Interleukin-1 receptor antagonist as a novel therapeutic target for obesity

Obesity has become one of the most fast-growing economic burdens in the world. It is associated with increased susceptibility to modern diseases, such as diabetes, cardiovascular diseases, and cancer. One of the common physiological changes in obese individuals is a chronic inflammatory state from increased circulating pro-inflammatory cytokines and adipokines, which are secreted from excessive adipose tissue. Human recombinant interleukin-1 receptor antagonist (IL-1Ra), commercially called Kineret (anakinra), has been prescribed to treat rheumatoid arthritis because it antagonises a pro-inflammatory signalling cascade of interleukin-1. Clinical studies on rheumatism and diabetes have shown that anakinra improved glucose homeostasis and the inflammatory state. This thesis has focused on the effect of anakinra on the diet-induced obesity (DIO) animal model with or without change in dietary fat content. In this study, DIO mimicked common obesity of humans by promoting fast body weight gains, increased fat proportions, and impaired glucose homeostasis. The animal study in this thesis support the notion that anakinra boost the positive effect of dieting but may not be effective in preventing further weight gain in DIO without restricting fat content in diet. With dietary change to regular diet, anakinra treatment helped reduce body weight in DIO by suppressing appetite and energy absorption without changing energy expenditure. In relation to obesity-related diabetic symptoms, in this study, only dietary change improved glucose intolerance in DIO. Anakinra also influenced adipokine profile, including resistin and adiponectin levels. Plasma leptin concentration reduced to normal by dietary change as a consequence of decreased amount of adipose tissue, whereas circulating levels of both resistin and adiponectin were lowered by anakinra. The effect of anakinra on lipid metabolism, however, was not significant. Anakinra could not offset the detrimental effects of high-fat diet in DIO without dietary correction. Peripheral anakinra administration did not reverse weight gains from excessive fat mass due to positive energy balance, glucose intolerance, hyperleptinaemia, and high blood cholesterol in DIO without dietary change. However, a low dose of anakinra alleviated weight gain in DIO by increasing energy expenditure. In conclusion, anakinra effectively helps converting DIO to the healthy state only when accompanied with proper dieting. Therefore, peripheral anakinra administration may potentially be supplementary to dieting in the treatment of common obesity