Researchers have found that a specific protein secreted by the liver during intermittent fasting could potentially be targeted to treat obesity and diseases associated with the condition, like type 2 diabetes and cardiovascular disease.

During intermittent fasting, or alternating between a period of eating and at least 12 hours of not eating, white fat tissue — also known as adipose tissue — is remodeled in a metabolic process that can kickstart weight loss. Although the body needs a certain amount of white adipose tissue, as it provides insulation and serves as an energy reserve, an overabundance of it can lead to obesity. 

Promoting this fat remodeling process is a viable strategy for combating obesity, and researchers such as Bing Luan, a professor at Tongji University’s School of Medicine in Shanghai, China, have been searching for ways to tap into it. 

“This mechanism is crucial in combating obesity by increasing energy expenditure and helping to burn stored fats, thereby reducing overall body weight,” Luan explained.

Adipose tissue browning promotes fat loss

Luan and his colleagues discovered that the remodeling of white fat into “brown-like” or beige fat, a process called adipose tissue browning, is triggered by a protein called orosomucoid 2 (Orm2), which is secreted by the liver during fasting.

“Orm2 is a protein secreted from the liver during intermittent fasting that promotes the browning of adipose tissue,” explained Luan. The protein targets specific receptors on fat cells, boosting the cells’ ability to burn stored fat.

Brown fat burns calories and produces heat through metabolism rather than shivering, which relies on muscle contractions. This process, called thermogenesis, is possible because the cells that make up iron-rich brown fat tissue, called adipocytes, contain abundant mitochondria, which accelerate heat production.

To investigate how the liver communicates with adipose tissue during intermittent fasting, Luan and his team studied obese mice on an alternate-day fasting protocol.

Compared with mice fed a normal diet, the fasted mice were more efficient at producing energy, as indicated by their higher oxygen consumption, lower ratio of carbon dioxide production to oxygen uptake, and higher energy expenditure, the amount of energy used to maintain essential body functions and movements.

In the white adipose tissue of fasted mice, the researchers detected an increase in the levels of genes associated with thermogenesis. Orm2 levels in the liver and bloodstream were also elevated. All of these measurements indicated that the fasting protocol induced adipose tissue browning.

After feeding mice a high-fat diet for 10 weeks without fasting, the researchers injected Orm2 directly into the white adipose tissue. They found that the injections, delivered daily over 21 days, effectively counteracted weight gain in by reducing the mass of white adipose tissue brought on by the high-fat diet. The injections also improved glucose tolerance, another reported benefit of intermittent fasting.

“In our studies with obese mice, Orm2 treatment significantly increased adipose tissue browning and led to weight loss,” Luan stated.

“This effect was absent in mice treated with a mutant form of Orm2, which lacks the ability to bind to its specific receptors, underscoring the importance of this interaction,” he added.

This finding in line with recent evidence that an Orm2 deficiency aggravates obesity caused by a high-fat diet by creating an imbalance in gut microbiota and increasing intestinal inflammation.

Findings should not shift focus away from healthy diet and exercise 

Although these findings suggest that Orm2 promotes fat burning, any future weight-loss treatment based on Orm2 should not be regarded as a replacement for healthy eating habits and exercise.

Fat remodeling stimulated by Orm2 treatment differs from the mechanism of weight loss drugs. Most of these drugs, like Ozempic, work by suppressing appetite, thus reducing calorie consumption. However, individuals taking these drugs face the risk of malnourishment if they do not eat enough calories and nutritious foods.      

In fact, eating certain nutritious foods, like apples, has been shown to activate brown and beige fat production. Although some mice and human studies have suggested that exercise can also stimulate adipose tissue browning and thermogenesis, the situation is more complex according to other researchers. 

“While there is potential concern that Orm2 treatment might shift focus away from essential lifestyle changes like diet and exercise, it is important to view such treatments as complementary to, rather than replacements for, these foundational health practices,“ Luan stressed.

As the study involved mice, whether humans would benefit in the same way is also unclear. Mice have a much higher metabolism than humans, and research has shown that intermittent fasting on its own does not automatically make someone healthier.

“Our study’s primary limitations include its reliance on mouse models, which may not fully replicate human physiological responses, the unexplored long-term effects and safety of Orm2 treatment, and the potential for other mechanisms to contribute to the observed effects,” Luan commented.

Before they consider human trials, a few prerequisites need to be met, Luan added. This includes extensive safety and efficacy testing in preclinical settings, dosage optimization, and obtaining regulatory approvals to ensure that Orm2 is both safe and effective.

Reference: Donglei Zhou, Junfeng Han, Bing Luan, et al, Intermittent Fasting-Induced Orm2 Promotes Adipose Browning via the GP130/IL23R-p38 Cascade, Advanced Science (2024). DOI: 10.1002/advs.202407789

Feature image credit: Dushawn Jovic on Unsplash