and nonstop weight gain.
As it happens, there is a drug available that can lower insulin secretion as a side-effect. It is called octreotide (Sandostatin, made by Novartis Pharmaceuticals) and is what we used to treat Marie. It is normally used to reduce pituitary growth hormone secretion in patients who have tumors of the pituitary gland, a disease called acromegaly. But it also happens to reduce pancreatic insulin secretion. It doesn’t wipe it out completely—that would cause diabetes—but it does reduce the rapid early release of insulin in response to a meal or a glucose tolerance test. But it’s expensive, requires injections, has side-effects, and with regard to obesity, it is for experimental studies only.
We have treated many children with hypothalamic obesity with octreotide.13 When we were successful in reducing their insulin release, the patients lost weight and started to feel better. Parents were calling me up within the first few weeks, saying, “I’ve got my kid back!” Most amazingly, the children had started to be active. When we got the insulin down, Marie and patients like her improved physically, mentally, and socially.
These studies highlight a crucial concept of obesity. Each of us is really two compartments: lean body mass (heart, liver, kidneys, brain, and muscles), which burns energy; and fat, which stores energy. Every molecule of energy consumed has a choice: to which compartment does the energy go? Is the energy burned or stored? Your consumption of energy is never high enough to overwhelm both compartments at the same time; no one can eat that much. This means that there is an issue of energy flux to the two compartments. What factor determines which compartment gets the energy?
Your insulin does. The more insulin there is, the more energy goes to fat. Normally your fat makes more leptin, which would feedback on your hypothalamus and decrease your insulin by reducing appetite and limiting your energy intake. In this way, the “servo-mechanism” between leptin, the brain, your pancreas, your insulin, and your fat cells maintains normal energy balance. But…if your hypothalamus can’t see your leptin (in this case, because those neurons are dead from a brain tumor), then your brain thinks it’s starving. It will reduce your activity to conserve energy, and increase your appetite to store more energy. When leptin doesn’t work, the biochemistry comes first and the behaviors of gluttony and sloth are secondary.
This is all well and good for Marie and the few unfortunate souls with hypothalamic obesity. They have a brain tumor. They have a legitimate excuse for being fat, and at least there is now a rational, if painful and expensive, approach to treatment. For them, the biochemistry dictates the behavior. However, the overwhelming majority of obese people do not have a goombah sitting in the middle of their heads wreaking havoc on their energy balance pathway. What does this phenomenon have to do with the obesity pandemic? As you will see, everything.
Back in 1998, after three years of my working at St. Jude, the response of these patients was quite a revelation. My colleagues at the University of Tennessee and I wondered, “Is it possible that an adult population without brain tumors might manifest the same problem? Did they also have increased vagal tone driving excess insulin secretion and causing their obesity? If we gave them octreotide to suppress their insulin, might they lose weight, feel better, and start exercising?” We didn’t know what these patients looked like. So we did a pilot study in forty-four morbidly obese adults recruited from off the street. We treated all of them with octreotide for six months, courtesy of Novartis Pharmaceuticals. No dieting, no exercise, just the drug. We told them, “If the drug works, it will work by itself.”
We’ve done this experiment twice, first as a pilot and then as a placebo-controlled trial. The majority of patients did not respond to the drug. But in about 20 percent of the adults, there was big-time weight loss. The thing that predicted their success was their insulin status. The lucky responders released insulin rapidly and in high amounts at baseline, just like the brain tumor kids,14 and their quality of life improved with the drug.
There is one final lesson to glean from these studies. All these obese adult subjects had high leptin levels. They were leptin resistant; if their leptin worked right, they wouldn’t have been obese. If leptin falls, the brain should interpret this as starvation and reduce the patient’s resting energy expenditure accordingly. But these patients’ resting energy expenditures went up! And their improvement in energy expenditure correlated with the suppression of their insulin levels, the same as with the brain tumor kids. When we were successful in getting their insulin down, their leptin resistance improved.15 This suggests that insulin can block leptin signaling in the brain, and therefore insulin acts as a “leptin antagonist.”16
Many scientists have now shown that insulin actions in the VMH block leptin signaling.17 A reduction in insulin concentrations results in a decline in leptin. Insulin and leptin are independent hormones that bind to separate receptors in the VMH. They have their own separate pathways of action, but they share the same signaling cascade. When insulin levels at the VMH are chronically high, leptin cannot signal the hypothalamus.
Deconstructing Darwin
Whenever paradoxical events occur in biology, one has to look for an evolutionary explanation. Why should insulin block leptin signaling? What’s the advantage for insulin, the hormone that tells the body to store energy, to block leptin, the hormone that tells your brain to burn energy? Leptin is a necessary signal to the VMH for the initiation of high-energy processes, such as puberty and pregnancy. If leptin always worked right, then nobody could gain weight. Think of the 97-pound weakling at the beach. The crucial weight gain during puberty and pregnancy would be compromised, and our reproductive capacity would be shot. Twice in our lives we need to stop leptin from working, or we can’t gain the weight, and the species dies out. Since insulin drives energy storage, it makes sense that it should do double-duty, and also be the central blocker of leptin—one hormone, two coordinated actions. Indeed, both puberty and pregnancy are hyperinsulinemic states. When adulthood or the postpartum state is reached, the insulin levels fall, weight stabilizes or is lost, and leptin levels return toward baseline.18 However, in maladaptive conditions, when insulin is high all the time and leptin signaling is impaired, the energy gets stored yet the brain sees starvation, and obesity worsens.
When you examine the symptoms of obese and starved individuals, they are very similar. On first thought this sounds ludicrous, but it actually makes sense. Both claim fatigue, malaise, and depression. The reason for this in both groups is the inability to adequately respond to the leptin signal—in starvation because of the inadequacy of leptin, and in obesity because of the resistance to leptin. Furthermore, leptin concentrations drop precipitously during periods of short-term fasting (within twelve hours), declining faster than body fat stores. You haven’t lost any weight in that time, but your fat cells are already telling your brain you’re starving, driving your food intake back up. By the time you’re one day into any weight-loss regimen you’re already leptin deficient on top of being leptin resistant, meaning, you really can’t see the signal. Trying not to eat for a day to fit into that little black dress? Oops. This actually drives gluttony and sloth to return your weight to its baseline level. In a nutshell, this is the recidivism of obesity. If your brain thinks there’s no leptin (due to either leptin deficiency or leptin resistance) you’re pretty miserable. Your sympathetic nervous system goes into conservation mode, driving down your energy expenditure, physical activity, and quality of life. Your vagus nerve then goes into overdrive, driving up your appetite, your insulin, and your energy storage.
The Alternate Interpretation of the First Law
No matter the mechanism, insulin blocks leptin signaling both in rodents and in humans. In the body, insulin causes energy storage in fat cells. In the brain, insulin causes leptin resistance and “brain starvation.” Insulin delivers a one-two punch to drive gluttony and sloth, weight gain, and obesity the world over. Insulin is the bad guy in this story.
This idea turns obesity on its head. The standard thinking in obesity is: “If you eat it, you had better burn it, or you’re going to store it”—in which case the weight gain is secondary to the two behaviors of increased energy intake (gluttony) and decreased energy expenditure (sloth). What these data are telling us is that it is the other way around. Storing energy is a biochemical