Decreased Fat Mass in Interleukin-1 Receptor Antagonist–Deficient Mice

Abstract

Interleukin (IL)-1 is a regulator of inflammation but is also implicated in the control of energy homeostasis. Because the soluble IL-1 receptor antagonist (IL-1Ra) is markedly increased in the serum of obese patients and is overexpressed in white adipose tissue in obesity, we studied the metabolic consequences of genetic IL-1Ra ablation in mice. We have shown that IL-1Ra ؊/؊ mice have a lean phenotype due to decreased fat mass, related to a defect in adipogenesis and increased energy expenditure. The adipocytes were smaller in these animals, and the expression of genes involved in adipogenesis was reduced. Energy expenditure as measured by indirect calorimetry was elevated, and weight loss in response to a 24-h fast was increased in IL-1Ra ؊/؊ animals compared with wild-type mice. Lipid oxidation of IL-1Ra ؊/؊ mice was higher during the light period, reflecting their reduction in diurnal food intake. Interestingly, IL-1Ra؊/؊ and IL-1Ra ؉/؊ mice presented an attenuation in high-fat diet-induced caloric hyperphagia, indicating a better adaptation to hypercaloric alimentation, which is in line with the role of IL-1Ra as a mediator of leptin resistance. Taken together, we show that IL-1Ra is an important regulator of adipogenesis, food intake, and energy expenditure. Diabetes 54: [3503][3504][3505][3506][3507][3508][3509] 2005

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

“…2). Whereas Somm et al observed an augmented level of energy expenditure in Il1ra −/− mice on a normal diet [10], we only detected a significant increase in energy expenditure on a HFD; the discrepancy is probably due to differences in the diet or housing conditions. As locomotor activity was decreased in Il1ra −/− mice under HFD (Fig.…”

“…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.…”

“…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].…”

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…We also observed an increase in the mRNA level of interleukin 1 receptor antagonist (Il1rn, previously known as Il1ra) (Fig. 3a), recently shown to regulate adipogenesis, food intake and energy expenditure [32]. A similar tendency was noticed in epididymal adipose tissue (Fig.…”

“…Il1rn −/− mice, in which excess IL1 signalling may be induced, show a lean phenotype [45]. This phenotype has been associated with a defect in adipogenesis, a reduction of genes involved in lipogenesis, an increase in energy expenditure and a reduction in diurnal food intake [32]. The increase in IL1RN production in WAT may be directly involved in the phenotype obtained in TLR4 mutant mice, which exhibited both increased peripheral lipogenesis and lower thermogenesis.…”