Obesity and the Brain

Nature Genetics just published a paper that caught my interest (1). Investigators reviewed the studies that have attempted to determine associations between genetic variants and common obesity (as judged by body mass index or BMI). In other words, they looked for "genes" that are suspected to make people fat.

There are a number of gene variants that associate with an increased or decreased risk of obesity. These fall into two categories: rare single-gene mutations that cause dramatic obesity, and common variants that are estimated to have a very small impact on body fatness. The former category cannot account for common obesity because it is far too rare, and the latter probably cannot account for it either because it has too little impact*. Genetics can't explain the fact that there were half as many obese people in the US 40 years ago. Here's a wise quote from the obesity researcher Dr. David L. Katz, quoted from an interview about the study (2):

Let us by all means study our genes, and their associations with our various shapes and sizes... But let's not let it distract us from the fact that our genes have not changed to account for the modern advent of epidemic obesity -- our environments and lifestyles have.

Exactly. So I don't usually pay much attention to "obesity genes", although I do think genetics contributes to how a body reacts to an unnatural diet/lifestyle. However, the first part of his statement is important too. Studying these types of associations can give us insights into the biological mechanisms of obesity when we ask the question "what do these genes do?" The processes these genes participate in should be the same processes that are most important in regulating fat mass.

So, what do the genes do? Of those that have a known function, nearly all of them act in the brain, and most act in known body fat regulation circuits in the hypothalamus (a brain region). The brain is the master regulator of body fat mass. It's also the master regulator of nearly all large-scale homeostatic systems in the body, including the endocrine (hormone) system. Now you know why I study the neurobiology of obesity.


* The authors estimated that "together, the 32 confirmed BMI loci explained 1.45% of the inter-individual variation in BMI." In other words, even if you were unlucky enough to inherit the 'fat' version of all 32 genes, which is exceedingly unlikely, you would only have a slightly higher risk of obesity than the general population.

Vacation

I'll be out of town until the beginning of November, so I won't be responding to comments or e-mails for a while. I'm going to set up a post or two to publish while I'm gone.

As an administrative note, I get a number of e-mails from blog readers each day. I apologize that I can't respond to all of them, as it would require more time than I currently have to spare. The more concise your message, the more likely I'll read it and respond. Thanks for your understanding.

Sleep Post Correction

An astute commenter pointed out that I misread the numbers in the paper on sleep and fat loss. I wrote that out of the total 3.0 kg lost, the high-sleep group lost 2.4 kg as fat, and the low-sleep group lost 1.4 kg of fat out of 2.9 kg total.

In fact, the high-sleep group lost 1.4 out of 2.9 kg as fat, and the low-sleep group lost 0.6 out of 3.0 kg as fat. So I got the numbers all mixed up. Sorry for the mistake. The main point of the post still stands though: sleep deprivation negatively influences body composition.

The correct numbers are even more interesting than the ones I made up. Even in the high-sleep group, nearly half the body weight lost by simple calorie restriction was lean mass. That doesn't make calorie restriction look very good!

In the sleep-deprived group, 80% of the weight lost by calorie restriction came out of lean mass. Ouch!

That illustrates one of the reasons why I'm skeptical of simple calorie restriction as a means of fat loss. When the body "wants" to be fat, it will sacrifice lean mass to preserve fat tissue. For example, the genetically obese Zucker rat cannot be starved thin. If you try to put it on a severe calorie-restricted diet, it will literally die fat because it will cannibalize its own lean mass (muscle, heart, brain, etc.) to spare the fat. That's an extreme example, but it illustrates the point.

The key is not only to balance energy intake with expenditure (which the brain does automatically when it's working correctly), but to allocate energy appropriately to lean and fat mass.

The Big Sleep

This blog usually focuses on diet, because that's my specialty. But if you want Whole Health, you need the whole package: a diet and lifestyle that is broadly consistent with our evolutionary heritage. I think we all know that on some level, but a recent paper has reminded me of it.

I somehow managed to get on the press list of the Annals of Internal Medicine. That means they send me embargoed papers before they're released to the general public. That journal publishes a lot of high-impact diet studies, so it's a great privilege for me. I get to write about the studies, and publish my analysis at the time of general release, which is the same time the news outlets publish their stories.

One of the papers they sent me recently is a fat loss trial with an interesting twist (1; see below). All participants were told to eat 10% fewer calories that usual for two weeks, however half of them were instructed to sleep for 8 and a half hours per night, and the other half were instructed to sleep for 5 and a half hours*. The actual recorded sleep times were 7:25 and 5:14, respectively.

Weight loss by calorie restriction causes a reduction of both fat and lean mass, which is what the investigators observed. Both groups lost the same amount of weight. However, 80% of the weight was lost as fat in the high-sleep group (2.4/3.0 kg lost as fat), while only 48% of it was lost as fat in the low-sleep group (1.4/2.9 kg lost as fat). Basically, the sleep-deprived group lost as much lean mass as they did fat mass, which is not good!

There are many observational studies showing associations between insufficient sleep, obesity and diabetes. However, I think studies like that are particularly vulnerable to confounding variables, so I've never known quite what to make of them. Furthermore, they often show that long sleep duration associates with poor health as well, which I find highly unlikely to reflect cause and effect. I discussed one of those studies in a post a couple of years ago (2). That's why I appreciate this controlled trial so much.

Another sleep restriction trial published in the Lancet in 1999 showed that restricting healthy young men to four hours of sleep per night caused them to temporarily develop glucose intolerance, or pre-diabetes (3).

Furthermore, their daily rhythm of the hormone cortisol became abnormal. Rather than the normal pattern of a peak in the morning and a dip in the evening, sleep deprivation blunted their morning cortisol level and enhanced it in the evening. Cortisol is a stress hormone, among other things, and its fluctuations may contribute to our ability to feel awake in the morning and ready for bed at night.

The term "adrenal fatigue", which refers to the aforementioned disturbance in cortisol rhythm, is characterized by general fatigue, difficulty waking up in the morning, and difficulty going to sleep at night. It's a term that's commonly used by alternative medical practitioners but not generally accepted by mainstream medicine, possibly because it's difficult to demonstrate and the symptoms are fairly general. Robb Wolf talks about it in his book The Paleo Solution.

The investigators concluded:

Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.

So there you have it. Besides making us miserable, lack of sleep appears to predispose to obesity and diabetes, and probably sets us up for the Big Sleep down the line. I can't say I'm surprised, given how awful I feel after even one night of six hour sleep. I feel best after 9 hours, and I probably average about 8.5. Does it cut into my free time? Sure. But it's worth it to me, because it allows me to enjoy my day much more.

Keep your room as dark as possible during sleep. It also helps to avoid bright light, particularly in the blue spectrum, before bed (4). "Soft white" bulbs are preferable to full spectrum in the evening. If you need to use your computer, dim the monitor and adjust it to favor warm over cool colors. For people who sleep poorly due to anxiety, meditation before bed can be highly effective. I posted a tutorial here.

1. Nedeltcheva, AV et al. "Insufficient Sleep Undermines Dietary Efforts to Reduce Adiposity." Annals of Internal Medicine. 2010. Advanced publication.


* The study was a randomized crossover design with a 3 month washout period, which I consider a rigorous design. I think the study overall was very clever. The investigators used calorie restriction to cause rapid changes in body composition so that they could see differences on a reasonable timescale, rather than trying to deprive people of sleep for months and look for more gradual body fat changes without dietary changes. The latter experiment would have been more interesting, but potentially impractical and unethical.