Rodents Lead the Way

The study of obesity genetics dates back more than half a century.  In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene.  They named this the “obese” (ob/ob) mouse.  Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, “agouti” (Avy) mice, and “Zucker” (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome.  All they knew is that the mutations were in single genes, and they resulted in extreme obesity.  Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way.  Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators’ pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned.  Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

At the same time, several groups were researching a fascinating new “anti-lipogenic factor” (also “satiety factor”) they had identified by literally fusing together obese and normal rats, allowing their circulation to (very slowly) communicate (1).  Their results suggested the existence of a previously unidentified, powerful circulating factor that regulates food intake and body fatness, and they were able to rule out insulin, glucose, fatty acids, cortisol, and a variety of other potential contenders.  Furthermore, their findings suggested that ob/ob mice lack the anti-lipogenic factor, db/db mice lack its receptor, and the factor acts primarily in a brain region called the hypothalamus (2).  Yet the identity of the factor remained unknown until 1994.

Realizing that a full understanding of obesity in ob/ob mice would require identifying the mutation, a research team led by Dr. Rudolf Leibel set out to identify it through a laborious process called positional cloning.  In 1994, this led to the cloning and sequencing of the ob gene (3), which encoded a previously unknown protein of 16 kilodaltons.  They named it leptin, after the Greek word “leptos”, meaning “thin”.  Here is the full abstract of the paper:

The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

Further work confirmed that leptin is produced primarily by fat cells and acts in the brain to constrain food intake and body fatness (4).  Remarkably, all of the original single-gene mutations that cause rodent obesity ended up being in the leptin signaling pathway.  ob/ob mice lack leptin, db/db mice and fa/fa rats lack the leptin receptor, and Avy mice have a mutation that mimics the effects of leptin deficiency in the brain.  The obesity, elevated insulin, and alterations in fat cell metabolism in these models were all downstream consequences of defects in the leptin signaling pathway– via the brain.

Humans Follow

Shortly after the cloning of the leptin gene, researchers identified a family of humans that also lacked leptin function (5), providing “the first genetic evidence that leptin is an important regulator of energy balance in humans”.  Not only were they obese, with an abnormally large appetite, but treating them with leptin normalized their appetite and returned them to a normal weight (6), as shown in the photo to the left (6b).  As of 2013, a number of human families with obesity due to single-gene mutations have been identified.  If we consider only those mutations that cause obesity without causing significant developmental abnormalities, all of them turned out to be in the leptin signaling pathway– either in leptin, the leptin receptor, or the brain circuits that respond to leptin and related signals (7)*.  As was the case in rodents, spontaneous mutations in humans pointed to the leptin-brain axis as the primary regulator of body fatness.

More recently, researchers have performed large-scale genetic screens on people who have severe or early-onset obesity to see if some cases can be attributed to variance in specific genes.  About 4 percent of severely obese people have a mutation in the melanocortin receptor 4 (MC4R) gene that causes it to lose function (8), and two recently published papers identified a loss-of function variant of the gene SIM1 in another subset of early-onset obese subjects (9, 10).  MC4R is a receptor for alpha-MSH**, the product of leptin-responsive POMC neurons, and SIM1 is an important protein for the development and function of the paraventricular nucleus of the hypothalamus, a major target of POMC neurons.  In other words, they are both part of the same system in the brain that regulates body fatness in response to leptin and other signals.  Both the MC4R and SIM1 variants cause an increase in food intake due to a defect in satiety (11).  For people with these variants, achieving real leanness is unlikely.  Other studies have also uncovered mutations in genes associated with the brain regulation of body fatness in severe early-onset obesity (11b).

So far, I’ve described rare mutations that lead to severe obesity.  These mutations only account for a very small fraction of the obese population.  To understand what genes are involved in common obesity, we’ll have to turn to another method: genome-wide association studies (GWAS).  The GWAS method takes advantage of the fact that everyone’s genome is a little bit different.  By sequencing these areas of difference between people***, they can associate them with specific traits, for example, obesity.  This allows researchers to “map” sites of particular importance to the trait in question, which tells us something about what biological processes are relevant to the trait.  For example, diabetes-linked regions are mostly associated with genes affecting the pancreas, as one would expect (12)  though some obesity genes do show up as well****.

The findings of obesity GWAS studies are basically consistent with the other evidence described above (12b).  For many of the identified regions, we don’t know which gene is involved.  For the genes that we have identified, most of them are involved in brain function, particularly the leptin-responsive hypothalamus.  Here’s a quote from a review paper that sums it up (13):

…when we look at the information gleaned from the past 15 years of molecular genetic activity we cannot avoid concluding that, as much as type 2 diabetes is clearly a disease in which pancreatic beta-cell dysfunction is a critical element, obesity is a condition in which inherent genetic predisposition is dominated by the brain.

That being said, GWAS studies have failed to identify the majority of the genetic differences that account for the 70 percent heritability of body fatness (less than 3% accounted for).  We have enough information to know what types of biological processes are involved in common obesity, but we don’t know all the details yet.  As the old saying goes, “more research is required”!

What does it Mean?

The genetic data converge powerfully with other fields such as neurobiology, endocrinology, and physiology, together demonstrating conclusively that:

1. The brain is the main regulator of body fatness.
2. The brain regulates body fatness in response to internal signals of energy stores, particularly leptin.
3. Genetic variability in body fatness is likely predominantly determined by genetic differences in brain function, particularly the hypothalamus.

In the next post, I’ll explain why genes are not (usually) destiny.

* Those that do cause deformity also involve brain energy balance circuitry (14).

** Also AgRP, which is an inverse agonist at the MC4R and increases food intake.

*** Typically, single-nucleotide polymorphisms.

**** E.g., FTO, the #1 obesity GWAS hit.