William Haseltine
William Haseltine

With every possible combination of salt, fat, and sugar lining our grocery stores and filling fast-food restaurants, the temptation to eat junk food often feels too hard to resist. These foods tap into our deep carnal desire for pleasure. Think about the last time you went to a fast-food chain. The sounds of burgers sizzling and fries browning is enough to make your mouth water. Even before you take a bite, the fantasy is in full effect. Anticipation builds as you unwrap the meal, ignoring the fact that it never looks quite like the picture. The moment your taste buds meet the first bite, electrical signals race to your brain and activate the pleasure-seeking reward system. As the flavors mush in your mouth, your unconsciousness has already started to crave more. Without realizing it, you have already eaten thousands of calories in just one sitting.

The fact that eating has become so mindless has contributed to an epidemic of overeating. Regardless of body shape or size, most people can recall a time when they ate beyond the feeling of being full. It feels harmless at the moment, but doing so at every meal introduces your body to more calories than it can feasibly burn. When energy intake exceeds energy expenditure, you see the evidence around your waistline.

Now, one may ask, “how do I keep myself from overeating?” Overeating does not fit neatly into any classified eating disorder, and as a result, people that struggle with excess weight are often blamed for their own lack of willpower. But how can individuals be expected to make healthier food choices when our food is specifically engineered to keep us wanting more? This is the topic of The End of Overeating, a New York Times bestselling book by former FDA commissioner David Kessler. Despite having been published more than a decade ago, Kessler’s observations ring true now more than ever.

He writes that chronic overeating is a consequence of overstimulating the brain’s reward system. “We are living in a food carnival,” Kessler argues. Food advertisements are everywhere. The food industry spends millions of dollars on putting up billboards, creating commercials, and paying celebrity sponsors because they know that if their consumers see and think about food all the time, they will never stop craving it.

When you go to a fast-food restaurant, every part of the experience is curated to appeal to your senses, not to mention encourage you to spend more money. These businesses are not trying to hide this manipulation scheme, either. In fact, in his book, Kessler interviews Cinnabon owner and founder Jerilyn Brussaurs. As she plainly put it, “What creates irresistibility is caring, attention, visual appeal, and the appeal of aroma, texture, and consistency.”

The next time you go to the grocery store or order from a fast-food restaurant, pause to think about the amount of engineering that goes into highly processed foods. Kessler writes, “Those fat-on-sugar-on-fat-on-salt-on-fat combinations generate multiple sensory effects. Which is just what the industry wants.” Sugar and salt stimulate our taste buds; fat makes everything go down easy.

Neuroimaging studies show that eating activates dopamine reward receptors in the brain that enhance your appetite. Normally, the dopamine hit you get from eating only lasts a few moments before your brain becomes habituated, or used, to the taste. This explains why that first bite usually tastes better than the last. What the food industry has figured out is that adding more fat, salt, and sugar prolongs the release of dopamine and that pleasurable feeling. Too much of a good thing, however, never ends well. Individuals who struggle with being overweight or obese have been shown to have significantly fewer dopamine receptors, similar to what is often seen in the brains of people with drug or alcohol addictions. Decreased receptors can be a consequence of too much dopamine in the brain and also correlates with fewer monoamine oxidase enzymes, which are critical for the effective removal of these neurotransmitters. In the same way that drugs and alcohol enhance the release of dopamine to stimulate that feeling of pleasure, food can become just as addictive.

We cannot blame individuals for indulging in junk food if the food industry controls the type of food we have access to. “Food deserts” and “food swamps” have long been established as key drivers of obesity in low income communities. Even someone with tremendous willpower to eat less and exercise more will struggle to resist the temptation when there seem to be no other options. Rather than blaming the individual for their poor choices, it may be time to consider how the food industry enables overconsumption.

From end to end: Taste drives our appetites

Eating is a multi-sensory experience. Every detail from how a meal looks to how it feels in our mouths adds to the sensory experience. However, the real magic happens in our taste buds. Humans have thousands of different taste receptors, each attuned to detect specific tastes. Within minutes of taking a bite of food, taste receptors begin sending signals to the brain.

Illustration of simultaneous synaptic transmission and hormone release in an intestinal neuropod cell
Figure 1: Illustration of simultaneous synaptic transmission and hormone release in an intestinal neuropod cell. Glutamate neurotransmitters are released and stimulate the vagus nerve, the primary nerve that connects the gut to the brain. [ADAPTED FROM: NEUROPOD CELLS: EMERGING BIOLOGY OF THE GUT-BRAIN SENSORY TRANSDUCTION KAELBERER ET. AL. 2021]

How something tastes can provide the first hint to its nutritional value. For instance, sweet foods contain sugar and other carbohydrates that can be broken down for energy. Salty tastes can signal the presence of minerals and other vitamins. Umami, or savory flavor, suggests that there may be proteins or amino acids. It is no surprise that the foods we crave are often sweet, salty, savory, or some combination of the three. Alternatively, when the brain receives signals for other, less pleasant tastes like bitterness or sourness, we are less inclined to seek out more of that food.

