This Genetic Mutation Makes People Feel Full — All the Time - The New York Times

Good morning everyone,

Our lecture on Tuesday of this week described the essentials of digestion, and Thursday's topic followed with consideration of metabolism and energy balance as a whole.  In the science news this week is a new study on these very topics, with description of a genetic mutation that influences both.

During our digestion lecture, I noted that much of its function is regulated autonomically, by local reflexes mediated in the ENS.  That is to say, the digestive tract functions more or less on its own when food is presented to it.  By inference then, regulation of food acquisition controls the overall amount of digestion we perform, and the number of calories we have available to use or store.

Regulation of hunger, food-seeking, and feelings of satiety (satisfaction of hunger, or "fullness") occur largely through the hypothalamus, where a variety of chemical signals are known to promote either orexigenic (food-seeking) or anorectic (satiety) states.  These include a number of cryptically-named chemicals such as CART, alpha-MSH, agouti-related peptide (AgRP), and melanocortin (MC), each acting at hypothalamic cells bearing specific receptors for them.  A great deal of experimental work over the last several decades (mostly in mouse models) has demonstrated that disruption of their signaling (via increased activation of their receptors, or blockade of them) can cause food consumption and body mass to either increase, or decrease.

Abnormally-elevated body mass to the point of obesity has reached critical levels in this country.  Depending upon the guidelines one uses, it has been estimated that 30-40% of adults in this country are obese, with another substantial proportion of the population classified as overweight.  Extra body mass is a significant health complication, raising one's risk of a number of diseases (including hypertension and diabetes) and complicating treatment and prevention of many others.  As such, there is an enormous research effort underway to explore the roots of obesity.  We know for certain that the issue is complex - socioeconomic status, willpower, behavior, access to high-quality foods, and sociality influence our food choices, eating habits, and body mass, in ways that are both many and complicated.  Increasingly, there is growing appreciation of genetic components to obesity as well.

Modern genetic assessments of health have benefited by technological advances that allow sequencing of individual genomes, resulting in large databases of genetic information.  When these are paired with health profiles and lifestyle data, they make possible genome-wide association studies (GWAS).  GWAS represent a powerful way to take two very large sets of data (gene sequences and health/lifestyle data) and see how/where they intersect.  In contrast to the twin study I described to you in my science news email last week, GWAS are useful only when based upon thousands (usually, hundreds of thousands) of individuals.  These are not experimental methods, so they cannot provide definitive proof of anything, but they can reveal interesting "associations" - places where genetics and health vary in consistent ways.

This new study describes a GWAS that sought genetic bases for obesity.  In a very large sample of human subjects (500,000 individuals), the researchers looked for consistent genetic mutations in people who were, or were not, obese.  They found evidence for specific genetic variation in the MC4R gene (melanocortin receptor 4) that was associated with obesity:  persons whose MCR4 gene was mutated (causing reduced function) were much more likely to be obese that those who carried the 'normal' version of the gene.  To some extent, this finding was not new - this effect of MCR4 mutation had been described previously, in smaller studies.  Here, though, the researchers also found evidence that if mutations in the gene(s) that regulate MCR4 cause it to be 'turned on' all of the time (instead of occasionally, such as after eating), it causes chronic satiety, or "fullness".  Persons with this form of mutation are much less likely to be obese, so the researchers interpret this alteration of MCR4 function as protective, and preventive of obesity.

Thus, we may have a single gene, which if mutated in one fashion can contribute to obesity, and if dis-regulated in another way can protect against it.  A second study described in this same article uses similar data to create a genetic risk assessment for obesity, with the hope of reducing its prevalence, potentially by intervening before it reaches criticality.

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

The genetic associations described in this study are not enormous, just a few percent (perhaps 6%).  Still, they represent the largest known genetic association for obesity, and that in and of itself is a very worthwhile finding.  Many persons who are obese suffer from anxiety, depression, and feelings of low self-worth, thinking (and too-often being told) that they are 'fat', or overweight, because of their behavior and lack of willpower.  What if the problem lies in their genes, and not in their self-control?  We all know how difficult it is to resist food when we are hungry - what if that feeling never goes away?

Like most science, these studies raise more questions than they answer.  Obesity and weight control are such significant problems, though, that their investigation is crucial to improved public health.  Here's to more studies and more information on these topics - they are likely to benefit us at a variety of levels: individually, via our loved ones, or as part of society as a whole.


Have a great weekend -
Dr. Nealen