Fat Chance

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,[40 - P. A. Velasquez-Mieyer et al., “Suppression of Insulin Secretion Promotes Weight Loss and Alters Macronutrient Preference in a Subset of Obese Adults,” Int. J. Obesity 27 (2003): 219–26; R. H. Lustig et al., “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Trial of a Long-Acting Formulation of Octreotide in Promoting Weight Loss in Obese Adults with Insulin Hypersecretion,” Int. J. Obesity 30 (2006): 331–41.] 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.[41 - R. H. Lustig et al., “Obesity, Leptin Resistance, and the Effects of Insulin Suppression,” Int. J. Obesity 28 (2004): 1344–48.] This suggests that insulin can block leptin signaling in the brain, and therefore insulin acts as a “leptin antagonist.”[42 - R. H. Lustig, “Childhood Obesity: Behavioral Aberration or Biochemical Drive? Reinterpreting the First Law of Thermodynamics,” Nature Clin. Pract. Endo. Metab. 2 (2006): 447–58.]

Many scientists have now shown that insulin actions in the VMH block leptin signaling.[43 - M. Kellerer et al., “Insulin Inhibits Leptin Receptor Signalling in HEK293 Cells at the Level of Janus Kinase-2: a Potential Mechanism for Hyperinsulinaemia-Associated Leptin Resistance,” Diabetologia 44 (2001): 1125–32; J. W. Hill et al., “Acute Effects of Leptin Require PI3K Signaling in Hypothalamic Proopiomelanocortin Neurons in Mice,” J. Clin. Invest. 118 (2008): 1796–805; T. Klöckener et al., “High-fat Feeding Promotes Obesity via Insulin Receptor/PI3K-Dependent Inhibition of SF-1 VMH Neurons,” Nat. Neurosci. 14 (2001): 911–18.] 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.[44 - V. D. Castracane et al., “Serum Leptin in Nonpregnant and Pregnant Women and in Old and New World Nonhuman Primates,” Exp. Biol. Med. 230 (2005): 251–54.] 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 process not under the patient’s control. Burning energy is synonymous with quality of life. Things that make you burn energy faster – such as exercise, ephedrine (off the market now), and caffeine (for about two hours) – make you feel good. Conditions that make you burn energy slower – starvation and hypothyroidism, for example – make you feel lousy. So, the first law needs to be reinterpreted: “If you are going to store it, and you expect to burn it, then you will have to eat it.”[45 - Lustig, “Childhood Obesity,” pp. 447–58.] In this interpretation, the biochemical process is primary, the weight gain is secondary, and the behaviors are a result of the biochemistry.

Obesity is a biochemical alteration in the brain promoting leptin resistance with resultant weight gain and secondary changes in behavior to maintain energy balance. The apparent character defects of gluttony and sloth are not the cause of the problem; they are the result of the problem. The biochemistry drives the behavior, not vice versa. The linchpin in this biochemical alteration is the hormone insulin. The majority of humans, regardless of weight, release double the insulin today that we did thirty years ago for the same amount of glucose. Now we’re left with the $147 billion (the annual financial cost of obesity) question: If insulin is the bad guy and we’re all hyperinsulinemic as never before in the history of humankind, where did the excess insulin come from? And how do we reverse it?

The plot thickens.

Chapter 5

Food Addiction – Fact or Fallacy

Salvador is a fifteen-year-old Latino boy with obesity, a fatty liver, and high blood pressure. He drinks four sodas a day. His mother does not buy them for him or keep them in the house. Rather, he buys them at the convenience store on the way to and from school. Salvador enrolls in our research study whereby each day, for ten days, he will consume the same number of calories from our hospital’s Metabolic Kitchen, which will provide all his food, prepared by a chef and sugar free. Nonetheless, each day, he buys a can of soda and brings it home, putting it on his dresser, next to those from the day before. He tells his mother, “When the study is over, I’m drinking them all.” Indeed, the evening of the end of the study, he drinks every last one, to his mother’s chagrin. He may not have been addicted physically, but the mental obsession and craving indicated dependence, and could not be suppressed.

