The Obesity Code. Jason Fung

a key regulator of energy balance, and was also a vital clue that obesity is a hormonal imbalance.

      Neurons in these hypothalamic areas were somehow responsible for setting an ideal weight, the body set weight. Brain tumors, traumatic injuries and radiation in or to this critical area cause massive obesity that is often resistant to treatment, even with a 500-calorie-per-day diet.

      The hypothalamus integrates incoming signals regarding energy intake and expenditure. However, the control mechanism was still unknown. Romaine Hervey proposed in 1959 that the fat cells produced a circulating “satiety factor.”¹² As fat stores increased, the level of this factor would also increase. This factor circulated through the blood to the hypothalamus, causing the brain to send out signals to reduce appetite or increase metabolism, thereby reducing fat stores back to normal. In this way, the body protected itself from being overweight.

      The race to find this satiety factor was on.

      Discovered in 1994, this factor was leptin, a protein produced by the fat cells. The name leptin was derived from “lepto,” the Greek word for thin. The mechanism was very similar to that proposed decades earlier by Hervey. Higher levels of fat tissue produce higher levels of leptin. Traveling to the brain, it turns down hunger to prevent further fat storage.

      Rare human cases of leptin deficiency were soon found. Treatment with exogenous leptin (that is, leptin manufactured outside the body) produced dramatic reversals of the associated massive obesity. The discovery of leptin provoked tremendous excitement within the pharmaceutical and scientific communities. There was a sense that the obesity gene had, at long last, been found. However, while it played a crucial role in these rare cases of massive obesity, it was still to be determined whether it played any role in common human obesity.

      Exogenous leptin was administered to patients in escalating doses,¹³ and we watched with breathless anticipation as the patients . . . did not lose any weight. Study after study confirmed this crushing disappointment.

      The vast majority of obese people are not deficient in leptin. Their leptin levels are high, not low. But these high levels did not produce the desired effect of lowering body fatness. Obesity is a state of leptin resistance.

      Leptin is one of the primary hormones involved in weight regulation in the normal state. However, in obesity, it is a secondary hormone because it fails the causality test. Giving leptin doesn’t make people thin. Human obesity is a disease of leptin resistance, not leptin deficiency. This leaves us with much the same question that we began with. What causes leptin resistance? What causes obesity?

PART THREE

       A New Model of Obesity

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       A NEW HOPE

      THE CALORIC-REDUCTION THEORY of obesity was as useful as a half-built bridge. Studies repeatedly proved it did not lead to permanent weight loss. Either the Eat Less, Move More strategy was ineffective, or patients were not following it. Health-care professionals could not abandon the calorie model, so what was left to do? Blame the patient, of course! Doctors and dieticians berated, ridiculed, belittled and reprimanded. They were drawn irresistibly to caloric reduction because it transformed obesity from their failure to understand it into our lack of willpower and/or laziness.

      But the truth cannot be suppressed indefinitely. The caloric-reduction model was just wrong. It didn’t work. Excess calories did not cause obesity, so reduced calories could not cure it. Lack of exercise did not cause obesity, so increased exercise could not cure it. The false gods of the caloric religion had been exposed as charlatans.

      From those ashes, we can now begin to build a newer, more robust theory of obesity. And with greater understanding of weight gain, we have a new hope: that we can develop more rational, successful treatments.

      What causes weight gain? Contending theories abound:

      •Calories

      •Sugar

      •Refined carbohydrates

      •Wheat

      •All carbohydrates

      •Dietary fat

      •Red meat

      •All meat

      •Dairy products

      •Snacking

      •Food reward

      •Food addiction

      •Sleep deprivation

      •Stress

      •Low fiber intake

      •Genetics

      •Poverty

      •Wealth

      •Gut microbiome

      •Childhood obesity

      The various theories fight among themselves, as if they are all mutually exclusive and there is only one true cause of obesity. For example, recent trials that compare a low-calorie to a low-carbohydrate diet assume that if one is correct, the other is not. Most obesity research is conducted in this manner.

      This approach is wrong, since these theories all contain some element of truth. Let’s look at an analogy. What causes heart attacks? Consider this partial list of contributing factors:

      •Family history

      •Age

      •Sex

      •Diabetes

      •Hypertension

      •Hypercholesterolemia

      •Smoking

      •Stress

      •Lack of physical activity

      These factors, some modifiable and some not, all contribute to heart-attack risk. Smoking is a risk factor, but that doesn’t mean that diabetes is not. All are correct since they all contribute to some degree. Nonetheless, all are also incorrect, because they are not the sole cause of heart attacks. For example, cardiovascular-disease trials would not compare smoking cessation to blood-pressure reduction since both are important contributing factors.

      The other major problem with obesity research is that it fails to take into account that obesity is a time-dependent disease. It develops only over long periods, usually decades. A typical patient will be a little overweight as a child and slowly gain weight, averaging 1 to 2 pounds (0.5 to 1 kilogram) per year. While this amount sounds small, over forty years, the weight gained can add up to 80 pounds (35 kilograms). Given the time it takes for obesity to develop, short-term studies are of limited use.

      Let’s take an analogy. Suppose we were to study the development of rust in a pipe. We know that rusting is a time-dependent process that occurs over months of exposure to moisture. There would be no point in looking at studies of only one- or two-days’ duration, as we might very well conclude that water does not cause pipe rust since we did not observe any rust forming during that forty-eight hours.

      But this mistake is made in human obesity studies all the time. Obesity develops over decades. Yet hundreds of published studies consider only what happens in less than a year. Thousands more studies last less than a week. Still, they all claim to shed light on human obesity.

      There is no clear, focused, unified theory of obesity. There is no framework for understanding weight gain and weight loss. This lack impedes progress in research—and so we come to our challenge: to build the hormonal obesity theory.

      Obesity is a hormonal dysregulation of fat mass. The body maintains a body