IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome

 Murphy et al., (2016) Cell Metabolism 23, 155-164

Speaker: Chih-Yu Huang (黃智裕)             )                 Time: 15:10-16:00, Mar 16, 2016

Commentator: Dr. Yao-Sheng Tsai (蔡曜聲)      )    Place: Room 601

Abstract

  IL-18已知在發炎小體經過caspase-1切除過後會進一步引發後續的免疫反應。除此之外，其他文獻指出它亦參與在能量調節以及代謝性疾病的病因。而失去IL-18會導致惡性肥胖和胰島素抗性，這也揭示IL-18可能有抗肥胖的效果。然而哪一種發炎小體調控此過程則還未知。作者發現和缺乏IL-18小鼠一樣，缺乏發炎小體1的小鼠亦會累積過多脂肪而導致肥胖、血糖及胰島素不穩定、瘦素增加的情形，而這些徵狀都與代謝性疾病相似。給予高脂飲食和高蛋白飲食則使得小鼠的肥胖和代謝症候群徵狀更加惡化；但給予高纖飲食則未見此情形。這些不正常的現象都能在發炎小體突變小鼠(Nlrp1^MUT)身上獲得改善，此種老鼠能產生高濃度的IL-18。Nlrp1^MUT小鼠在給予高脂飲食也會產生高濃度的IL-18。不幸的是這種因高脂飲食所產生的過量IL-18對這些老鼠是致命的。這些老鼠最後都死於肌肉和脂肪組織大量流失的惡質症，IL-18 deletion則可防止此種情況發生。總而言之，作者發現了發炎小體1作為能量的感受器，當感受到攝取過多能量後便會維持IL-18的恆定以防止肥胖和代謝性疾病的發生。IL-18 is known for its role in initiating immune responses after being processed by caspase-1 in inflammasome complexes. IL-18 is also indicated to play roles in regulating energy homeostasis and causing metabolic diseases ^[1]. Loss of IL-18 results in exacerbated adiposity and insulin resistance ^{[2] [3]}, the phenotype of obesity, which suggests that IL-18 has anti-obesity effects. However, which inflammasome regulates this process is still unknown. Here, the authors found that in consistent with mice lacking IL-18, mice lacking NLRP1 inflammasome develop spontaneous obesity due to lipid accumulation and fail to properly regulate blood glucose, insulin, and leptin levels that resembles the metabolic syndrome. This is even worsened when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not HFD with high fiber content. These abnormalities are reversed in mice with an activating mutation in NLRP1, with the increase in IL-18 level. Feeding these mice a HFD further increases the IL-18 level. Surprisingly, the increase of IL-18 due to HFD is fatal for these mice with a great loss of adipose tissue and cachexia, but this could be prevented by IL-18 deletion. In conclusion, the authors demonstrated that NLRP1 functions as a sensor in detecting increased energy intake to produce IL-18 for preventing obesity and metabolic syndrome.

References

1.     Febbraio, M.A. (2014). Role of interleukins in obesity: implications for metabolic disease. Trends Endocrinol. Metab. 25, 312-319.

2.     Esposito et al. (2002). Weight loss reduces interleukin-18 levels in obese women. J. Clin. Endocrinol. Metab. 87, 3864-3866.

3.     Hung et al. (2005) Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler. Thromb. Vasc. Biol. 25, 1268-1273.

1.           

Hung et al. (2005). Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler. Thromb. Vasc. Biol. 25, 1268-1273.