-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

 

[Greg Bernhardt]

I always wonder if you change this gene it could help them feel full but unless we understand everything this gene affects it could have side effects? Is that a worry or are these genes simple singular switches?

 

[BillTre]

Until something becomes well studied, something like this is always possible.

Effects a particular mutation has on phenotypes other than its "primary" effect, are called pliotrophic in genetics jargon.
When I first started doing genetic research, the number of pliotrophic effects associated with "simple" mutations was surprising.
Similarly, the underlying molecules are often shown to be involved in more than one molecular mechanism.

Since animal genomes are not infrequently doubled in evolution, many multiply used genes (and their products) have had their multiple roles somewhat separated in the resulting duplicated genomes. This is called subfunctionalization and could be a source of new genetic variability.

 

[TeethWhitener]

Is that a worry or are these genes simple singular switches?

It’s certainly a worry, but note the abstract @Ygggdrasil posted: variants in the gene are quite widespread (61 variants over 500,000 people in the UK). This should make it easier to do large-scale observational studies of potential adverse effects of these mutations.

 

[Ygggdrasil]

I always wonder if you change this gene it could help them feel full but unless we understand everything this gene affects it could have side effects? Is that a worry or are these genes simple singular switches?

This is certainly the case for MC4R, which has additional functions in other tissues. For example, researchers have developed drugs that activate MC4R, but while these drugs do suppress appetite, they raise blood pressure (https://www.nejm.org/doi/full/10.1056/NEJMoa0803085), which has halted their clinical development. MC4R is likely involved in the regulation of blood pressure as people with inactivating mutations in MC4R show lower blood pressure than normal. Some MC4R drugs also affect the related melanocortin-1 receptor, which is involved in skin pigmentation.

One advance made by the new study is that it improves understanding of some of the molecular pathways that control MC4R activity, so the hope would be that this knowledge could help design drugs that affect only MC4R's role in appetite without affecting its other roles in the body.

 

[cyboman]

Summary: Variants of the gene MC4R protect against obesity and point to MC4R as a potential target for anti-obesity drugs.

Published this week in the journal Cell, researchers report discovering variants of the human gene MC4R that protect against obesity by helping to make people full. These new findings, combined with previous work on other MC4R variants that contribute to obesity, suggest the potential for new anti-obesity therapies that target MC4R.https://www.nytimes.com/2019/04/18/health/genetics-weight-obesity.html

Citation to the paper discussed:
Lotta et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 177: 597 (2019)
https://doi.org/10.1016/j.cell.2019.03.044

Abstract:

If only 6% of people from the current data set show this gene as always active effectively causing more satiation, what were the selective pressures that would lead that to be the case? Access to food? Long periods of fasting during lack of food access that would select for increased appetite to increase fat stores?

It's interesting to me that by playing with the genes themselves, were effectively interjecting an artificial manipulation to the incredibly complex mechanics of the body. Is it really possible to understand all the ramifications and affects such a change could have across all metabolic pathways? I mean potentially 100,000s of years of evolution select such a gene to be not be active all the time. Now, in our short blip in the timescale we have an obesity issue. Is it really the solution to manipulate the fundamental code of our dna and gene expressions in an effort to control satiation?

Always was fascinated with genetics, evolution and anthropology. Just a laymen's perspective.

 

[InfiniteEntity]

Isn't all this in the end regulated by leptin?

 

[Ygggdrasil]

If only 6% of people from the current data set show this gene as always active effectively causing more satiation, what were the selective pressures that would lead that to be the case? Access to food? Long periods of fasting during lack of food access that would select for increased appetite to increase fat stores?

That is a good question. It is certainly true that the selective pressures regarding food intake and obesity are quite different in modern times versus throughout the majority of human evolution.

It's interesting to me that by playing with the genes themselves, were effectively interjecting an artificial manipulation to the incredibly complex mechanics of the body. Is it really possible to understand all the ramifications and affects such a change could have across all metabolic pathways? I mean potentially 100,000s of years of evolution select such a gene to be not be active all the time. Now, in our short blip in the timescale we have an obesity issue. Is it really the solution to manipulate the fundamental code of our dna and gene expressions in an effort to control satiation?

I agree. We are definitely a far ways off of genetically manipulating MC4R in healthy individuals as a means to control satiety. As previous research has shown (see post #5), MC4R has additional functions in other parts of the body (e.g. the regulation of blood pressure), so genetic alterations to MC4R could have many effects elsewhere in the body. The hope with the research presented in the paper is that studying the specific ways in which the new MC4R variants affect MC4R signaling pathways could aid in the design of new drugs that are able to specifically control MC4R's affects on appetite without affecting its roles in other processes (and it is still an open question whether this is possible or not). There is definitely more research that needs to be done.

With regard to your general point on genetic manipulations, the wider scientific community seems to agree. There are a number of rare gene variants that have been identified that seem to offer protection against certain conditions. For example, mutations in PCSK9 seem to protect against cardiovascular disease, mutations in CCR5 seem to confer immunity to HIV, and mutations to APP seem to protect against Alzheimer's disease. While one might imagine wanting to introduce these into the wider population, guidelines on gene editing from the United States National Academies of Science caution against introducing rare variants through gene editing. The worry is that these rare variants could have unexpected interactions with other gene variants found in other populations to cause adverse outcomes. It is still an open question about the extent to which the safety of such gene edits should be evaluated before clinical use.

 

[cyboman]

Your reply has a lot of great information @Ygggdrasil. Thanks!

It did seem surprising to me that the mutation is qualified as "protective". I mean, if you have an issue with obesity than of course such a mutation would be. But I would imagine that that's not the case for all populations and certainly not through different populations at different times in our evolutionary history. Perhaps the language is contextual referring to it's application to pharma.

It's also concerning because there is so much money in the weight loss business. Many magic pills etc... The economic incentives to have a drug that controls MC4R would likely be very great. It would almost be on the level of a telomere manipulating type of anti aging drug. It seems to me the application of this type of research is fundamentally different than using gene therapy for treating a genetic disorder like sickle cell anemia.

It's reassuring to hear that those guidelines are set forth. Considering all the number of environmental variables and the immense complexity of the genome, there is the potential for an almost infinite number of unintended phenotypical expressions. But it's been some time since I've read about these things and I'm not up to date on the latest. I imagine super-computing and AI also play a large role in "decompiling" the genome when doing this type of research. I would be interested in the computer science aspect of how current genetic research is carried out. I'll have to search for some threads on that.

Again, thanks @Ygggdrasil for the very informative reply.