A primary function of cytokines is to initiate immune responses; however, it has become increasingly apparent that they play major roles in the regulation of energy homeostasis, implicating them in metabolic disease. One such cytokine is interleukin-18 (IL-18). Obese individuals have increased levels of IL-18 that correlate strongly with metabolic syndrome and insulin resistance. Recent evidence suggests that IL-18 acts to trigger AMP-activated protein kinase (AMPK) signaling and lipid oxidation in skeletal muscle, which can balance lipid accumulation on a high-fat diet (HFD). In contrast, administration of IL-18 has been shown to prevent weight gain, where the loss of IL-18 results in exacerbated adiposity and insulin resistance.
Previous studies show that NLRP1 is a biological sensor that can respond to and prevent obesity and metabolic syndrome, which are causing a dramatically increasing burden of disease throughout the world. The sensor is activated if it detects that the body’s energy intake is too high. When the sensor is activated, it tells cells to burn fat stores to prevent excess build up of fat.
Earlier studies from the group show that NLRP1 is an active part of the immune system, recognizing Toxoplasma infection. They also showed that NLRP1 is activated in the context of hematopoietic stress such as chemotherapy or severe infection. However, as with the aforementioned study, a direct NLRP1 ligand was not identified, suggesting a sensor role in homeostatis, which when disturbed activates an inflammatory response involving the enzyme responsible for the activation of IL-18. The current study shows that without NLRP1, fat stores continue to build up, especially with a high-energy diet, leading to obesity.
The current study used a mouse model lacking NLRP1. Data findings show that the mice lacking NLRP1 develop a large increase in adipose tissue spontaneously and that this is exacerbated by high-fat feeding. This is exacerbated when the mice are fed a high-fat diet or a high-protein diet, however, not when mice are fed a HFD with a low energy density diet (high-fiber diet). Results show that NLRP1-deficient mice inappropriately regulate blood glucose, insulin, and leptin levels, which mirror the metabolic syndrome observed in mice lacking IL-18.
Results show that all of these abnormalities are reversed in mice with an activating mutation in NLRP1, where the anti-obesity, anti-glucose intolerant effects are abolished by genetic deletion of IL-18. The team observed that the IL-18 increase due to a high-fat diet is fatal for NLRP1 activating mutation mice, with a marked loss of adipose tissue and cachexia. The lab explain that NLRP1 functions in the context of increased energy intake to produce IL-18 as a negative feed-back signal that prevents obesity and metabolic syndrome. They go on to conclude that NLRP1, more commonly known for its role in the immune system, also has an important role in regulating metabolism.
The team surmise that their findings provides evidence that the immune system is activated during infection, and in response to the loss of metabolic ‘equilibrium’ associated with a high-energy diet. They go on to add that their research shows that activation of NLRP1 could be exacerbated by some diets, and identify a fine balance between increasing the cell’s fat burning abilities and causing harm. For the future, the researchers state that they plan to develop a small molecule which activates the pathway to produce IL-18, and, in people who are obese, help the body to switch on this system and burn existing fat stores.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.