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Brain’s Wiring, Not Lack of Willpower, May Drive Obesity: Study

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June 6, 2022 – “You want fries with that?

How you answer that question may have less to do with willpower than you might think.

Virginia Tech scientists are taking a deep dive into the brain chemistry that drives cravings for unhealthy fatty foods. Their goal: To find out if the nation’s ever-expanding waistline has as much to do with that’s in our heads as what we put into our bellies.

Armed with a new $2 million grant from the National Institutes of Health, the researchers have launched a new study to understand the brain circuitry that may be a key driver of the nation’s obesity crisis. Specifically, the scientists are looking at the wiring in our brains that makes us eat too much high-fat food after a period of avoiding them.

Lead researcher Sora Shin, PhD, says she hopes the work will explain a key reason why so many dieters fail. The findings could clarify why cutting your favorite tasty treats out of your diet can actually make you crave them even more – and point the way to potential new approaches to combat overeating.

“Excessive consumption of palatable foods … such as cake, potato chips, and ice cream is a major public health problem leading to obesity,” says Shin, an assistant professor at the Fralin Biomedical Research Institute at Virginia Tech. “Although numerous appetite control strategies are developed for the treatment of obesity, most of the individuals who achieved a successful diet show high rates of relapse to HFD [high-fat diet] overconsumption.”

“Understanding neural [brain] circuit mechanisms leading to HFD overconsumption after abstinence is arguably the core issue in developing therapeutic strategies for the long-term treatment of obesity,” she says.

Shin and her colleagues hope to build on decades of research – including her own past studies involving mice – showing that certain hormones, such as leptin, have a profound impact on appetite and overeating. The Virginia Tech study will focus on the “leptin-response circuit” in the brain “in hopes of speeding the development of novel therapeutic strategies for the treatment of maladaptive eating disorders and obesity,” she says.

In the long run, experts say Shin’s research could lead to game-changing medications to help fight the obesity crisis. But in the short term, health specialists say the work could likely dash the idea that obese people are solely to blame for their weight problems.

“I think studies like this are necessary because [when] we see an obese person, you just probably blame the person for not taking enough action to combat obesity,” notes Dipali Sharma, PhD, a professor of oncology at Johns Hopkins University School of Medicine and an expert in obesity and cancer.

“But we have seen in our own trials that some people actually have a propensity to gain weight [even] when they are following up with the exercise routines and food regimens that are recommended to everyone. So, we should be appreciative of the facts – that this is not just willpower and stop the blame game – and then clinically we can look at other approaches.”

Leptin: The Key to Obesity?

According to the World Health Organization, more than a billion people worldwide are obese, which increases the risk for heart disease, stroke, diabetes, certain cancers, and other leading causes of preventable death.

In the U.S. alone, more than four in 10 adults are clinically obese, according to the CDC. And those numbers are rising – up 30.5% over the past 2 decades, the agency estimates.

A primary culprit? Access to so many low-cost, high-calorie, fat-rich treats that our brains are prewired to crave, experts say. But another key factor has been the subject of a great deal of scientific research: leptin, the “hunger hormone.”

Leptin is one of several hormones made by fat cells that can lessen your appetite by signaling to your brain that you are “full” after eating and that your body has enough energy stores (such as body fat). Some is also produced by your stomach when you eat; it circulates in your blood and travels to your brain.

Leptin helps maintain a healthy body weight over long periods of time through its interaction with your brainstem and hypothalamus, the region of the brain responsible for self-regulating processes, such as body temperature, thirst, and hunger.

Leptin also appears to affect metabolism, endocrine system regulation, the immune system, and cancer growth, Sharma notes

In general, blood levels of the hormone are lower in thin people and higher those who are overweight or obese, studies show. But leptin levels can vary depending on many things, including when you last ate and your sleep patterns.

Leptin has a more profound effect when you lose weight. As you lose body fat, your leptin levels decrease, which signals your brain to think that you are starving. This stimulates intense hunger and appetite and can lead to overeating.

Avoiding high-fat foods can help ease your appetite and cravings by affecting leptin levels. But eating fatty foods can increase caloric intake, weight gain, and fat storage – all of which contribute to obesity.

What’s more, many obese people don’t respond well to leptin’s appetite-suppressing signals even though they have higher levels of leptin, Sharma explains. Some research shows obesity can lead to a kind of resistance to the appetite-suppressing effects of leptin, which makes it harder for people who have obesity to resist cravings for fatty foods.

If you have leptin resistance, your brain doesn’t respond as well as it should to leptin, so you don’t get the sensation of feeling full, and you eat more, even though your body has enough fat stored. Leptin resistance also causes your body to enter starvation mode, so your brain decreases your energy levels and makes you use fewer calories to preserve fat reserves.

