Genetics of Obesity

It seems that some people are destined to be skinny. They have never known being fat, and they make being thin look easy. Others of us are in the opposite situation. It is a struggle to lose weight, and being thin seems impossible. Could it be that our genes have something to do with it? As it turns out, there are several genes that play a role in obesity. Defects in some of these genes cause certain syndromes to develop. Not everything is known about the genetics of obesity, but our knowledge is expanding.

A part of the brain called the hypothalamus controls several functions of the body. One of these is the regulation of the sense of hunger. There is an interplay between various chemical messengers and the hypothalamus. This interplay is called the hypothalamic leptin-melanocortin system. Our fat cells make a signal called leptin. The more fat we have, the more leptin is produced. It binds to the leptin receptor in the hypothalamus. The hypothalamus senses a minimal amount of leptin which tells the brain that the body has at least the required amount of fat to function. Once the receptor is activated, a protein called proopiomelanocortin (POMC) is made. POMC is then cut into smaller parts by enzymes. One of these enzymes is proenzyme convertase 1 (PC-1). One of the smaller proteins produced by PC-1 is called alpha-MSH which binds another receptor in the hypothalamus called MC4R. Once MC4R is turned on, it triggers some intracellular signals that end up telling your brain that you are not as hungry. Got all that?! Check out the link at the end of this article and go to the "Genetics" tab. On the "leptin" page, there is a diagram that explains it.

A defect in the genes for any of the signals, enzymes, and receptors mentioned above can lead to an increased appetite. The most common of these mutations is a defect in MC4R. However, it is not the most severe, and some people with a defective MC4R gene are still thin. Mutations in other genes cause a voracious appetite in very young children, and they are nearly destined to eat far more than their bodies will ever need. In addition to becoming very obese, associated problems can include: small ovaries and testicles, thyroid dysfunction, decreased immunity, and low functioning adrenal glands. Fortunately, these more severe conditions are rare with only a handful of known cases. There are treatments for a few, like replacing leptin with shots. For others, like MC4R, there are to treatments.

A few genes that aid in the development of the hypothalamus are also associated with obesity. The SIM1 gene encodes signals that come from the MC4R receptor. One case of a young girl with a SIM1 mutation was obese and also tall. In addition to development of the hypothalamus, the tropomysin-related kinase B (TrkB) receptor and the chemical signal called brain-derived neutrotrophic factor (BDNF) play roles in memory, behavior, and intellect. Defects in either of these two can cause obesity and memory problems.

In the reward center of the brain, dopamine is released when we eat food. People who have mutations in a stretch of DNA called TaqIA have fewer dopamine receptors and thus need to eat more to feel the same sense of reward. This lends weight to the fact that some people may literally be addicted to food, and the sweeter the food, the stronger the addiction.

There are also several genetic syndromes associated with obesity that involve more than one gene. They are too complex for this article, but here is a list of some of them: Prader-Willi, Bardet-Biedl, Ahlstrom, Cohen, and Carpenter syndromes.