Life’s too short to eat bad food, even if it’s cheap. Eating is supposed to be an enjoyable experience, especially when the food is special. There’s nothing quite like going to a nice restaurant with the sights, sounds, and smells of a well-prepared meal. It’s one of the true enjoyments of life. Yet familiarity breeds greater cravings. Ask Philadelphians about their cheesesteaks, New Orleans denizens about their Po-Boys and beignets, or Memphians about their barbecue. Surprise! Those are among the three most obese cities in the country. Coincidence?

As prodigious as some American cuisine is, is there really anything special about a soda, a French fry, or any item in a fast food restaurant? Yet we devour fast food as if it were going out of style. Americans consume Big Macs as if each one might be our last. (Given the mortality rates in the obese, each one just might be.) Fast food comprises a growing portion of food eaten outside the home. In the United States of the 1950s, fast food accounted for 4 percent of total sales of food outside the home. In 1997 it accounted for 34 percent. Each day, 30 percent of U.S. adults eat at a fast food outlet, and McDonald’s feeds forty-six million Americans.

What about the rest of the world? They didn’t experience fast food growing up, yet it’s now the biggest seller in developing countries. There is no familiarity here; they weren’t raised on the stuff; they’re consuming it de novo. Why do they eat fast food when it’s not their traditional fare? Because it’s cheap? It certainly isn’t abroad. Why do the locals frequent Taco Bell in Mexico when the original tacos are cheaper and ostensibly healthier? Something more is going on here. Is the world addicted to fast food? The biology of addiction is at the center of this question.

Might as Well Face It, We’re Addicted to…

Our brains are wired for reward – it is the primary force behind human survival. Reward is the reason to get up in the morning. If you take away reward, you take away the reason to live. We know this from recent experience with the anti-obesity drug rimonabant, which was deep-sixed after it failed to gain approval from the FDA in 2007. Rimonabant is an endocannabinoid antagonist, or the “anti-marijuana” medicine – which means it’s also “anti-munchies.” It inhibits the sense of reward. While it worked to promote weight loss, 20 percent of the subjects who used it experienced serious psychiatric side effects, especially depression, and there were several suicides. Kill the reward system, and you just might want to kill yourself.

Although the brain’s reward system is complex and has many inputs, it can be reduced to the “hedonic pathway.” This pathway is where primal emotions, reproductive drive, and the survival instinct are all housed and expressed. These reward mechanisms are thought to have evolved to reinforce behaviors that are essential for perpetuation of the species and survival: such as sex for reproduction and the enjoyment of food so that you eat. This is also the pathway that reinforces the positive and negative aspects of drugs of abuse such as nicotine, cocaine, morphine, and alcohol. In order to maintain eating as one of the most powerful urges in animal and human behavior, evolution has also made it a rich source of pleasure and reward.

The hedonic pathway comprises a neural conduit between two brain areas: the ventral tegmental area (VTA) and the nucleus accumbens (NA, also known as the reward center), both of which are deep-brain structures. Pleasure occurs when the VTA signals the NA to release dopamine, a neurotransmitter. It’s a signal from one brain center to another. When the released dopamine binds to its specific dopamine D

receptor in the NA, the sense of pleasure is experienced.[46 - K. D. Carr et al., “Evidence of Increased Dopamine Receptor Signaling in Food-Restricted Rats,” Neuroscience 119 (2003): 1157–67.]

So what are neurotransmitters and receptors? Think of keys and locks. Each neuron is a cell body, and at its end is an axon (special fiber of the neuron that sends information). This axon has a synapse, or pathway, that connects to the dendrites (specialized fibers of the nerve cell that receive information) of the next neuron. When a neural impulse is generated in the first cell, it pulses down to the end of the axon, which contains little packets of neurotransmitters that are then released. These are the keys. They travel across the synapse to the receptors (locks), located in the dendrites of the next cell. There are many keys that take the path along the synapse, and not all of them make it to their destination. Along their way via the synapse, some are metabolized and some are “re-uptaken.” Dopamine is one of these types of keys traveling to fit into the locks of the D

receptors in the next cell, thus determining the triggering and firing of the next cells down the chain.

