Will New Drugs Be a Game-Changer for Appetite Control?

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There has been a lot of press lately about the new drugs for type II diabetes that, lo and behold, also result in dramatic weight loss. The drugs work well for controlling the insulin response. It is not clear how much the concomitant weight loss contributes to improving the disease of type II diabetes. But it didn’t take long for people to want these drugs to help them lose weight—diabetes or no diabetes.

The drugs, most notably Ozempic, Wegovy, and Mounjaro (there are others in the pipeline), work in two ways. They decrease blood sugar levels by increasing insulin production and lowering the amount of sugar that the liver makes. And they slow down the rate that food passes through the body, thereby making a person feel full longer.

Apparently, these actions are enough to change the brain’s response to food. People on these drugs often rave about the fact that they don’t think about food all the time anymore. This comes as a huge relief to many. Being able to get a handle on their appetite seems to be the key to weight loss in this case. This effect on weight control is why the Food and Drug Administration has now put Mounjaro on the fast track to be approved for weight loss.

Other things to consider

There are a few glaring caveats that can sometimes be overlooked in the rush of enthusiasm accompanying these drugs.

1. The cost. These are as of now injectable drugs that currently come with a cost of around $1,300 a month. Many insurers do not cover the cost when it is being used off-label for weight loss. This means that, currently, using these drugs to combat obesity would be a non-starter for many.
2. The use of these drugs is meant to go along with coaching to help individuals make permanent lifestyle changes—in other words, changing their food choices and adding more exercise to their lives. How often this is the case, or how often these changes are successful, remains a mystery.
3. Last, but not least, is the fact that once the drugs are discontinued, weight comes back on.

Because the weight comes back on, an important question needs to be asked: Why don’t these drugs permanently change the brain’s response to food? Taking a look at this can provide some interesting insights into the whole mess of appetite control.

First, let’s take a look at recent research out of Yale University. A team took a group of 28 people identified as “lean” and another group of 30 identified as “obese.” They put the obese group on calorie restriction so that they lost about 10 percent of their body weight. Before and after, they did functional magnetic resonance imaging (fMRI) brain scans on everyone as they infused their stomachs with glucose and fat. They then checked several areas of the brain that have been linked to the rewarding and motivational aspects of food intake.

Long story short, they discovered that the obese group showed a blunted response to nutrient intake both before and after their weight loss. In other words, weight loss did nothing to change the brain’s lack of response to nutrients. These findings are compatible with other research that has shown reduced nutrient sensing in people with obesity.

As usual, the research raises a lot of questions, but it is intriguing to consider what exactly is happening in the brain that causes diminished nutrient sensing. It also appears, as shown in this study, that losing weight does not impact this diminished response. It is clear that just about everyone who loses weight puts it back on eventually, whether the weight loss is due to dieting (calorie restriction) or the apparent change in appetite caused by drugs.

Frustration abounds, including among those working in the field of obesity. Randy Seely, Ph.D., director of the National Institutes of Health-funded Michigan Nutrition Obesity Research Center, puts it this way: “We’ve run lots of different trials to do obesity prevention, and almost all of them have been abject failures.”

Why does the weight come back on? Why doesn’t the brain change the way it controls appetite once it learns to eat less?

What’s involved

To put us on the road to an answer, let’s take a look at how our body deals with food intake and regulation of our appetites. Casting a wide net, there are two basic and complex systems involved: the endocrine system and the nervous system. Located centrally in our brains, the hypothalamus is a key regulator of appetite. It gets feedback from the liver, pancreas, the entire gut, gallbladder, and kidneys. This is the endocrine system. In the nervous system, neurotransmitters tell various areas of our brains what is going on as we digest food or seek food.

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It appears that, as is the case with the diabetes drugs, influencing a few systems (even though those systems are in themselves highly complex) is not enough to change the brain’s response to food permanently. While it helps to control appetite in the short run, their effects apparently are not comprehensive enough to have lasting effects.

This is where we can circle back to one of the caveats mentioned above — that is, the drugs producing weight loss are also supposed to be accompanied by lifestyle changes that support weight loss. Those lifestyle changes are related to what we eat and how we move. Both of these changes involve many of our complex bodily systems all at once. It is not an approach that uses a specific substance to target a specific response to food intake.

The same could be said of calorie restriction (dieting). Rather than involving the brain in comprehensive approaches that change how we relate to food, dieting just puts a Band-Aid on the appetite and demands short-term control. The solution appears to lie with taking actions that obesity researchers have found to be effective for weight loss and maintenance of weight loss:

1. Avoid processed carbohydrates. Actually, avoid as much processed food as possible.
2. Get enough fiber. How? Eat fruit, vegetables, whole grains, legumes, beans, nuts, and seeds. In other words, eat whole, nonprocessed foods.
3. Focus on the Mediterranean style of eating. It has been shown again and again to reduce cravings and lead to weight loss.
4. Exercise. Those who exercise get more efficient at using body fat as fuel. People who don’t exercise use more carbohydrates, which leads to blood sugar fluctuations and appetite swings.

Is this an easy road to take? Unfortunately, no. It is a long, arduous process that needs a lot of support. And it takes our brains and the rest of our systems a long time to adjust. Little wonder that taking a pill is an alternative that many find appealing.