11

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Is the Hypothalamus Ill-Equipped to Cope with Obesity?

Answered on August 19, 2014
Created September 15, 2011 at 9:49 PM

Rather than thinking of leptin as a satiety hormone, I'm beginning to think of it as a body fat census questionnaire, and the hypothalamus as a group of policy-makers who are interpreting that data and making decisions (with regard to appetite, metabolism etc.) based upon it. Our fat cells release less leptin when they are small than when they are large. The hypothalamus is constantly receiving this data, which should for the most part be fairly consistent. The problem is that our hypothalamus has evolved with probably a fairly tight range of probable leptin concentrations. Leptin gets very low during times of starvation, but rather than waiting for that to drop completely, triglycerides rise during starvation, which in addition to providing energy, happens to block the passage of leptin across the blood-brain barrier. This keeps appetite elevated and hopefully results in the animal finding food.

Now, as I've mentioned before, if some factor raises triglycerides out of a realistic range without starvation, such as consuming tons of fructose, the hypothalamus thinks you're starving because little leptin is being received and increases appetite accordingly. What I've been thinking about this morning though is that there is probably also a maximum amount of fat that the hypothalamus can account for (too few employees to accept and process the questionnaires). It may be that leptin receptors increase in density as leptin rises, but I bet they max out at some concentration, which means that the hypothalamus may be able to raise metabolic rate or decrease appetite up until a certain fat mass but that any fat above that won't continue to affect those things. For example, assuming there is no restriction at the BBB, there may be a leptin detection bottleneck where the receptors are saturated and the hypothalamic response reaches a plateau. So, 200 pounds may result in the same metabolic compensation as 400 pounds. It may just max out since this situation is so unlikely evolutionarily.

When someone gains fat, adipocytes experience hypertrophy (increase in size) and eventually hyperplasia (increase in number) if fat gain continues. Apparently this is more common with the gynoid fat deposition that women have vs. the android pattern that men have. I used to think that this would only happen at very large fat levels, but it's apparently pretty common. The differentiation in adipocytes can result in a person having several times as many fat cells as they did before they became obese. I don't believe that the release of leptin from fat cells is completely linear; I believe it starts to be secreted above a certain threshold of triglyceride content in the adipocyte. Therefore, if you are back at a healthy weight but you have 2-3x as many fat cells, even though you have as much bodyfat total as before, the hypothalamus is receiving a disproportionately low amount of leptin and thinks that you are starving. It is my belief that this is why it's so easy to experience a relapse toward greater bodyfat once fat is lost.

The real question is how to promote adipocyte apoptosis/deletion once the fat is lost. I've seen evidence that the sex hormones inhibit differentiation and may promote deletion, but they themselves are inhibited in this model as the hypothalamus shuts down GnRH secretion. The same thing happens when, for example, a female athlete drops too low in body fat % and becomes amenorrheic as a result. I'm hopeful that the previously obese can simply "wait it out" by utilizing VLC or whatever means are necessary in order to keep fat mass down while the additional adipocytes go through their life cycle and eventually die. I don't know for sure if this is what actually happens or how long it would take. I think the solution to obesity relapse lies in finding a naturally-occurring adipocyte deletion promoter or waiting it out.

I therefore think the condescending advice myself and others have been giving to the formerly obese with regard to the innocuous nature of carbohydrates should cease. While I don't think they're "metabolically damaged," they clearly have a challenge in coping with tens of billions of additional adipocytes. If VLC keeps them weight stable and they feel fine, so be it. Hopefully there would come a time down the road where they'd be back at their original number of adipocytes and can eat a mixed diet with ease.

Medium avatar

(39831)

on September 15, 2011
at 10:35 PM

I've also seen high-calcium diets linked to it, but calcifying other tissues could be really dangerous.

Medium avatar

(39831)

on September 15, 2011
at 10:32 PM

Yeah, I've seen CLA coupled with ajoene (from garlic) linked to apoptosis of mature adipocytes, but I don't really know how safe that is.

Cfc7dee889a66db9cd76c4f348109294

(1652)

on September 15, 2011
at 10:29 PM

yes, this may go back to another poster's comment about how we love studies that tell us what we want to hear ;-) http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05845.x/full

77877f762c40637911396daa19b53094

(78467)

on September 15, 2011
at 10:25 PM

Haha smartcookie, apparently I am trying to kill mine off with red wine.

77877f762c40637911396daa19b53094

(78467)

on September 15, 2011
at 10:22 PM

I'd love to know the life expectancy of my billions of additional adipocytes!

Cfc7dee889a66db9cd76c4f348109294

(1652)

on September 15, 2011
at 10:20 PM

i read some preliminary studies linking resveratrol with adipocyte apoptosis.

100fd85230060e754fc13394eee6d6f1

(18696)

on September 15, 2011
at 10:06 PM

I think you are right about leptin being a signaler more than a regulator. Also I think it shows extremely noble character to change your mind publicly based on learning.

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3b02df41cc7b9daa386e81e3c82f5fc2

on September 16, 2011
at 04:46 PM

There's an old wives' tale that if you can keep the weight you've lost off for a year, then it's likely to stay off. I had originally thought that this was because the changes in behavior would be habit by that time, but habits are usually made or broke in ~three weeks. Perhaps there's some wisdom in old wives that it takes about that long for all the extra fat cells to die off and put a person back to their normal amount. They saw the results, but didn't know why. Makes a lot of sense to me.

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