Wednesday, August 20, 2008

Cardiovascular Risk Factors on Kitava, Part IV: Leptin

Leptin is a hormone that is a central player in the process of weight gain and chronic disease. Its existence had been predicted for decades, but it was not identified until 1994. Although less well known than insulin, its effects on nutrient disposal, metabolic rate and feeding behaviors place it on the same level of importance.

Caloric intake and expenditure vary from day to day and week to week in humans, yet most people maintain a relatively stable weight without consciously adjusting food intake. For example, I become hungry after a long fast, whereas I won't be very hungry if I've stuffed myself for two meals in a row. This suggests a homeostatic mechanism, or feedback loop, which keeps weight in the body's preferred range. Leptin is the major feedback signal.

Here's how it works. Leptin is secreted by adipose (fat) tissue, and its blood levels are proportional to fat mass. The more fat, the more leptin. It acts in the brain to increase the metabolic rate, decrease eating behaviors, and inhibit the deposition of fat. Thus, if fat mass increases, hunger diminishes and the body tries to burn calories to regain its preferred equilibrium.

The next logical question is "how could anyone become obese if this feedback loop inhibits energy storage in response to fat gain?" The answer is a problem called leptin resistance. In people who are obese, the brain no longer responds to the leptin signal. In fact, the brain believes leptin levels are low, implying stored energy is low, so it thinks it's starving. This explains the low metabolic rate, increased tendency for fat storage and hyperphagia (increased eating) seen in many obese people. Leptin resistance has reset the body's preferred weight 'set-point' to a higher level.

Incidentally, some reaserchers have claimed that obese people gain fat because they don't fidget as much as others. This is based on the observation that thin people fidget more than overweight people. Leptin also influences activity levels, so it's possible that obese people fidget less than thin people due to their leptin resistance. In other words, they fidget less because they're fat, rather than the other way around.

The problem of leptin resistance is well illustrated by a rat model called the Zucker fatty strain. The Zucker rat has a mutation in the leptin receptor gene, making its brain unresponsive to leptin signals. The rat's fat tissue pumps out leptin, but its brain is deaf to it. This is basically a model of severe leptin resistance, the same thing we see in obese humans. What happens to these rats? They become hyperphagic, hypometabolic, obese, develop insulin resistance, impaired glucose tolerance, dyslipidemia, diabetes, and cardiovascular disease. Basically, severe metabolic syndrome.

This shows that leptin resistance is sufficient to cause many of the common metabolic problems that plague modern societies. In humans, it's a little known fact that leptin resistance precedes the development of obesity, insulin resistance, and impaired glucose tolerance! Furthermore, humans with leptin receptor mutations or impaired leptin production become hyperphagic and severely obese. This puts leptin at the top of my list of suspects.

So here we have the Kitavans, who are thin and healthy. How's their leptin? Incredibly low. Even in young individuals, Kitavan leptin levels average less than half of Swedish levels. Beyond age 60, Kitavans have 1/4 the leptin level of Swedish people. The difference is so great, the standard deviations don't even overlap.

This isn't surprising, since leptin levels track with fat mass and the Kitavans are very lean (average male BMI = 20, female BMI = 18). Now we are faced with a chicken and egg question. Are Kitavans thin because they're leptin-sensitive, or are they leptin-sensitive because they're thin?

There's no way to answer this question conclusively using the data I'm familiar with. However, in mice and humans, leptin resistance by itself can initiate a spectrum of metabolic problems very reminiscent of what we see so frequently in modern societies. This leads me to believe that there's something about the modern lifestyle that causes leptin resistance. As usual, my microscope is pointed directly at industrial food.