Summary: Variants in the inflammatory gene RIPK1 have been identified in people with obesity. These variants increase RIPK1 expression in adipose tissue, which is linked to a higher risk of obesity.
Source: University of Queensland
Researchers at The University of Queensland have found that a gene that controls inflammation can increase the risk of obesity and that reducing its activity in mice prevents weight gain.
Dr. Denuja Karunakaran, a researcher at the UQ Institute for Molecular Bioscience, led the investigation to clarify how inflammation and obesity are connected beyond diet and physical activity. Her team focused on the inflammatory regulator RIPK1 and how small genetic variations affect its role in adipose tissue.
“We identified subtle changes in the RIPK1 gene among people with obesity,” Dr. Karunakaran said. “Those variants were associated with higher levels of RIPK1 in fat tissue, which in turn correlated with an increased risk of obesity.”
RIPK1 plays a key role in coordinating immune responses; however, when its regulation is disrupted, it can drive excessive inflammation. The researchers measured inflammatory markers in people and observed elevated inflammation linked to higher RIPK1 activity in adipose tissue.
To test causality, the team manipulated RIPK1 function in mice. Mice that lacked or had therapeutically reduced RIPK1 remained at normal weight despite being fed a high-fat diet and showed lower risk factors associated with diabetes. In contrast, mice with normal RIPK1 expression gained weight on the same diet.
The human portion of the study included more than 2,000 participants. Over half of them were classified as severely obese, with an average body mass index of 41, while the remainder were within a healthy weight range. The genetic analysis revealed that particular RIPK1 polymorphisms were associated with increased gene expression in adipose tissue.
Dr. Karunakaran explained the biological mechanism observed: when fat stores expand beyond healthy limits, adipose tissue becomes stressed and some cells die, which activates the immune system. “In obesity, immune cells become overactive and drive damaging inflammation when they fail to switch off,” she said. “By mapping these inflammation pathways, we can identify new therapeutic targets to treat obesity, particularly in groups of people who struggle to lose weight despite healthy lifestyle efforts.”
The study suggests that genetic variants near the RIPK1 locus alter regulatory sequences that increase promoter activity and RIPK1 expression in fat tissue. These variants are not common—Dr. Karunakaran noted they occur in roughly 8–12% of the population—so they may help explain why some individuals find weight loss especially difficult even when following recommended diet and exercise plans.
Collaborators on the project included Associate Professor Katey Rayner and Professor Ruth McPherson from the University of Ottawa Heart Institute.
About this genetics research article
Source:
Garvan Institute of Medical Research
Contacts:
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., published in Nature Metabolism.
Abstract
RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice
Obesity represents a major global health challenge and is characterized by chronic, low-grade inflammation driven by interactions between 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, integrating signals that control inflammation, apoptosis and necroptosis in response to inflammatory stimuli. This study shows that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 expression and obesity. One identified single nucleotide polymorphism falls within a binding site for the transcription factor E4BP4 and enhances RIPK1 promoter activity, leading to elevated RIPK1 expression in adipose tissue. Therapeutic silencing of RIPK1 in a mouse model of diet-induced obesity significantly reduced fat mass and total body weight and improved insulin sensitivity. These changes were accompanied by reduced macrophage accumulation and increased invariant natural killer T cell presence in adipose tissue. The findings indicate that RIPK1 is genetically linked to obesity and that reducing RIPK1 expression may be a viable therapeutic strategy to target obesity and related metabolic diseases.