Inflammatory Gene Provides Clue to Obesity Risk

Summary: Mutations of the inflammatory RIPK1 gene have been identified in people with obesity. The variation caused an increased amount of the gene in fat tissue. This increased risk of obesity.

Source: University of Queensland

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 from The University of Queensland has found.

UQ Institute for Molecular Bioscience researcher Dr. Denuja Karunakaran said she was determined to unravel the links between inflammation and obesity that went deeper than excessive eating or lack of exercise.

“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,” Dr. Karunakaran 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 researchers then looked at the effect of turning the inflammatory gene on and off in mice.

Without the gene, the mice remained at a normal weight despite eating a high-fat diet and their risk of diabetes was reduced.

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.

Dr. Karunakaran said that when stores exceeded healthy levels, the fat tissue became overwhelmed, cells died and the immune system was activated.

This shows DNA
The mice with a normal level of the inflammatory gene put on weight from eating the same high-fat diet. Image is in the public domain.

“In obesity, the immune cells are working in overdrive, causing damaging inflammation when they don’t switch off,” she 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% of the population—so maybe these are the people who struggle to lose weight despite doing all the right things.”

The University of Ottawa Heart Institute’s Associate Professor Katey Rayner and Professor Ruth McPherson collaborated on the study.

About this genetics research article

Garvan Institute of Medical Research
Press Office – University of Queensland
Image Source:
The image is in the public domain.

Original Research: Closed access
“RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice” by Denuja Karunakaran et al. Nature Metabolism.


RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We 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. 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. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.

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