Eat Fat to Lose Fat

Many aspects of the low-carb lifestyle are surprising. For example, the successful low-carber soon learns that he or she must eat fat to lose fat. Why would that be?

A possible explanation comes from a couple of studies published last summer in Cell Metabolism, one by Inagaki et al and one by Badman et al. For those who are interested in the specifics, see the PDFs here and here. These studies were performed in mice but were quite exhaustive and appear to have application to humans as well.

The requirement for eating fat to lose fat begins with a cellular receptor called peroxisome proliferator-activated receptor-alpha or PPAR-alpha for short. PPAR-alpha is a protein found inside liver cells. When dietary fat diffuses into the liver cell as fatty acids, the fatty acids are able to bind to PPAR-alpha and activate it. Activated PPAR-alpha then binds to another protein called the retinoid X receptor or RXR, and these dimerized proteins in turn are able to bind to the cell's DNA. In so doing, they enhance the production of a third protein--fibroblast growth factor-21 or FGF-21.

FGF-21 is secreted by the liver and produces several effects. In white adipose tissue, it stimulates lipid breakdown. The breakdown of stored lipids allows them to be used as fuel. In the liver, FGF-21 upregulates ketone body production. Ketone bodies provide another source of fuel. The two studies showed that production of FGF-21 was greatly enhanced when the mice were fed a low-carb/high-fat (ketogenic) diet. When few carbohydrates are provided in the diet, but the diet does contain fat, mice are able to switch to an efficient mode that allows them to consume stored fat for energy. Mice are not people, and the usual admonition applies--more research is required. But the observation that a ketogenic (low-carb/high-fat) diet allows mice to produce lots of FGF-21, mobilize fat stores and upregulate ketone production suggests an explanation for what low-carbers know by experience--you have to eat fat to lose fat.

Calories Count

One of the great things about low-carbing is that (at the beginning anyway) low-carbers don't need to count calories.

Low-carbers do have to learn what a normal portion size is--a portion of macadamia nuts is 1/4 cup, not half a bag. A portion of cucumbers is 1/2 cup, not a whole cucumber. Low-carbers also need to learn that it's okay to subtract fiber carbs from their carbohydrate count. Once that's accomplished, it becomes a simple matter to look up various foods, figure out the carb content and add up the number of carbs consumed in a day. The target number is normally in the double digits, which is a fairly easy calculation for those of us who are arithmetically challenged.

Since low-carbers count grams of carbohydrate, does that mean that for low-carbers calories don't count? No. Calories do count.

Typically in a low-calorie versus a low-carb scientific study, the low-calorie group is given a target number of daily calories while the low-carb group is given a target number of daily carbs. When the results are tabulated, the net caloric intake will be compared between the two groups. Rather surprisingly, the two groups will have ingested almost the same number of calories. Examples are the recent study published in the New England Journal of Medicine and the A to Z Weight Loss Study published last year in JAMA. See Table 2 in each link for comparisons of daily energy intake from group to group.

Why do low-carbers unconsciously limit calories when they count carbs? One reason is the action of the signaling hormone leptin, discussed in the previous two posts. As low-carbers become more sensitive to the signals provided by leptin, they have an improved ability to perceive satiety. Their brains detect the leptin released by their fat stores and turn off the hunger signal at a caloric level that will allow them to use some of their fat stores for energy. The study group that eats a low-calorie diet without carbohydrate restriction will have a harder time getting the satiety signal. The participants in that group will have to turn off their eating at an intellectual level. When they have eaten the allowed number of calories, they have to consciously make themselves stop eating.

In comparison studies of weight loss, both the carb counters and the calorie counters end up eating approximately the same number of calories. Both groups lose weight in approximate proportion to their decrease in energy consumption. One of the considerations in choosing a weight-loss diet is the ease of complying with the diet. A controlled carbohydrate diet severely restricts the consumption of carbohydrate-containing foods but allows the dieter to eat to satiety. By contrast, a controlled calorie diet allows the dieter to eat balanced portions of whatever he or she wants, but requires the dieter to stop eating even if satiety has not been reached. As always, it's a tradeoff. The dieter decides which parameters are most important to him or her and chooses the diet that best fits those needs.

Leptin Resistance II

As described in the previous post, leptin is a hormone released by white adipose cells in the body. Leptin allows the brain to keep track of the body's fat stores. It also permits the brain to sense satiety in response to food intake. One of the ways to overcome triglyceride-induced leptin resistance is by following the low-carb lifestyle.

That's fine at the beginning of the weight-loss journey. But what happens to a low-carb dieter who is successful? What happens when a large percentage of the body's fat stores have disappeared?

