The Mediterranean Zone (23 page)

Control of hunger is a consequence of the dynamic balance of these and other hormones in the blood, gut, and brain. Making it even more difficult to lose weight and keep it off is the fact that the body goes to great efforts to defend the loss of excess body fat. For example, when you lose weight by dieting, the levels of the hunger hormone ghrelin increase and the levels of the satiety hormone PYY decrease. This makes trying to cut back on calories by simply using willpower to try to eat less such a difficult process.

The last major hormonal players in the brain that can override this intricate balance of external endocrine hormones on the satiety and hunger neurons are the endocannabinoids. Anyone who has had the experience of smoking marijuana knows one of its most immediate side effects is increased hunger (“the munchies”); the active ingredient in marijuana (tetrahydrocannabinol, or THC) interacts with these endocannabinoid receptors in the brain that make you incredibly hungry. These hunger-inducing hormones interact in a different part of the hypothalamus to regulate appetite. Since the natural endocannabinoids in your brain are derived from AA, the more AA you produce by your diet, the hungrier you become. One of the most important benefits of the Mediterranean Zone is that you are not as hungry. Why? You are reducing the production of endocannabinoids by reducing the formation of AA. This is why the Mediterranean Zone places a strong emphasis in keeping omega-6 fatty acids as low as possible as well as reducing the glycemic load of the diet. Those two factors will reduce excess levels of AA in the body and the brain.

Another way to reduce elevated endocannabinoid levels is to also make sure that you are consuming adequate levels of omega-3 fatty acids (either by eating a lot of fish or taking purified omega-3 fatty acid supplements) to reduce the formation of endocannabinoids.

One final factor that can disrupt satiety signals is simply consuming too many calories at any one meal, which causes metabolic inflammation in the hypothalamus. This is why I prefer the maximum calories at a meal to be 400 or less. All of the Mediterranean Zone meals presented earlier in this book contain less than 400 calories, yet supply adequate protein, carbohydrate, fat, vitamins, and minerals, and, most importantly, satiety.

Besides disrupting the hormonal communication that turns off satiety signals, increased production of AA also induces the development of new
fat cells. This is known as adipogenesis. It has clearly been shown in animal models in which diets rich in omega-6 fatty acids and poor in omega-3 fatty acids are maintained for several generations. Each generation of the offspring becomes fatter than the previous even though the calorie intake remains constant. Epigenetic fetal programming may be the mechanism by which these events are generated. The same trend appears to be happening to Americans.

There’s no question that keeping weight from coming back after it has been lost is very difficult. Hormones in the gut are now working against you after weight loss. The appearance of appetizing food also excites the reward centers in the brain to a greater extent as a consequence of weight loss. You become hungrier and more preoccupied with food after losing weight. And your body becomes more efficient in converting dietary calories into energy, meaning you have to eat even less food to avoid regaining weight. Invariably, much of the lost weight is regained because of these biological mechanisms that defend against weight loss. Maybe this explains why the data on long-term weight control is so sparse, because people hate to admit to defeat. One source of data is the National Weight Control Registry, which is a self-selected group of individuals who have been successful in losing at least thirty pounds and keeping it off for more than a year. It appears that the use of a combination of long-term calorie restriction (less than 1,400 calories per day) coupled with an hour of exercise per day is probably needed for weight loss maintenance success. Since the National Weight Control Registry consists of only about ten thousand individuals since 1994, this might suggest that most people who lose weight have significant difficulty in keeping it off.

Currently the best way for losing weight and keeping it off is gastric bypass surgery. The most radical type of bypass surgery is known as Roux-en-Y, in which much of the small intestine is bypassed. As a result, the dietary components of your meal directly enter the ileum (the lower part of the small intestine), where the greatest concentrations of L-cells are located. The L-cells of the gut lining contain receptors for glucose and protein. If these receptors are activated, then hormonal signals to stop eating are sent directly to the brain via the vagal nerve. This is why if the carbohydrates (especially high-glycemic ones) and protein you are eating are quickly absorbed in the upper part of the intestine, there are less of these nutrients available to the L-cells in the lower part of the intestine.
Therefore, the body is less likely to release the necessary hormonal “stop-eating” signals to the brain. As a result, you are constantly hungry. On the other hand, with the gastric re-routing by bypass surgery, more of the ingested food is being delivered to the lower part of the intestine. In particular, the levels of PYY and GLP-1 are increased and levels of ghrelin are decreased. Gastric-bypass patients get immediate freedom from hunger on the first day. That’s why they can maintain long-term weight loss.

