New research in mice suggests that muscle mass changes less than expected, but muscles may still get weaker, pointing out an urgent need for clinical studies to pin down the full effects of the popular medications.

"If we want to really help the individuals who may be losing muscle mass, then we need to know that they're actually losing muscle mass," says Katsu Funai, PhD, associate professor of nutrition and integrative physiology in the University of Utah College of Health and the senior author on the study. "We have data in mice that suggest that things are not as straightforward as they might seem."

The results are published in Cell Metabolism.

A weighty concern

Researchers found that Ozempic-induced weight loss did decrease lean mass by about 10%. Most of this lost weight wasn't from skeletal muscles but instead from other tissues like the liver, which shrunk by nearly half. The researchers emphasize that more research is needed to determine whether similar changes to organ size occur in humans -- and whether those changes come with any risks.

"Loss of mass in metabolically active organs, such as the liver, is expected as part of healthy weight loss," says Ran Hee Choi, PhD, research instructor in nutrition and integrative physiology at U of U Health and co-first author on the study. In both mice and humans, weight gain and loss can affect the size of organs like the liver without affecting their function. "It's unlikely that the observed lean mass loss represents a serious adverse effect," says Takuya Karasawa, PhD, postdoctoral researcher in the U of U Molecular Medicine Program and co-first author on the study.

Some skeletal muscles did shrink as the mice lost weight -- on average, by about 6%, not enough to explain the overall loss in lean mass. Other muscles stayed the same size.

Some of this loss in muscle mass is a return to baseline, the researchers say. Gains in fat also tend to lead to gains in skeletal muscle, since the body must do more work to move around. So loss of fat can lead to loss of muscle without affecting overall quality of life.

Size isn't strength

Interestingly, when the researchers tested the amount of force the mice's muscles could exert, they found that, for some muscles, strength decreased as the mice lost weight, even when the size of the muscle stayed roughly the same. For other muscles, strength was unchanged. It's unknown how weight loss drugs affect this balance in people, the researchers say.

A potential loss of strength when taking Ozempic may be of particular concern for adults over the age of 60, who are at higher baseline risk for muscle loss and reduced mobility. "The loss of physical function is a strong predictor of not just quality of life but longevity," Funai adds.

Clinical trials are needed

The researchers caution against extrapolating their results directly into humans, because mice and humans gain and lose weight in different ways. In people, obesity is associated with lower physical activity, but mice don't tend to become less active when they gain weight. And the mice in this study became overweight because they ate a high-fat diet, whereas people become overweight for a wide variety of reasons that include genetics, diet, sleeping patterns, and age.

Instead of drawing a one-to-one parallel with humans, the researchers say their results emphasize the need for more clinical studies. "There remains a significant need for validation in humans, especially concerning muscle strength," Karasawa says.

Funai adds that clinical trials should check for changes in muscle strength not just for Ozempic but also future weight-loss drugs. "There are many additional weight loss drugs that are in clinical trials and coming out in the next three to five years," Funai says. "But with all those clinical trials, if they're interested in measuring lean mass loss, they need to consider physical function."

"Our findings are really interesting, but this is a preclinical model," he adds. "We need these data in people."

The results were published in Cell Metabolism as "Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice."

This study was supported by the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers DK107397 and DK127979), the National Institute of General Medical Sciences (grant number GM144613), the National Institute on Aging (grant numbers AG074535, AG065993, AG076075, and AG086328), and the National Cancer Institute (grant number CA286584), as well as by the Grant-in-aid for Japan Society for Promotion of Science Fellows (grant number 24KJ2039). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

• Lipoedema is thought to be a common, but little-known disease that mainly affects women.
• The disease is painful. Lipoedema is characterized by disproportionate and excess fatty tissue on the thighs and calves, and sometimes on the arms, while the hands and feet are unaffected.
• A new doctoral thesis at NTNU investigated the relationship between two different diets and the effect on pain, quality of life, body weight and body composition, appetite and inflammation.

It all started when she was in lower secondary school.

Her thighs, calves and upper arms suddenly began to grow, and she could not understand why it was so painful. It was not until she was over 40 years old that Sunniva Kwapeng was diagnosed with lipoedema.

However, before a correct diagnosis was made, she tried all sorts of diets -- with little success.

A recent NTNU study shows that her experience is quite typical. It is unlikely that the body fat associated with lipoedema can be lost through dieting.

Limited knowledge

"Despite this being a disease that affects many women, little is known about it, which is rather thought-provoking," said Julianne Lundanes, a former PhD candidate at NTNU.

