Ozempic settles the obesity debate: it’s biology over willpower

The success of weight loss drugs shows the importance of chemistry in losing the kilos, with research showing the brain decides how much weight it wants to carry.

The success of Ozempic and other weight loss drugs shows obesity is caused by brain chemistry rather than motivation.

Ozempic and similar drugs are transforming the world’s understanding of obesity. It isn’t so much about willpower : It’s about biology.

The success of the powerful new class of diabetes and weight-loss drugs shows how important chemistry is to determining a person’s weight. The brain is the body’s chief chemist, regulating appetite and making it difficult for many people to shed pounds and keep them off. The brain determines how much fat it wants people to carry, according to years of research bolstered by the new drugs.

The amount is like a setting on a dial, or what many researchers call a “set point” or “defended fat mass.” The brain maintains the dial setting or set point by regulating how much a person eats. Ozempic, its sister drug Wegovy and another, Mounjaro, lower the dial setting, or set point, in effect by acting on the brain to reduce hunger and make a person feel full sooner, some obesity researchers say .

The new set point lasts as long as a patient is on the drug, they say. Patients who ate a lot before they started taking one of the drugs feel less hungry and fill up more quickly -- sometimes after one slice of pizza when they once ate the whole pie.

“This is not about willpower or personal choice,” said Dr. Florencia Halperin, an endocrinologist and chief medical officer of Form, a virtual medical weight-loss clinic. “This is about your brain driving behaviors.”

Ozempic was originally approved by the FDA to treat people with Type 2 diabetes, but in recent months it has seen a spike in popularity due to its weight loss benefits.

The drugs and their insights into biology have arrived at a precarious point in the losing battle against obesity. Although Americans spend billions of dollars a year to shed pounds, growing numbers are overweight. Nearly 42% of U.S. adults have obesity, according to the latest government statistics, up from 31% in 1999. So do one in five children.

People with obesity are more likely to develop heart disease, stroke and diabetes. Treating them is driving more than $170 billion in yearly costs. Wegovy has been shown to reduce cardiovascular risk, and Mounjaro is being studied for additional health benefits.

The new medicines have put some long-held assumptions about weight and health on the chopping block. “What these drugs have proven is that patients are right: It’s not their fault,” said Dr. Louis Aronne, an obesity treatment specialist and professor of metabolic research at Weill Cornell Medical College.

He and many other specialists who study obesity or prescribe the new drugs have advised or conducted studies for the companies making them.

Jon Weisman was about 300 pounds, prediabetic and at risk of heart disease when he sought help losing weight in 2020. The 46-year-old, who works in mortgage banking and real estate in Boston, had tried restricting food but always then felt hungrier. “I’m not wired for 2,000 calories a day,” he said. “I’m probably wired for 4,000.” He went back on an earlier-generation weight-loss drug, Saxenda, that he had tried before. He lost about 30 pounds, but then hit a plateau.

In September 2021 he conferred with Dr. Halperin, who prescribed Wegovy. His hunger quickly abated. He no longer craved onion rings, mac and cheese and other heavy foods that he once chowed down in marathon dinners with friends, now preferring greens and proteins.

He reached his goal weight of 180 pounds a couple of months ago, and is staying on the drug, which he sometimes has to call around to a few pharmacies to find. “This is something I am going to have to have treated for the rest of my life,” he said. He is off the two blood pressure medications he was on, has switched to a low dose of a cholesterol-lowering drug and is no longer prediabetic. He eats a little more now, to maintain rather than lose weight.

The obesity epidemic is a product of forces, old and new, that have collided in people like Weisman: human biology shaped over millennia of struggle to find sustenance; lives that are largely lived sitting down; and the abundance of cheap, processed foods.

Potato chips, soda and other cheap processed foods are a big culprit because they are high in calories, sugar, salt and fat, and they are hard to put down, studies suggest. People who lived for a month in a research facility at the National Institutes of Health ate more and gained weight on a diet of processed meats and cheeses, tater tots and other processed foods compared with when they were on a diet of vegetables, whole grains, fish and other unprocessed foods, according to a 2019 study.

Tik Tok accounts talking about the obesity weight loss Ozempic.

For some people, high-calorie foods are especially problematic. At least 1,500 genes are linked with weight. Some people are genetically predisposed to gain weight, depending on the combinations of variants in those genes, said Ruth Loos, a professor focused on the genetics of obesity at the Novo Nordisk Foundation Center for Metabolic Research at the University of Copenhagen and at the Icahn School of Medicine at Mount Sinai. These genes often act in the brain.

Primitive parts of the brain that control breathing, heartbeat and other essential functions collaborate with hormones and the central nervous system to determine how much fat the body wants to have and keep it at the set point. The system has been shaped by thousands of years of humans foraging to survive.

The brain sends hunger signals when a person needs fuel to reach or maintain their set point, and signals a sense of fullness when they reach or exceed it. That is why people who lose weight fighting off an illness are ravenous once they recover, or why people feel sick when they overeat. It’s also why people -- like some participants in “The Biggest Loser” TV series -- tend to regain weight even after they try to lose it, according to research.

The set point isn’t set: It changes naturally throughout a person’s lifetime. Babies lose body fat. Women gain weight during pregnancy and menopause. It can make small changes, with a person gaining or losing a few pounds.

In a person with obesity, however, the set-point system has gotten out of whack , said Dr. Lee Kaplan, director of the Obesity and Metabolism Institute in Boston. The body-fat dial moves to a new higher set point.

Obesity causes overeating, rather than the other way around, Kaplan said. The new drugs are based on a hormone called glucagon-like peptide 1, or GLP-1, secreted primarily in the lining of the gut in response to food, and in the brain. Drug hunters were initially interested in GLP-1 because it plays an important role in regulating blood sugar. The first GLP-1 drugs were approved to treat diabetes in 2005.

Tik Tok accounts talking about the obesity weight loss Ozempic.

Wegovy is the only GLP-1 drug approved by the Food and Drug Administration as an anti-obesity treatment, while Ozempic, with a lower dose of the same active ingredient, semaglutide, is approved for diabetes. The FDA is expected soon to approve Mounjaro for weight loss. Mounjaro, already cleared to treat Type 2 diabetes, mimics the action of a hormone called GIP in addition to GLP-1.

The medications essentially lower the set point by activating GLP-1 receptors in the hypothalamus and brain stem that regulate weight and appetite, said Randy Seeley, a professor of surgery and director of the Michigan Nutrition Obesity Research Center at the University of Michigan. The drugs also indirectly reach neurons in parts of the brain involved in reward sensations and impulse control.

“We are in a constant search to identify the most critical neurons that respond to these drugs,” he said.

Once a patient reaches a new set point, some of their appetite returns -- they are no longer feeling overfed -- but the medications keep them at their new level, Seeley said. If a patient stops taking the medication, the new set point no longer holds, which is why people regain weight, he said.

The set point concept is hard to prove definitively, some researchers say. The makers of the drugs, Novo Nordisk and Eli Lilly, say their drugs reduce hunger and increase satiety while a person takes them.

Researchers want to figure out what makes the set point go way up for some people, leading to obesity, Kaplan said: “For the moment, it’s a black box.”

WSJ