Everything we eat is made up of a complex combination of nutrients and molecules that our bodies need to survive. Something as simple as a banana, for example, can provide fiber, sugar, potassium, vitamin C, and many other nutrients in differing amounts. Being able to decipher between these nutrients once everything is mixed together in the gut takes a specialized type of cell called a neuropod. Similar to cells with olfactory and gustatory receptors, these gut-based sensory cells can also form synapses with the vagus nerve.

When a neuropod receptor activates, it triggers the release of glutamate neurotransmitters that stimulate the nervous system, as well as the secretion of metabolic hormones into the bloodstream. Stimulating the vagus nerve sends a message to the brain within a fraction of a second to activate the dopamine reward-system. Prolonged activation of the nervous system then encourages the brain to suppress appetite and slow down eating. While this is happening, the circulating hormones tell the rest of the gut to slow down digestion. This negative feedback loop is critical for providing a long-lasting feeling of satiation.

Depending on the type of food, however, it is possible that stimulating the gut-brain axis can also enhance cravings and act as a positive feedback loop. Food high in fat, in particular, often leaves us wanting more even after we are already full. Craving high-fat foods like French fries or deep-fried onion rings is not driven by taste alone. The way these foods smell and how they feel in our mouths make them easy to overeat. According to a recent study by investigators at Columbia University, our attraction to fat may be outside our conscious control. When presented with a high fat drink vs. an artificially sweetened option, they found that mice consistently developed a preference for fat. Even when they were blinded to taste and fed intragastrically, the animals continued to prefer the fat option over the artificially sweet drink.

The most intriguing finding was what the researchers saw happening in the brain. While the mice drank, investigators attached electrodes to their heads to measure neural activity. To their surprise, they saw increased activity in a particular part of the brain called the caudate nucleus when the mice drank the high-fat options but not the artificially sweetened drinks. This area is critically involved in reward-driven behaviors and associative learning. The investigators speculate that this may be the part of the brain that lights up when you eat your favorite food.

Therapeutic interventions for weight loss

People who struggle with weight have long been told that diet and exercise are the only ways to control their weight. While this works for some, there are plenty of people that eat right and exercise daily but cannot lose stubborn fat. Studies have found that people who undertake extreme diets or intense exercise regimens often end up gaining much of the weight back and then some when these habits prove to be unsustainable.

Alternative intermittent fasting diets suggest that when you eat may matter just as much as what you eat. In this sense, intermittent fasting may be regarded as an eating pattern rather than a change to diet per se. This time-restricted form of eating limits the opportunity to eat throughout the day, making it easier to stay in a calorie deficit. Once all the calories from the day’s meals are exhausted, the body is forced to start burning body fat. Being in a calorie deficit is critical for weight loss.

A recent study from the University of Utah has also reported that time-restricted eating may help you live longer. In mice, investigators observed that the animals that only had access to food during a 9-hour window had greater expressional changes in almost 80% of the gene samples collected, compared with those that were allowed to eat throughout the day. These gene expression changes were associated with greater metabolic flexibility in various organ systems, including the liver, kidneys, intestines, and different brain regions. The authors speculate that alternating periods of eating and fasting promotes greater rhythmicity in biological processes that help cellular function, while also suppressing inflammation.

What happens when diet, exercise, and changing your eating patterns fails? Leading excerpts argue now that overeating, and subsequently being overweight or obese, is a chronic disease, and like any other disease with a biological basis, we can treat it with drug interventions. As a result, emerging weight loss drugs are expected to be a $50 billion dollar industry by the end of the decade.

The new generation of weight loss drugs that specifically target the gut-brain appetite regulating system offer a new hope for those trying to manage their weight. One drug, in particular, seems to be especially promising, with estimates that it may be FDA approved for weight loss as early as this year. Tirzeptaide, a product of Eli Lilly, not only lowers body fat but also normalizes blood glucose levels. Previously approved for treating diabetes, this once-a-week injection promotes weight loss with little to no side effects.

The New England Journal of Medicine recently published a clinical study that has only increased the excitement over this new drug. Over 2,500 adults with measurably high body mass index volunteered for this study. Participants were given weekly injections of 5-, 10-, or 15-mg of tirzepatide or a placebo injection. Over the course of 72 weeks, the participants also attended regular lifestyle counseling sessions that encouraged healthy eating habits and exercise.