In a formerly-fat person, leptin will still be released in response to insulin secretion. However, because there is less body fat to synthesize leptin, the consumption of food will cause less leptin to be released into the circulation. After a meal, the signal for satiety won't be as strong. If a person wishes to maintain a lower body weight, it will become important to maximize the response to the leptin that is released.

The illustration above shows leptin on the outside of a cell, bound to its receptor (the pincer-like structure that crosses the plasma membrane or cell wall). The leptin receptor transmits several signals into the cell, including signals for satiety and increased thermogenesis. Another signal that is sent causes the production of a protein called SOCS-3, a member of the family called Suppressors of Cytokine Signaling. SOCS-3 is a protein that shuts down the signaling of the leptin receptor. The pattern of a signal producing a response which then produces downregulation of the response is quite a typical one in the body. Including an automatic off switch on metabolic reactions keeps reactions under tight regulation and control.

In the case of leptin signaling, it is normal for the leptin response to be downregulated within a few hours. The SOCS-3 protein shuts off the satiety signal and allows the rate of metabolism to decrease. Within a short time, the SOCS-3 protein itself is degraded and the leptin diffuses away from its receptor. This in turn resets the leptin system, allowing it to be ready to respond in time for the next meal. The result is a cycle of eating, satiety, and the gradual return of hunger. Unfortunately for the person who has successfully lost weight, this system can also become leptin resistant.

Consider the case in which leptin is released continuously from the fat cells. One way this could happen is when frequent small meals are eaten. Each feeding will cause the release of insulin, which in turn will cause the release of leptin. The constant presence of leptin on its receptor will prevent the receptor from resetting itself. It will no longer be able to send adequate signals for satiety and increased thermogenesis. The result, inevitably, will be weight gain.

One way to counteract this type of leptin resistance is to allow five to six hours to pass between meals. This will allow the receptor to reset itself and to become sensitive to leptin the next time leptin is released. Even though less leptin is produced by the diminished fat stores, if meals are taken at 5-6 hour intervals, if meals are eaten slowly to allow the leptin signals sufficient time to reach the brain, and if a low-carbohydrate lifestyle is maintained, this will allow the available leptin to have a maximal effect in producing its desired effects of satiety and increased thermogenesis.

Leptin Resistance I

Leptin, pictured above, is a hormone produced by fat cells. When we eat a meal containing carbohydrate and/or protein, our pancreas releases insulin. Insulin, in turn, causes the body's fat cells to release leptin into the circulation.

The receptors for the hormone leptin are found in the brain, most abundantly in a structure called the arcuate nucleus of the hypothalamus. When leptin binds to its receptor, it sends several sets of signaling cascades into the brain. Since food has just been eaten, one set of signals acts to downregulate the appetite, while another set of signals tells the body to increase its metabolic rate to burn the calories that are now available. So far, so good.

But what if the leptin receptors in the arcuate nucleus fail to "see" the leptin that has been released by the fat cells? Leptin in the blood does not simply diffuse into the brain. It has to enter the brain through a specific transport system. In 2004 it was shown that high triglycerides in the blood will prevent leptin from being transported into the brain. In other words, a fat person can eat a meal, release plenty of leptin, and his brain will receive only a weak signal that it needs to downregulate appetite and upregulate metabolism. That person is leptin resistant. Because of the leptin resistance, his body will create a higher set point for appetite and a lower set point for metabolic rate than it would normally need.

Obviously this is not a good situation. If a person has leptin resistance, can it be circumvented? How can the resistant leptin receptors in the hypothalamus "see" the leptin that is being produced by the fat cells of the body?

Because excessive serum triglycerides are blocking the entrance of leptin into the brain, one possible solution would be to reduce serum triglycerides. As we have discussed in a previous post, numerous studies have shown that low-carbohydrate diets consisently and significantly reduce the level of triglycerides in the blood. (See Volek & Feinman, Table 4, percent change in TAG.) As triglyceride levels decline, leptin responsiveness increases. With this in mind, it is not surprising that people who eat a low-carb diet experience better control of their appetite and an increase in metabolic rate compared with those whose meals are higher in carbohydrates.

When people follow a low-carb lifestyle, the leptin they produce is able to reach their leptin receptors, to tell their brains that they are full and to upregulate their body's metabolism to utilize the food they have just eaten. Because they have lowered their serum triglycerides, their bodies will have a lower set point for appetite and a higher metabolic rate than they did when their brains were not "seeing" the leptin that their fat cells were producing.

If a low-carber decides to return to his or her former way of eating, triglycerides will rise and the set points for appetite and metabolism will restabilize at their previous values. Inevitably, any weight that was lost will eventually return. The regulation of leptin sensitivity helps explain why low-carb eating does not work very well as simply a short-term diet, but needs to be done over the long term as a lifestyle change.