A risk factor for obesity is written in your genes

October 5, 2020

“Do these genes make me look fat?”

A new study suggests the answer is yes, and for the first time ever, scientists believe it is the genes that cause inflammation that are at fault.

In a study published in Nature Metabolism, a leading academic journal covering a full-spectrum of metabolic research, scientists from the University of Ottawa Heart Institute (UOHI) bring to light that elevated levels of a natural pro-inflammatory protein called RIPK1 is a genetic risk factor for obesity.

The study’s principal investigator, director of the Cardiometabolic MicroRNA Laboratory at the UOHI, Dr. Katey Rayner, says scientists have long studied the association between inflammation and obesity, but that the finding is a first for metabolic science.

"Our work here is significant because it proves for the first time that an inflammatory factor predisposes genetically to obesity."

- Dr. Katey Rayner

“[Scientists] understood that obesity causes inflammation, but until now, there was still debate whether the reverse was true – that inflammation causes obesity,” Rayner told The Beat in a telephone interview. “RIPK1 is such an important factor in infection and other forms of inflammation, and we had been studying the gene mechanistically for its impact on cardiovascular health. Our work here is significant because it proves for the first time that an inflammatory factor predisposes genetically to obesity.”

Dr. Katey Rayner, UOHI.
Dr. Katey Rayner’s Cardiometabolic MicroRNA Laboratory studies how microRNAs alter the expression of key genes involved in the pathogenesis of atherosclerosis and other chronic inflammatory diseases, such as type II diabetes. The team also studies novel mechanisms of inflammation that promote plaque vulnerability.

More specifically, Dr. Rayner’s research (RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice) found that a genetic polymorphism of the RIPK1 gene – a variant identifiable to scientists as rs5873855 – is associated with obesity in humans. Scientists separated subjects of mice into two groups: those with elevated copies of the RIPK1 gene and those with normal levels of RIPK1. Researchers found that subjects with greater expression of RIPK1 were more susceptible to being obese and having other associated metabolic complications than their counterparts. When treated with an anti-sense oligonucleotide (ASO) therapy to inhibit the expression of the variant gene, the mice in the therapy group demonstrated to be leaner and healthier overall after the test period.

“What this data suggests is that by therapeutically targeting to silence RIPK1 expression, we can effectively reduce body weight and fat mass, with no effects on lean mass,” explains Rayner. “Similarly, mice in the test group demonstrated improved glucose tolerance, insulin sensitivity, and reduced inflammation of fatty adipose tissue.”

Rayner says the findings carry huge potential for future trials in obese humans.

“The type of drug used to inhibit RIPK1 in this study – the ASO – the style and chemistry of it, is clinically available today,” she said. “Translationally, it is not such a huge leap to use this exact same technology in humans in future trials because this type of drug is already proven to be safe and tolerated and effective for human use.”

Rayner adds: “We know with all certainty that a person’s likelihood for experiencing a heart attack is very much influenced by whether or not their parents or nearest relatives have had one. We know now it’s the same thing with obesity, however, like with heart attacks, we know this is not the end of the story.

“We hope our research serves as a beacon of hope for those who have been struggling with their own health and fitness goals, that this work in some way relieves any feelings of helplessness and failure in populations struggling with obesity.”

Dr. Rayner recently appeared as a guest on CBC’s All in a Day to discuss her work with host Alan Neal.