Those treated with 15-mg of tirzepatide experienced the greatest benefit with an average weight change of 20%, compared to only a 3% change in the placebo control group. Putting that into perspective, existing FDA-approved weight loss drugs on average report 3.0 to 8.6% reductions in weight.

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In addition to the benefits for managing weight, nearly all the participants in the tirzepatide-treated group who were pre-diabetic had normal glycemic levels by the end of week 72. These changes were also associated with reduced risk for cardiovascular disease, chronic kidney disease, fatty liver disease, and several other complications. Less than two-thirds of those in the placebo group experienced similar benefits.

The benefits of tirzepatide comes from its two-pronged approach in regulating energy and glucose levels. This drug mimics the activity of a naturally produced hormone called long-acting glucagon-like peptide 1 (GLP-1). As you eat, the gut releases GLP-1 to tell your brain that it is getting full and simultaneously slow down the movement of food through the gut. This hormone normally does not last long in your system. Supplementing with tirzepatide can help you feel full faster and longer.

Secondly, tirzepatide can mimic another key gut hormone, glucose-dependent insulinotropic polypeptide (GIP). In doing so, this drug can encourage the release of insulin, which supports metabolism. In fat tissue, this drug stimulates GIP receptors to mediate how calories are burned and stored in different parts of the body. Tirzepatide and other drugs like it seem to be effective because of their ability to target both GLP-1 and GIP receptors.

Although weight loss drugs can facilitate weight loss, we must remember that they are not a substitute for diet and exercise. The conscious decision to choose healthy foods is what is going to fuel your body. Pharmaceutical companies have huge financial incentives to market these drugs widely, but there are many questions that remain regarding their social impact. Who will have access to these prescriptions? Who will cover the costs? What are the consequences of taking these drugs for vanity reasons? Will medically treating obesity and being overweight like a disease further stigmatize those affected? If we are ever going to reverse the global obesity crisis, we must take these moral and ethical implications seriously.

Genetics matters

It is important to note that not everyone who eats junk food is obese, or even overweight. There are also plenty of individuals with high BMIs who, more often than not, choose healthier food alternatives. Even if we all ate the same type of foods and number of calories, natural deviations in weight would still exist across the population. Genetics determines our body shape and size.

Regardless of diet or exercise, some people are predisposed to thinness. In a study of almost 800 adult volunteers, a team of researchers in Spain discovered a thin gene that may lower the risk of obesity. More than 60% of Europeans reportedly have the thin gene. Across billions of inherited units that make up our DNA, having a C versus T nucleotide at this critical position may protect you from packing on excess weight.

The advantage of having the “thin” variant boils down to how this gene influences metabolism and satiety. Unlike the T-carrying allele, which blocks the expression of metabolic FNIP2 enzymes, the C-carrying variant optimizes its expression. Fernandez et al. found that thin mice had more FNIP2 enzymes in their blood, compared to the mice with excess weight. This suggests that the prevalence of these enzymes correlates with thinness, and the “thin” variant may be key to upregulating its activity.

As with any other genetic finding, we must be careful to not overgeneralize these results. It is unlikely that only one gene determines your risk for being overweight. We can look to our genes, however, to understand the ways in which energy is stored and consumed. Genetics only tells one part of the story. To understand and optimize our eating habits, we cannot ignore the biological mechanisms that drive our appetite.

Considerable weight gain over time not only contributes to poor weight management but also increases your risk for significant comorbidities including diabetes, cardiovascular diseases, and cancers. A recent study, for example, found that a 10 kg (22 lbs) weight gain contributed to substantial increases in blood pressure among adult men and women.

It should be noted that not all weight gain leads to obesity. Gaining weight in your 20s and 30s is very common. For most people, there are no associated health risks. The trouble comes when you continue to gain significant weight in your 40s and beyond. These trends are not unique to the United States. There is an epidemic of chronic weight gain happening globally. The 2021 Health Survey for England, for example, reported that the prevalence of excess weight correlated with age, with nearly three-quarters of individuals aged 45 to 72 affected. Becoming overweight or obese does not happen overnight; it is a consequence of small increases in weight over the span of years.

Who is to blame for the global obesity crisis? The easiest and most common argument to make is to blame the individual. You make your own choices about what to eat and when. An increasing number of studies now suggest that our eating habits are largely mediated by factors outside of our conscious control. Environmental factors, such as socioeconomic status, where you live, and the type of job you have, all influence our lifestyle choices. On the biological level, however, there is so much we have yet to learn about how our bodies respond to the food we consume.


William R. Haseltine, PhD, is chair and president of the think tank ACCESS Health International, a former Harvard Medical School and School of Public Health professor and founder of the university’s cancer and HIV/AIDS research departments. He is also the founder of more than a dozen biotechnology companies, including Human Genome Sciences.

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