Obesity Protein Identified Controls Energy Consumption in Adipose Tissue

The rise in obesity rates worldwide is a disconcerting fact, to say the least, and can put an undue burden on many public health systems. For instance, in Portugal, almost half of the population is overweight and close to one million adults suffer from obesity. Known as a risk factor for the development of cardiovascular disease and diabetes, obesity is associated with chronic inflammation in fat tissues. A deeper understanding of the mechanisms involved in metabolic deregulation is critical to approaching the obesity problem and identifying new strategies to fight this disease.

“It is important to understand the fundamental mechanisms underlying how metabolic dysregulation occurs,” explained senior study investigator Colin Adrain, PhD, principal investigator at the Gulbenkian Institute of Science (IGC), in Portugal. “iRhom2 protein is strongly present in metabolic tissues and organs, which made us decide to study the role of iRhom2 in obesity in more detail.”

In the current study, the researchers sought to demonstrate how they used an animal model, comparing groups with iRhom2 deletion to controls, and feeding them with a normal diet versus a high-fat diet. Findings from the new study were published in Molecular Metabolism through an article titled, “Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.”

Surprisingly, they found that during obesity, iRhom2 protein levels increase specifically in brown adipose tissue (BAT) in obese animals compared to controls. Following up on this, they found that, on a high-fat diet, the animals lacking iRhom2 protein were metabolically healthier than their wild type counterparts.

“Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high-fat diet,” the authors wrote. “Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals.”

“The deletion of iRhom2 led to enhanced energy consumption in adipose tissue, which protected animals from fat accumulation and inflammation, fatty liver, and insulin resistance when the animals were placed on a diet that predisposed them to obesity,” added lead study investigator Marina Badenes, PhD, a researcher at the IGC. “At the cellular level, deletion of iRhom2 leads to an increase in thermogenesis (heat production) in brown adipose tissue. Thermogenesis in brown adipose tissue is an important physiological mechanism to consume excess body energy.”

Interestingly, no deleterious side effects were found in the animals with iRhom2 deletion, indicating that blocking iRhom2 may potentially be beneficial in the treatment of obesity and associated complications. The researchers intend to continue the project to further understand the mechanisms and cell types involved in the iRhom2 control of obesity. They also want to find out the specific targets involved in the protection against obesity-associated with loss of iRhom2.

“Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease,” the authors concluded.