For years, researchers have been working to develop therapeutics that can control hunger hormones like leptin to fight obesity and leptin resistance. Early results of that research have been promising:

  • Mayo Clinic scientists have found that injecting a hunger-blocking hormone into mice stopped the typical weight gain after dieting and helped prevent rebound obesity. “We think this approach – combined reduction of calories and hormone ─ may be a highly successful strategy for long-term weight control,” says W. Stephen Brimijoin, PhD, a Mayo Clinic pharmacologist and co-author of the study, published in the Proceedings of the National Academy of Sciences. “Given the growing obesity crisis worldwide, we are working hard to validate our findings for medical intervention.”
  • Heike Muenzberg-Gruening, PhD, director of the Central Leptin Signaling Laboratory at Pennington Biomedical Research Center in Louisiana, has just launched one of seven new National Institutes of Health-backed studies to find out how the brain and fat tissue “communicate” to control the release of leptin and other hormones. “Fat tissue plays an important role in our health,” she notes, saying the research could lead to new therapies. “It stores and breaks down fat but also secretes hormones like leptin to impact energy expenditure, food intake, and blood sugar levels.”
  • And Baylor College of Medicine scientists have found that leptin may be only one part of the gut-brain connection to obesity. In a study published in the Journal of Clinical Investigation, researchers found high-fat diets increase production of a gut hormone (known as GIP) that blocks leptin’s effects – possibly explaining leptin resistance. “We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight,” says study co-author Makoto Fukuda, PhD, an assistant professor at Baylor. “We didn’t know how a high-fat diet or overeating leads to leptin resistance. My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods, [and] we discovered a connection between the gut hormone GIP and leptin.”

Decoding the Gut-Brain Connection

Scientists who have been studying leptin since its discovery in 1994 aren’t entirely certain just how and why this complex interaction of fat, hormones, and brain circuitry drive obesity.

“When leptin was discovered, everybody thought that we found the magic bullet for obesity,” Sharma says. “But it’s more complicated than that. We know now, it’s not that simple that leptin is acting alone – that’s not the case. Leptin does induce a lot of circuits in our cells and in a lot of pathways that trigger a lot of responses … not only in the brain, but also in various kinds of cells, including cancer cells.”

That’s where Shin and her team of researchers come in – to understand the complex but elusive gut-brain circuits that leptin impacts.

The Virginia Tech team is targeting this gap in scientific knowledge to identify the brain pathways responsible for high-fat diet relapse.

In lab research, Shin and her colleagues discovered that mice exposed to a high-fat diet tended to select high-fat foods when given the choice over their normal diet. But they also found the rodents ate too much after a period of not having fatty foods.

And not only mice tend to do that, she says. Anyone who’s ever been on a diet that restricts fat knows that you may lose weight at first but feel powerful cravings for such foods. Eventually, most dieters relapse – returning to their former high-fat eating habits, just like Shin’s mice, and overeating.

What drives that pattern, she says, has less to do with willpower than with the brain’s response to leptin.

“Our study is significant, because for the first time, we will have an important framework for clarifying how the leptin-responsive brain circuit responds to high-fat food exposure, and how that interaction increases the risk of emotional overeating following a period of abstinence,” says Shin, an assistant professor in the Department of Human Nutrition, Foods and Exercise in the College of Agriculture and Life Sciences at Virginia Tech.

Her study is the first of its kind to look more closely at the various brain regions believed to play a central role in regulating food intake and body weight, advancing what is known about obesity-related hormones.

“It should lead to a conceptual advance in how we think about the central leptin’s action and its sensitivity from the cellular level, one brain site, to a more holistic, distributed network level,” she says. “In the practical point of view, we can also expect that successful completion of this study will provide important insights for developing precise brain circuit-based targets which will guide translational work to create new circuit therapeutics for treating pathological binge-eating habits or relapse to obesity.”

The big picture: Shin says the evidence shows that obesity is, at least in part, a result of a “problem of brain circuit dysfunction in molecular and neuronal level, instead of [an] individual willpower issue.”

So, what’s the practical take-home message of the emerging science on leptin, obesity hormones, and weight gain?

While future therapies may help target high leptin levels or leptin resistance, Sharma and other experts say the best thing you can do today is follow the tried-and-true advice on maintaining a healthy body weight.

  • Eat nutrition-rich, balanced meals and limit high-fat foods and snacks.
  • Get regular exercise – aim for about 30 minutes most days of the week.
  • Manage stress levels and aim to get at least 7 hours of sleep each night. (Poor sleeping habits and high levels of stress are both linked with weight gain.)

There is another big take-away from the emerging science on leptin and obesity, Sharma says.

“I think definitely, this kind of research will actually uncover a lot of new circuits, so maybe in the future, we can have some new tools to help these people,” she says. “But from the get-go at least, this research will lead to more understanding, in the sense of why do people fall off their diet plans, because that is a very big problem, and how we should not be just blaming them for having no willpower.”

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