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.


E said...

Great read, thanks.

mess talker said...

hey stephen. another great post thanks. Is that a typo in the 5th or 6th paragraph after sloth? Thin people fidget more than obese...

Question. One can fight insulin resistance with exercise, how can one fight leptin resistance? Would cutting out grains, especially wheat produce a turn around? I often wonder for myself how I have to mindfully stop eating after others are "so full."

Dr. B G said...

Hi Stephan!

Thank you for the insulin info -- I suspected that their levels were optimal with the 'whole-grain deficiency' their culture was 'afflicted' by...

My parents are from indigenous (ke-jia/Hakka) Taiwan -- the national veggie is the sweet potato -- because it resembles the shape of the Taiwan island! So the indigenous food (outside of the the total unhealthy reliance on rice) actually may have health benefits like those replicated among the Kitavans.

I really appreciated the info on fish fat and DHA intake -- with sufficient DHA, high daily sun intake and vit D, vit A from yams/fruits/meat -- I can really believe their cardiovascular health was prestine.

You are a gem -- thanks for your post and this neat series!

Jo said...

Hi Stephen,

This is off topic, from a post I was reading about the okinawans. I'm curious about the amount of soy in their diet? They eat a lot and it doesn't seem to have any ill effects on them.
Just curious about your thoughts on that. And also what does polish the rice mean?

Stephan Guyenet said...

Mess talker,

Yes, that was a typo, thanks for pointing it out.

Leptin resistance has been studied much less than insulin resistance, so it's difficult to know the best ways to correct it. However, fasting may work. It up-regulates leptin receptors in the brain while reducing circulating leptin. I don't know what the optimal fast length would be for this.

I do believe cutting out gluten grains would probably help leptin resistance. Anecdotally, I'm constantly hearing about people who lose weight when they cut out wheat specifically. That suggests leptin is normalizing. Dr. Davis often talks about this on the Heart Scan blog. If you try cutting out wheat, let me know how it works for you!

Stephan Guyenet said...

Hi G,

Thanks. It sounds like the Taiwanese have a pretty good diet.

The Kitavans really do have a lot of good things going on in their diet. It's basically a carb-heavy version of a paleolithic diet.

Hi Josephine,

Traditionally, Okinawans eat soy regularly in small amounts. They eat traditionally-prepared soy foods like miso and tofu, not the commercially produced soy foods that line our grocery stores in the US. Their consumption of fatty pork and fish is greater than their soy intake. They also traditionally use lard as a cooking fat.

Many people claim that the Okinawans prove soy is a healthy staple. My interpretation is that the human body can tolerate modest amounts of traditionally prepared soy when the diet is otherwise good. Soy is no substitute for animal protein.

Jo said...

Thanks, that actually makes a lot of sense.

Stephan Guyenet said...

Oh and by the way, "polished" rice is white rice. The polishing process is what removes the bran and the endosperm from brown rice.

Sue said...

Is rice better to eat than wheat?

Stephan Guyenet said...


I believe so. It should be soaked overnight before cooking like all grains and legumes. This is especially true for brown rice.

Jeff Rothschild said...

Hi Stephan, just curious about the hyperlink for the sentence "it's a little known fact that leptin resistance precedes the development of obesity, "

It doesn't seem to work any more, which study were you referencing on that?

Thanks very much!

Felix said...

Hi Stephen,
What do you think about this rather new study:
"High-fat diet induces leptin resistance in leptin-deficient mice." J Neuroendocrinol. 2014 Feb;26(2):58-67. doi: 10.1111/jne.12131.
Seems sound to me. What do you think?

Tom Tuduc said...

@Jeff, the correct link is

Unknown said...

I was recently, as in the past 6 months, diagnosed as being leptin resistant, and pre-diabetic. All my life, I had been thin, and healthy. When I hit 39 and had a complete hysterectomy, that all changed. I am going to try cutting out all wheat, and TRY to cut out processed foods as well. I don't make very much money, and my husband is on disability, and we all know that "healthy" foods are much more expensive than processed. My guess is, that is why our society is so much more obese than it used to be.

MelNaillon said...

I am trying to lose weight. In the past, I have tried both Atkins style low carb diets and McDougall style high starch (not necessarily carb) diet. I had more success with McDougall and, incidentally, felt better. But dragging my husband, who complained that his teeth felt loose in his mouth and my three young children, who started begging me for meat sounds like torture. I read other articles about the Kitavans but honestly their lifestyle seems to support a high starch diet and the inclusion of oil (coconut). I am confused by it all. Why do you think a vegan version of paleo works for Kitavans?