The Mediterranean Zone provides an effective and risk-free option for the holy grail of long-term weight control. You are consuming about 1,200 to 1,500 calories per day but without hunger. This is within the range of calorie consumption needed for long-term weight maintenance as indicated by the National Weight Control Registry. It does this by providing a significant increase in satiety using a variety of hormonal signaling strategies (using the balance of its food ingredients) to reduce cellular inflammation, as opposed to resorting to surgery and a lifetime of malnutrition.

U
nder ideal conditions, the inflammatory response should be self-limiting, turning on only when it is needed and then turning itself off to return the body to homeostasis. This means the initiation phase of inflammation is balanced by the resolution phase of inflammation. Unfortunately, the real world never works so smoothly. When the balance of these two distinct phases of the inflammation is disrupted, the result is often a constant low-level cellular inflammation that accelerates the development of chronic disease conditions.

If the resolution process is not satisfactorily completed, the body builds scar tissue around the injured site to prevent any further access by the neutrophils and macrophages. This is called fibrosis, which will stop the continuing oxidative stress, but damages that localized area of the organ. When this happens consistently because your internal resolution response is too weak, you will eventually develop loss of organ function. This is the last expression of the classical cardinal signs of inflammation (heat, swelling, pain, redness, and loss of function). The first four occur quickly; the last (loss of function) takes time to develop.

Elevated cellular inflammation can also disturb the integral hormonal signaling pathways that control our metabolism. The most well known
example of hormone resistance is insulin resistance, the poster child for the disruption of your biological Internet by cellular inflammation.

Insulin resistance simply means that the metabolic signal of insulin to do something is not being correctly transmitted to its target inside the cell. Since a primary role of insulin is to reduce potentially toxic levels of glucose and fats in the blood in the presence of insulin resistance, the pancreas responds by secreting more insulin to try to reduce the levels of glucose and lipids in the blood by brute force. This results in hyperinsulinemia. What caused insulin resistance was a black box to researchers until the 1990s, when it was discovered that inflammatory cytokines (especially tumor necrosis factor, or TNF) seemed to be at the center of this disturbance. TNF is one of the inflammatory cytokines that is expressed once NF-κB is activated so it is reasonable to believe that insulin resistance may be a consequence of excess cellular inflammation. Not surprisingly, when you follow an anti-inflammatory diet such as the Mediterranean Zone, insulin resistance is reduced, which means that lower levels of insulin can do its job more effectively, and the hyperinsulinemia in the blood is reduced. That’s why it is not surprising that the dietary guidelines of the Joslin Diabetes Research Center at Harvard Medical School for treating obesity, metabolic syndrome (pre-diabetes characterized by hyperinsulinemia), and diabetes are essentially that of the Zone Diet. The Mediterranean Zone simply takes those dietary recommendations to a much higher level of inflammatory control.

We often think of insulin resistance as being associated only with impaired insulin action in the liver and the muscles, but it really starts with the adipose tissue. In particular, the hormone-sensitive lipase, found in the fat cells, may be the first victim of insulin resistance. This enzyme controls the release of stored fats back into the bloodstream to be used as an energy source when insulin levels are low (such as when you are sleeping). With the development of insulin resistance, the stop signal of this enzyme, which is mediated by higher levels of insulin in the blood, becomes partially inhibited and fatty acids are now continuously released. Some of the
fatty acids will be reabsorbed by the fat cells to be resynthesized into triglycerides, but the rest will now travel to other organs such as the liver and muscle cells. If those fatty acids are rich in AA, then they become delivery agents for spreading cellular inflammation to these organs. As insulin resistance spreads to these organs, they, too, become resistant to insulin’s action, requiring the pancreas to secrete ever-increasing levels of insulin to bring down potentially toxic levels of fats and glucose in the bloodstream. This explains why the levels of AA in the fat cells have a striking correlation with the increased likelihood of developing metabolic syndrome. The spread of stored AA because of insulin resistance in the fat cells simply speeds up the metastatic flow of cellular inflammation into other organs.

