Could RAGE Be The Reason You’re Fed Up With Your Weight Loss Program?

We now know that a calorie deficit isn’t the end-all-be-all solution for losing weight. But why is this, and why do so many of us struggle to shed extra pounds? While poor diet is usually the number one culprit for stubborn excess body weight, a recent molecular finding sheds light on why weight loss may be so challenging. 

In a July 2019 study published in Cell, scientists uncovered a protein which resides on fat cell surfaces that plays an integral role in weight gain and loss. During times of stress, such as during dieting, excessive exercise, and overeating, the protein (RAGE, or receptor for advanced glycation end products) shuts down fat burning mechanisms. This protein could hold the answer for why it’s challenging to lose weight and even more challenging to keep weight off long term – especially when we’re trying our best by cutting calories and increasing our physical activity.  

During the study, scientists compared a group of regular mice to a second group of mice whose RAGE pathway had been deleted. The RAGE-absent mice gained 70% less weight and burned more calories while consuming the same high-fat diet and undergoing the same daily physical activity. The mice with the RAGE pathway intact hit metabolic ceilings resulting in significantly less calories burned and markedly more weight gained.  

Taking these findings further, researchers transplanted a small amount of brown fat from RAGE-absent mice to regular mice. Significant weight regulation benefits were observed.  

Takeaway: Scientists hypothesize that the RAGE pathway evolved to protect animals and humans from starving when the next meal was hard to come by – and because lifespan was so short, the negative impacts of RAGE (such as whole-body inflammation) were nonsequential. While testing and manipulating this pathway in humans will be a lengthy and meticulous process, scientists are hopeful that learning to regulate and manipulate the human RAGE pathway could help in fighting the obesity epidemic. And while transplanting RAGE-absent brown fat is in its early stages, the fact that this conferred significant weight management benefits in this preliminary mouse study is promising.