Before last week, I rarely thought about obesity. Not because it wasn’t in my life – my Dad and most of my uncles are obese – it had just become so present that I didn’t think anything of it. That all changed when I learned that obesity can be categorized as a brain disease. A main point in this classification is insulin resistance in the central nervous system that arises as a result of obesity and type 2 diabetes. It isn’t a surprise that insulin resistance connects these two diseases, as 90% of people with type 2 diabetes are also overweight or obese.
In the 1970’s, researchers discovered that insulin receptors exist in the brain and that signaling through these receptors regulates feeding behaviors and body weights. When functioning properly, insulin signaling in an area of the hypothalamus called the acruate nucleus (ARC) works to maintain a healthy appetite level. Within the ARC are two subsets of neurons, called the POMC and AgRP. Interestingly, these two types of neurons have opposing effects with POMC decreasing appetite and AgRP stimulating appetite.
Insulin signaling regulates POMC and AgRP through its deactivation of the transcription factor FOXO1. FOXO1, when activated, lowers the expression of POMC and increases the expression of AgRP neurons. The result, then, of insulin deactivating FOXO1 is a stimulating effect on POMC expression that ultimately leads to the decreased appetite from insulin. This is demonstrated in the figure below.
A decreased appetite in response to insulin makes logical sense when you consider that insulin is released in response to high blood sugar. In essence, the high blood sugar is a signal that the body has an adequate energy store in the form of sugars. And while this system works well in a healthy person, problems can arise when a person becomes resistant to the signaling from insulin.
Insulin resistance arises from a variety of sources. One interesting mechanism involves accumulation of saturated fatty acids in the hypothalamus from high fat diets. These fats can activate receptors on the neuronal surface leading to an inflammatory state in the brain that causes insulin resistance. A general inflammatory state arises from obesity and the subsequent production of pro-inflammatory cytokines can also signal through their own receptors to cause insulin resistance.
What can be stated generally is that obesity and overnutrition can lead to an inflammatory like state that renders the brain “resistant” to insulin signaling. That means that the insulin pathway discussed above, which normally responds to high-energy states by signaling through insulin to reduce appetite and expend energy, is shut down and the body doesn’t properly recognize that its energy needs are met.
One can begin to see how insulin resistance forms a cyclical process where obesity and overnutrition can lead to insulin resistance, which then leads to an unregulated appetite that further contributes to obesity. In the end, it’s a dangerous cycle that already plagues much of the world.
Perhaps the link between the brain and obesity will bring more awareness to the issue and catalyze positive changes to diets and lifestyles. Possibly it will also spur a new age of medicine that treats obesity through the lens of insulin resistance. Time will tell how the scientific and general community reacts to this research, but the fact remains that we must address the obesity epidemic. In my opinion, further research into the brain’s role is a great start.
What Does Your Brain Have to Do With Obesity?
