March 10, 2007
High Fat Diet Makes Mice Leptin Insensitive And Obese

Researchers at the Oregon National Primate Research Center at the Oregon Health & Science University have found that in mice on high fat diets their brain region called the arcuate nucleus changes to make the brain insensitive to leptin. Leptin is secreted by fat cells and normally signals the brain to have a lower appetite for food.

The research was conducted in mice and involved two separate groups that were fed high-fat and low-fat diets. Over time, the high-fat diet group developed symptoms of diabetes and obesity, as is often the case in humans. The low-fat diet group did not develop these health problems.

"This research demonstrates how a portion of the hypothalamus of the brain, called the arcuate nucleus, is negatively impacted by an overabundance of leptin," explained Michael Cowley, Ph.D., an associate scientist in the Division of Neuroscience at ONPRC. "By developing a special test of neuronal function, we were able to witness the breakdown in this group of specialized cells. Eventually the cells behaved as if there was no leptin present, even though levels were 40-times higher than in normal animals. We were also able to witness the eventual repair of this important system which occurs as the mice lost weight when returned to a low fat diet."

More specifically, the scientists determined that leptin resistance prevented the arcuate nucleus from taking part in an important signaling function that regulates appetite and body weight. Meanwhile, other portions of the weight regulation system remained intact and in fact became more responsive, thereby suggesting that arcuate nucleus function is the point of breakdown during leptin deficiency.

Finally the research highlighted a key gene called SOCS-3 involved in leptin deficiency. By targeting the gene with therapeutics, scientists may be able to repair leptin deficiency, aiding in weight loss.

What I'd like to know: Does a high fat diet also shrink the arcuate nucleus in humans? Also, do all types of fats equally shrink the arcuate nucleus

If leptin resistance in the arcuate nucleus is the major cause of human obesity then it will become a major target for drug development. We now need to know the chain of events in the neurons that cause them to become insensitive to signals of excess weight in one's body.

Update: A recent comparison of 4 diets (including the low fat Ornish diet) found the high protein Atkins diet worked best to keep off weight.

Premenopausal women who were assigned to follow the Atkins diet for one year lost more weight when compared to women who were assigned to follow the Zone, Ornish and LEARN diets, according to a study in the March 7 issue of JAMA.

Overweight and obesity are well-documented problems in the United States. National dietary weight loss guidelines (a diet low in calories and fat, high in carbohydrates) have been challenged, particularly by supporters of low-carbohydrate diets. However, limited evidence has been available to effectively evaluate other diets, according to background information in the article.

Christopher D. Gardner, Ph.D., of Stanford University Medical School, Stanford, Calif., and colleagues examined the effects of four diets-3 popular and substantially different diets and 1 diet based on national guidelines-representing a spectrum of carbohydrate intake, on weight loss and related metabolic variables in overweight and obese premenopausal women. The diets were Atkins (very low in carbohydrate), Zone (low in carbohydrate), LEARN (Lifestyle, Exercise, Attitudes, Relationships, and Nutrition; low in fat, high in carbohydrate, based on national guidelines), and Ornish (high in carbohydrate). The study, which included 311 overweight/obese (body mass index, 27-40) nondiabetic, premenopausal women, was conducted from February 2003 to October 2005. Participants were randomly assigned to follow for 12 months the Atkins (n = 77), Zone (n = 79), LEARN (n = 79), or Ornish (n = 76) diets and received weekly instruction for 2 months, then an additional 10-month follow-up.

The high protein Atkins and low carbo Zone diets both beat the low fat and high carbo Ornish diet in weight loss. Note this does not tell us how long people will live on average under each diet.

The researchers found that weight loss was greater for women in the Atkins diet group compared with the other diet groups at one year. Average 12-month weight loss was 10.4 lbs for Atkins, 3.5 lbs. for Zone, 5.7 lbs. for LEARN, and 4.8 lbs. for Ornish. At 12 months, measurements for lipids and levels of insulin, glucose and blood pressure for the Atkins group were comparable with or more favorable than the other diet groups.

Dean Ornish's diet is modelled on Nathan Pritikin's low fat diet and the Ornish diet is 10% fat, 20% protein, and 70% carbohydrate. So the Ornish diet is a low fat diet. Therefore these results do not provide evidence that a low fat diet will reduce appetite and promote weight loss by making human brains more sensitive to leptin.

What I'd like to see: Compare diets based on what they do to blood levels of leptin, ghrelin, and other hormones the body makes to regulate weight and appetite. Does the Ornish diet make the brain more sensitive to leptin while also decreasing the amount of leptin in the blood? That might explain why the Atkins diet works better. Maybe the Atkins diet keeps leptin higher than does the Ornish diet.

Also, the Ornish diet's use of carbohydrate as the major calorie source is problematic in one respect: Different carbohydrates vary greatly in how rapidly they get broken down and absorbed. Lower glycemic index foods might work far better than higher glycemic index foods to promote weight loss.

Share |      Randall Parker, 2007 March 10 01:09 PM  Brain Appetite

rsilvetz said at March 10, 2007 1:39 PM:

And remembering that carbohydrates, protein and insulin/glucagon levels all modulate the system in which leptin works, that perhaps the conclusion of the article should be taken with a grain of salt too.

Mthson said at March 10, 2007 1:43 PM:

The article attributes the leptin insensitivity to the obesity, not the fat content in the diet. I wonder if some of the health problems associated with high fat intake derive from the correlated obesity, rather than from the fat intake itself.

rsilvetz said at March 10, 2007 10:59 PM:

My previous comment now redundant as of Randall's update of the article....

Doug said at March 11, 2007 8:26 PM:

So few researchers seem to have thought of the importance of trying to learn and take into account what our ancestors ate before the rise of agriculture. For that, you have to turn to Loren Cordain, as far as I know. I'm sure these comparative studies have their place, but one has to use anthropological and paleo-anthropological investigation and reasoning in order to narrow down the possibilities; otherwise, the number of factors to be controlled and the number of variations to be tested are too large.

Doug said at March 11, 2007 8:29 PM:

Having remembered that this was a study of mice, I'll just add that the dietary requirements of a creature with such a small brain seem to be of doubtful value as a guide for us.

atkins diet said at May 6, 2007 9:07 PM:

Atkins "Nightmare" Diet

When Dr. Atkins Diet Revolution was first published, the President of the American College of Nutrition said, "Of all the bizarre diets that have been proposed in the last 50 years, this is the most dangerous to the public if followed for any length of time."[1]

When the chief health officer for the State of Maryland,[2] was asked "What's wrong with the Atkins Diet?" He replied "What's wrong with... taking an overdose of sleeping pills? You are placing your body in jeopardy." He continued "Although you can lose weight on these nutritionally unsound diets, you do so at the risk of your health and even your life."[3]

The Chair of Harvard's nutrition department went on record before a 1973 U.S. Senate Select Committee investigating fad diets: "The Atkins Diet is nonsense... Any book that recommends unlimited amounts of meat, butter, and eggs, as this one does, in my opinion is dangerous. The author who makes the suggestion is guilty of malpractice."[4]

The Chair of the American Medical Association's Council on Food and Nutrition testified before the Senate Subcommittee as to why the AMA felt they had to formally publish an official condemnation of the Atkins Diet: "A careful scientific appraisal was carried out by several council and staff members, aided by outside consultants. It became apparent that the [Atkins] diet as recommended poses a serious threat to health."[5]

The warnings from medical authorities continue to this day. "People need to wake up to the reality," former U.S. Surgeon General C. Everett Koop writes, that the Atkins Diet is "unhealthy and can be dangerous."[6]

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