Lipoedema is a poorly understood disease that primarily affects women.

The disease is characterized by disproportionate and excess fatty tissue on the thighs and calves, and sometimes on the arms, while the hands and feet remain unaffected.

Lundanes recently submitted her doctoral thesis at NTNU on the relationship between two different diets and their effects on pain, quality of life, body weight and composition, appetite and inflammation.

Some people also become obese

Lipoedema is painful. It can be painful to move, and it is easy for people with the disease to get caught up in a vicious cycle of inactivity and reduced quality of life. Lipoedema is often mistaken for obesity, but they are two distinct conditions.

If a person with lipoedema loses weight, it is common to see normal fat disappear, such as on the stomach, while the calves and thighs remain the same size. When a person is obese, fat can be stored all over the body, both under the skin and around the internal organs.

In lipoedema, the accumulation of fatty tissue occurs mainly under the skin on the hips, thighs, calves and arms.

The pain associated with the disease can have a significant impact on quality of life, making movement difficult.

"We don't know why the disease is so painful. We believe it involves an inflammatory condition in the fat, and that this is what causes the pain," said Lundanes.

Lipoedema is often hereditary

There are currently no Norwegian national guidelines for the treatment or follow-up of women with lipoedema.

"We also don't know much about why some women develop lipoedema, except that it appears to be hereditary. It is often the case that several people in the same family are affected by it. The disease often manifests during hormonal changes such as puberty, pregnancy and menopause," Lundanes said.

The aim of Lundanes's study was to determine whether a low-carbohydrate diet could serve as an alternative form of treatment for patients with the disease.

She had a sample of 70 women with lipoedema aged 19-73 years old, which was divided into two groups.

One group followed a low-carb diet, while the other followed a low-fat diet. Both groups ate the same number of calories each day, but the amount of carbohydrates and fat varied.

The participants received weekly follow-up for eight weeks and were tested at the beginning and end of the study. Pain and quality of life were measured through a questionnaire.

The results showed clear differences between the two groups.

Similar degrees of inflammation

"The women in the low-carb group had less pain. The participants in the other group did not experience any change in pain, but both groups reported better quality of life," said Lundanes.

Tests were also carried out to see if the reduction in pain was due to the low-carb diet leading to less inflammation in the body. This turned out not to be the case.

"There was no difference in changes in inflammation between the two groups. We also measured inflammation through blood tests, so inflammation in the fatty tissue itself still needs to be investigated in order to draw any conclusions," Lundanes said.

Greater weight loss on the low-carb diet

The women who followed the low-carb diet lost more weight than those who followed the low-fat diet.

"At the end of the study, we found that the women who ate fewer carbohydrates were less hungry than the other group. The feeling of being less hungry is a well-known benefit of low-carb diets once ketosis is achieved. This may have helped these women lose more weight than the other group," Lundanes said.

There is no treatment that can eliminate the causes of or cure lipoedema. There's only treatment that can alleviate some of the symptoms.

Liposuction is one option, but it is currently only offered as part of a research study at Haraldsplass Hospital in Bergen. The only other alternative is to pay for private surgery, and that can cost hundreds of thousands of Norwegian kroner.

"The long-term effects of lipoedema liposuction have still not been fully investigated. There is a lack of research in this area too," Lundanes said.

Compression reduces pain

Most people currently receive help in the form of physical therapy and compression garments that squeeze and support the fatty tissue.

"Compression garments give many people relief," says Lundanes.

For Kwapeng, compression garments have been a great help in managing the pain.

"I've also lost many centimeters on my legs because of the compression garments. My expenses for compression are covered, but in other parts of the country, they're not. It's completely random what kind of help you get," says Kwapeng.

At home, she has a machine that's also used by patients with other conditions. The machine is called a pulsator and is a vacuum treatment for the lymphatic vessels designed to activate the lymphatic system. Lymphatic drainage initiates several cleansing processes in the body and can help improve blood circulation.

The machine is like a giant pair of pants used while lying down.

"It works really well for me. It takes away the pain. I also get more energy. If I have low energy and lie down in it, it's like my body wakes up," says Kwapeng.

Over time, she has learned to live with the disease.

"It's frustrating to have a condition that is so poorly understood. A doctor once told me that at least I won't die from having lipoedema -- but I die a little every time I can't sit on the floor with my daughter. I die a little every time I can't go on a hike I want to take because of the pain. And I die a little every time people think I'm just fat and lazy," Kwapeng said.