The extreme case of insulin resistance occurs in a condition known as lipodystrophy in which the fat cells are destroyed. Now the circulating fat in the blood has nowhere to be safely stored, and rapidly ends up in the liver and the muscles, causing significant insulin resistance. Lipodystrophy was a rare disease before the advent of AIDS. Unfortunately, the drugs that inhibit viral replication of the HIV virus also destroy fat cells. The result is a reprieve from an earlier death from AIDS, but a dramatic increase in insulin resistance eventually leading to diabetes and heart disease.

Insulin resistance doesn’t always start out in the fat cells. There is some evidence from animal studies that ketogenic diets may force the circulating fat into liver cells instead of being safely stored in fat cells because insulin levels are lowered too much.

Eventually, as insulin resistance increases, there is a corresponding increase in hyperinsulinemia that puts you in metabolic trouble. The hyperinsulinemia accelerates the deposition of circulating fat into your adipose tissue, decreasing the amount available to go to other tissues for conversion into energy. The result is that you become hungry and fatigued. In addition you accelerate the formation of AA by activating the key enzymes required to produce AA from omega-6 fatty acids, which increases cellular inflammation in every cell in your body.

As you develop insulin resistance in the liver and muscle, you are also beginning to develop insulin and leptin resistance in the hypothalamus. As a consequence, both insulin and leptin (which act as satiety signals) are not recognized and hunger increases. As you eat more calories to try to satisfy your hunger, you gain more body fat due to increasing
hyperinsulinemia. In addition, the excess calories also cause increased inflammation in the hypothalamus, which further increases hunger by interfering with incoming satiety signals.

If left untreated, metabolic syndrome eventually becomes type 2 diabetes. This usually occurs within ten to twenty years after the initial diagnosis. The insulin producing beta cells of the pancreas simply become exhausted by the continued demand to make more insulin to control the ever-increasing levels of blood glucose. It appears part of this exhaustion is due to the infiltration of macrophages that attack the beta cells. As the pancreas becomes less able to produce insulin, the blood glucose levels begin to skyrocket, increasing the levels of oxidative stress throughout the body. Oxidative stress activates NF-κB, and cellular inflammation increases correspondingly. With the development of diabetes comes a host of other inflammation-related diseases, such as heart disease, Alzheimer’s, ocular disorders, kidney failure, neuropathy, and impaired wound healing (which can lead to infection, gangrene, and eventually amputation). Not a very pleasant picture.

One of the first consequences of insulin resistance in the liver cells is the disruption of lipoprotein metabolism. Small dense LDL particles (which are highly prone to becoming oxidized LDL particles) begin to accumulate, HDL particles begin to decrease, and triglycerides (TG) levels begin to rise. This is why the TG/HDL cholesterol ratio is a sensitive indicator of developing insulin resistance in the liver that results in a fatty liver. The development of non-alcoholic steatohepatitis (NASH) is usually the first step in this fatty liver disease. Left untreated, this can eventually progress to cirrhosis (caused by increasing scar damage due to the unresolved inflammation) and eventually liver failure if organ function is totally compromised by fibrosis.

The small dense LDL particles produced by an inflamed liver are more prone to oxidation because of their size. They are also more likely to begin to accumulate in the heart cells, generating atherosclerotic lesions. Oxidized LDL particles can readily circumvent the normal uptake mechanism of non-oxidized LDL particles that is self-regulating as the cell senses it has adequate levels of cholesterol and shuts down any further uptake of normal LDL particles. On the other hand, the oxidized LDL particles are rapidly taken up by macrophages in the atherosclerotic lesion in the form of the classic lipid-laden foam cells, which are more prone to rupture. This
helps explain why heart disease is highly correlated with metabolic syndrome and why elevated levels of AA in the adipose tissue are also correlated with increasing heart disease.