IL-1 Plays an Important Role in Lipid Metabolism by Regulating Insulin Levels under Physiological Conditions

Abstract

IL-1 is a proinflammatory cytokine that plays important roles in inflammation. However, the role of this cytokine under physiological conditions is not known completely. In this paper, we analyzed the role of IL-1 in maintaining body weight because IL-1 receptor antagonist–deficient (IL-1Ra−/−) mice, in which excess IL-1 signaling may be induced, show a lean phenotype. Body fat accumulation was impaired in IL-1Ra−/− mice, but feeding behavior, expression of hypothalamic factors involved in feeding control, energy expenditure, and heat production were normal. When IL-1Ra−/− mice were treated with monosodium glutamate (MSG), which causes obesity in wild-type mice by ablating cells in the hypothalamic arcuate nucleus, they were resistant to obesity, indicating that excess IL-1 signaling antagonizes the effect of MSG-sensitive neuron deficiency. IL-1Ra−/− mice showed decreased weight gain when they were fed the same amount of food as wild-type mice, and lipid accumulation remained impaired even when they were fed a high-fat diet. Interestingly, serum insulin levels and lipase activity were low in IL-1Ra−/− mice, and the insulin levels were low in contrast to wild-type mice after MSG treatment. These observations suggest that IL-1 plays an important role in lipid metabolism by regulating insulin levels and lipase activity under physiological conditions.

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

“…In this report, we analysed Il1ra −/− mice on a HFD and found that they are resistant to HFD-induced obesity, which is consistent with previous reports [9,10]. The SNS is activated in these mice, resulting in the activation of BAT and emergence of multilocular BAT-like cells in WAT depots.…”

“…The expression level of Ucp1 mRNA in the inguinal WAT of Il1ra −/− mice was significantly higher than in WT mice (Fig. 3a), whereas levels of Ucp1 in epididymal WAT and soleus muscles were not significantly different (data not shown) [9]. We also found that the expression of genes encoding rate-limiting enzymes of mitochondrial fatty acid oxidation, such as Mcad (also known as Acadm) and Mcpt1, was increased in inguinal WAT from Il1ra −/− mice, suggesting that the increased level of oxidation in the inguinal WAT of Il1ra −/− mice probably resulted from an increase in the number of metabolically active mitochondria.…”

“…mice under normal diet conditions [9]. Histologically, the BAT-like cells resembled brown adipocytes, and inguinal WAT depots from Il1ra −/− mice had increased levels of Ucp-1 (Figs 3 and 4).…”

“…Using Il1 −/− and Il1ra (also known as Il1rn)-deficient (Il1ra −/− ) mice, we demonstrated that IL-1 has a physiological role in feeding behaviour and energy metabolism [9]. Il1ra −/− mice, which have a defect in lipid accumulation in adipose tissue, are lean and have reduced serum insulin levels [9,10].…”

“…Il1ra −/− mice, which have a defect in lipid accumulation in adipose tissue, are lean and have reduced serum insulin levels [9,10]. Recently, Garcia et al demonstrated that Il1r1 −/− mice developed maturity-onset obesity, beginning to deviate from the weight of wild-type (WT) mice at 5 to 6 months of age [11].…”