A gene that helps to control inflammation increases the risk of obesity and could be turned off in mice to stop weight gain, a study has found.

"We found small changes in the inflammatory gene RIPK1 in the obese people, and these variations caused an increased amount of the gene being present in their fat tissue, increasing their risk of being obese," the senior author said.

"RIPK1 is essential for a healthy immune response, but it also causes hyper-inflammation when it 'goes rogue'.

"By finding an increased amount of inflammation in obese people, we can confidently say that obesity increases inflammation."

The authors show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. They show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue.

The researchers then looked at the effect of turning the inflammatory gene on and off in mice. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. 

The mice with a normal level of the inflammatory gene put on weight from eating the same high-fat diet.

More than half the 2000 participants were extremely obese with an average Body Max Index of 41 and half were a healthy weight.

The author said said that when stores exceeded healthy levels, the fat tissue became overwhelmed, cells died and the immune system was activated. "In obesity, the immune cells are working in overdrive, causing damaging inflammation when they don't switch off," the author said. "By understanding more about these inflammation pathways, we can find ways to intervene to treat obesity, especially in specific groups of people.

"These variations in the RIPK1 gene only occur in 8 to 12 per cent of the population - so maybe these are the people who struggle to lose weight despite doing all the right things."

https://www.uq.edu.au/news/article/2020/09/inflammatory-gene-provides-clue-obesity-risk

https://www.nature.com/articles/s42255-020-00279-2