Feast, famine and the genetics of obesity: You can't have it both ways

December 15, 2010

In addition to fast food, desk jobs, and inertia, there is one more thing to blame for unwanted pounds-our genome, which has apparently not caught up with the fact that we no longer live in the Stone Age.

That is one conclusion drawn by researchers at the Salk Institute for Biological Studies, who recently showed that mice lacking a gene regulating are protected from weight gain, even on a high fat diet. These findings have implications for the worldwide obesity epidemic and its consequences, such as type two diabetes.

In the December 16, 2010 issue of Nature, a team led by Marc Montminy, M.D., Ph.D, professor in the Clayton Foundation Laboratories for Peptide Biology, reports that a gene known as CRTC3 decreases by . "Ideas about obesity are based on concepts of feast or famine," said Montminy. "As humans, we developed ways of coping with famine by expressing genes like CRTC3 to slow the rate of fat burning. Individuals with these active "thrifty genes" had an advantage-they could survive long periods without food."

The idea that mammals harbor genes that slow fat burning was proposed in the 60's, before any was sequenced. Some theorized that such thrifty genes provided a survival advantage to our hunter-gatherer ancestors, who often went a long time between meals and needed to hold on to their fat depots. In 2010, however, those genes have become a liability.

To analyze its role in fat metabolism, the researchers engineered mice lacking the CRTC3 gene and put them on diets of varying fat composition. Normal and CRTC3 gene "knockout" mice appeared similar when fed a moderate fat diet. But when fed the mouse version of the Philly cheese steak diet, only the normal mice became obese. "The CRTC3 knockout mice were leaner and protected from obesity," reports Montminy. "They also had about twice as many brown fat cells than did normal mice."

To appreciate this finding, keep in mind that not all fat cells are "bad". When you deplore your waistline, what you are deploring is white fat tissue (also called WAT, for "white adipose tissue"), which serves as a fat storage depot around the midsection and hips. However, a second type of fat-known as brown fat (BAT)-is downright desirable.

"Brown fat is very different from white fat," says Youngsup Song, Ph.D., a postdoctoral fellow in the Montminy lab and the study's first author. "Brown fat tissue burns fat that has accumulated in white fat tissue to generate heat as a way to maintain body temperature."

In fact, some evidence suggests that humans with a genetic propensity to leanness have more brown fat cells than do "ample" individuals. As desirable as that trait may seem in a "super-size me" world, those folks likely had a pretty tough time in the Paleolithic era.

Although the researchers found that CRTC3 loss also perturbs how all fat cells respond to brain signals controlling energy expenditure, they remain particularly intrigued by the brown fat connection. "CRTC3 could be a switch controlling the number of brown fat cells, " says Montminy. "That is key, because if you could make more brown adipocytes, you could potentially control obesity."

To explore how relevant these studies are to humans, Montminy asked clinicians at Cedars-Sinai Medical Center in Los Angeles to search databases of patient genetic information for a particularly interesting human CRTC3 gene mutation, which appeared to represent a more potent form of the normal gene.

Since mice lacking CRTC3 resist obesity, the researchers reasoned that people carrying a revved-up version of the gene might show the opposite tendency. Indeed genetic testing of two groups of Mexican American patients revealed that individuals harboring the active CRTC3 mutation showed increased incidence of obesity.

"This is an example in which findings from rodent research led to a novel discovery in humans," says Mark Goodarzi, M.D., Ph.D., an endocrinologist at Cedars-Sinai and collaborator in the study. "Not all Mexican American individuals with the variant will develop obesity, but those carrying it are at higher risk." Interestingly, non-Hispanic Caucasians carrying the variant do not show increased obesity, a difference likely related to environmental or lifestyle factors.

Overall this study illustrates an important principle: that what is genetically advantageous in one cultural or historic context may not be in another. In fact, Montminy does not view obesity as an aberration or a "disease". "Storing in adipose tissue is a normal response. A lot people are obese but do not develop type 2 diabetes," he says, suggesting that genes like CRTC3 could serve as diagnostic tools as well as drug targets. "A goal is to go to your doc and learn whether you have the risk factors to progress to diabetes."

Explore further: Fat chance: Brown vs. white fat cell specification

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5 / 5 (1) Dec 15, 2010
In fact, some evidence suggests that humans with a genetic propensity to leanness have more brown fat cells than do "ample" individuals.

Dang, but I hate politically correct speech. The word is Fat, or Obese, or, for middle aged men, Portly, Rotund or Corpulent (size dependent). Ample, indeed.
5 / 5 (1) Dec 15, 2010
I like ample. It implies sufficiency to the job.

The next diet craze: brown fat enablers. Trust me.
not rated yet Dec 15, 2010
Why does the article repeatedly imply that dietary fat intake leads to fat gain in humans? When will this 1970s myth die? It's the carbohydrates, specifically from grain, that have caused the obesity epidemic.

Instead of wringing their fat hands and blaming their genes, fat people need to just stop eating grain and lose all of the fat they want.
not rated yet Dec 16, 2010
@ Ratfish do you mean "Refined Grains"?
not rated yet Dec 16, 2010
That's right world. Instead of not eating so much and spreading those extra food reserves to starving people we are going to change our genetics so we can still eat it all, but not become portly.
not rated yet Dec 16, 2010
I know this isn't new stuff. I remember seeing a discovery doc. on it. Interesting, but definitely not new.
not rated yet Dec 19, 2010
As a fat person who has lost the equivalent weight of two toddlers by cutting out grains, I agree with the sentiment that obese individuals need to take responsibility for our own health. However, understanding my genetic pre-disposition to obesity made a huge difference for me and removed some of the guilt associated with being fat.

Look, I'm not saying that I became fat eating carrots and jogging marathons. But, understanding the genetic component makes it less of a "character" issue and more of a "health issue." No one would blame someone with a predisposition to heart disease for having a heart attack or call them lazy and weak-willed -- even if their habits contributed to the heart attack. Once a person learns about their risk factors -- whether it's heart disease or obesity -- they are expected to make responsible dietary and lifestyle choices to protect their health.

Hold people accountable, but use science to learn which tools will be most effective for each individual.
not rated yet Dec 19, 2010
@ Ratfish do you mean "Refined Grains"?

No, I mean ALL grains. The sooner people liberate themselves from grain, the slimmer they'll be and the healthier in general they will become. There's no reason for me to ever deviate from my 28" waist so long as I never eat grain again. Seriously, try it.

The difference in genetics with regard to obesity is carbohydrate tolerance. There are a few among us who can eat carbohydrates and not get the resulting blood glucose/insulin spikes that cause more hunger and lead to weight gain. They are genetic freaks and should not be emulated. The rest of us must cut out grain.

Meat/eggs, vegetables, a piece of fruit and maybe some cheese for every meal. The level of satiety will surprise you.

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