Food intake is just one readout of the hedonic pathway.[47 - M. L. Pelchat, “Of Human Bondage: Food Craving, Obsession, Compulsion, and Addiction,” Physiol. Behav. 76, (2002): 347–52.] It appears to mediate feeding on the basis of palatability rather than energy need: I’m stuffed, but that chocolate cake looks so good. When functional, the hedonic pathway helps to curtail food intake in situations where energy stores are replete: I don’t need to finish that macaroni and cheese. However, when dysfunctional, this pathway can increase food intake, leading to obesity.

If you feed a rodent a palatable food (e.g., a high-fat, high-sugar food such as cookie dough), the animal experiences reward because dopamine is released from the VTA and binds to the D

receptor in the NA. As long as that continues, the animal will continue to eat and experience reward. There are three processes that modulate this system in one direction or another:

1. Anything that increases the dopamine transmission to the NA increases the feeling of reward.

2. Anything that clears dopamine from the NA will extinguish the feeling of reward.

3. Anything that reduces the number of D

receptors in the NA, or binding of dopamine to those receptors (such as chronic overuse of a substance), will shortchange reward. You then need more dopamine, and hence more of the substance, to get the same feeling of pleasure.

These precepts are as true for food as they are for addictive drugs. And food and drugs cross over. With time we can become sensitized to a substance and need more of it to get the same effect. Once sensitized, animals and humans may become hyperresponsive to a new substance; this is known as cross-sensitization. In other words, if the brain has been wired for addiction, it’s easy to switch from one substance to another. Ask recovering alcoholics about their incessant need for coffee, tobacco, and/or sugar. A reinforcer is a stimulus that increases the probability that an animal or human will respond to the addictive drug. Food is a form of positive reinforcement. Dopamine stimulation in the NA reinforces the intake of drugs or alcohol and also of food.

The reinforcing effect of dopamine is attributed to D

receptor stimulation. As stated before, food intake increases as a result of morphine and marijuana use. The film Harold and Kumar Go to White Castle details the odyssey of two very stoned guys who seek to overcome seemingly insurmountable obstacles in their quest for a hamburger. We can measure this by dopamine release and D

receptor signaling. Why does dopamine matter so much? In a normal person, dopamine will be cleared from the D

receptors after he is satiated. If you have a decreased dopamine binding capacity, there is a perceived need for compulsive food intake to provide excess stimulation of these depressed circuits, thereby driving continued weight gain.

The Usual Suspects: Leptin and Insulin

Yup, them again. Not only are they central in the starvation response, but they are also key players in this hedonic pathway, modulating reward in response to meals. In normal circumstances, after you’ve eaten a sufficient amount, leptin sends a signal to the VTA to suppress the release of dopamine, thereby reducing the reward of food.[48 - I. S. Farooqi et al., “Leptin Regulates Striatal Regions and Human Eating Behavior,” Science epub, August 9, 2007/science.1144599 (2007).]

So leptin extinguishes reward. But what if you are leptin resistant? That’s what obesity is: leptin resistance. If leptin can’t act, then the dopamine isn’t cleared from the NA, and the impetus for further consumption persists. If you’re leptin resistant, do you really think you have the willpower to ignore both the starvation signal and the reward signal, when every food outlet you pass by provides you with sight or smell cues to chow down? Starvation and reward conspire to thwart every obese person.

What about insulin, leptin’s accomplice? Normally, people are sufficiently sensitive to insulin. Insulin’s job is to clear dopamine from the synapses (that pathway between the cells) in the NA.[49 - L. Carvelli et al., “PI3-Kinase Regulation of Dopamine Uptake,” J. Neurochem. 81 (2002): 859–69.] Thus, the rise in insulin that occurs during a meal blunts the reward of further food intake (I’ve eaten enough – I really don’t need a second helping). This acts as a servomechanism built into the hedonic pathway to prevent overfeeding. But what happens when you are insulin resistant? Insulin resistance leads to leptin resistance in the VTA, contributing to increased caloric intake by preventing dopamine clearance from the NA. Increased pleasure is then derived from food when energy stores are full.[50 - E. Anderzhanova et al., “Altered Basal and Stimulated Accumbens Dopamine Release in Obese OLETF Rats as a Function of Age and Diabetic Status,” Am. J. Physiol. Regul. Integr. Comp. Physiol. 293 (2007): R603–R11.] Insulin and leptin resistance lead not only to increased food intake but to increased palatable food intake or anything that is high in both fat and sugar: the muffins, the Cinnabons, the cookies, the cheesecake. Is it any wonder Mrs. Fields is in every shopping mall?

Defining Food Addiction: Liking, Wanting, and Needing

Look, we all like fast food. And why wouldn’t we? It’s designed to contain the greatest concentration of fat, sugar, salt, and caffeine, and is placed into as small a package as possible. Yummmm. It provides food cheaply, quickly, and without table service. The pretty packaging and restaurant environment increase its salience (the properties that make you like it more). Ten years ago, fast food locations in the United States generated more than $125 billion, which accounts for 15 percent of sales of the entire U.S. food industry. But liking it isn’t the same as wanting it. And wanting it isn’t the same as needing it.[51 - K. C. Berridge, “ ‘Liking’ and ‘Wanting’ Food Rewards: Brain Substrates and Roles in Eating Disorders,” Physiol. Behav. 97 (2009): 537–50.]

Liking is an aesthetic state. You can turn it on and turn it off. As dopamine is released into the NA, our consumption of a Big Mac heightens our sense of reward. Then comes the insulin rush, and that should be the end of it. But when you’re insulin resistant, wanting is a psychological state and needing becomes a physiologic state. You can’t turn it on and off anymore. This is the nature of addiction to any substance of abuse. It’s what happens with nicotine, morphine, cocaine, and alcohol – and it happens with food. It can happen to anyone. It can happen to you.

Substance dependence, in this case synonymous with addiction, is defined by the American Psychiatric Association (APA) as “a maladaptive pattern of substance abuse leading to clinically significant impairment or distress.” There is currently no standardized definition for food addiction despite many hypotheses in the medical literature. There are seven criteria for substance dependence according to the APA Diagnostic and Statistical Manual, the DSM-IV-TR. The first two are considered physiologic, whereas criteria 3–7 are considered psychological dependence. All these are seen in the obese, especially those who frequent fast food restaurants. To be considered addicted to any substance of abuse, one must meet at least three of the seven.

1. Tolerance. This is defined as the need for more substance to get the same effect, or when the same amount of substance produces less effect with continued use. That Big Mac still generates the dopamine rush, but the reward isn’t maintained, as your insulin won’t clear the dopamine from the NA. Since insulin resistance generates leptin resistance, you can’t stop the dopamine neurons in the VTA from firing in the first place. So your NA is awash in dopamine, and the insulin rush from the meal can’t turn it off. Since your hypothalamus and your NA won’t respond to the leptin signal, the drive to eat just keeps coming. And here’s the kicker: the more and the longer your NA is exposed to dopamine, the more those D

receptors are going to be down-regulated. After chronic dopamine exposure, the D

receptors themselves start to disappear. The locks vanish, much to the chagrin of the keys, which have nowhere to go. Now it takes more dopamine to ensure that the few receptors that don’t disappear are occupied. You need to eat more Big Macs just to get the same level of reward.

2. Withdrawal. This is characterized by physical signs (such as tremors) and psychological ones (anxiety, depression). This occurs due to lack of dopamine D