In this paper, we examined the physiological role of IL-1 on feeding behavior and energy metabolism using IL-1−/− and IL-1Ra−/− mice. We found that IL-1Ra−/− mice have a defect in lipid accumulation in adipose tissue, although IL-1−/− mice do not show any apparent abnormalities. Thus, IL-1 signal is not necessarily required for the lipid metabolism, but its excess signaling is harmful for the energy homeostasis of the body. The defect was more severe in males than in females, probably reflecting hormonal differences.
It is well-known that IL-1 is involved in fever, anorexia (loss of appetite), and cachexia that develop during infection, inflammation, cancer, or physical stress (4
). Fever and feeding suppression caused by leptin are also mediated by hypothalamic IL-1 (44
). IL-1 can activate POMC neurons in the ARH where IL-1RI mRNA is expressed (9
), and the anorexic, but not pyrogenic, actions of IL-1 are mediated by central MC3/4Rs (23
). Recently, two groups reported that cachexia was ameliorated by central MC3/4R blockade, indicating cancer anorexia is also mediated by central melanocortin pathway (45
). Furthermore, it was reported that leptin was induced by LPS through induction of IL-1 (47
). Thus, it seemed likely that leanness of IL-1Ra−/−
mice might be resulted from feeding suppression mediated by the ARH–melanocortin pathway. However, our findings suggest that the lean phenotype of IL-1Ra−/−
mice is not caused by feeding suppression. This is because food intake per gram body weight is normal, and mutant mice showed a lean phenotype even when they were fed the same amount as wild-type mice. IL-1Ra−/−
mice show normal energy expenditure and heat production. Furthermore, expression levels of major hypothalamic factors involved in the melanocortin system are normal. Thus, we conclude that leanness of IL-1Ra−/−
mice results not from feeding suppression but from metabolic disorder in the periphery that is caused directly by excess IL-1 signaling or indirectly through central mechanisms. IL-1 signaling under physiological conditions may be too weak to evoke feeding suppression, and only a large excess IL-1 signaling, such as that produced under pathological conditions, may suppress appetite through a hypothalamic mechanism.
We have shown that IL-1−/−
mice do not show any apparent abnormality in feeding behavior or body temperature under physiological conditions. Consistent with our observations, it was reported that mice doubly deficient for the CRF RI and RII, which function down-stream of IL-1 in the hypothalamus, do not show any abnormalities under physiological conditions (22
). Furthermore, IL-1Ra transgenic mice, with either the endogenous IL-1Ra promoter or the glial fibrillary acidic protein promoter, did not show any alterations in body weight (48
). Chronic central administration of IL-1Ra also did not affect food intake and weight gain in rats (50
). Collectively, these observations indicate that IL-1 is not necessarily required for the control of appetite or body temperature under physiological conditions, although it plays most important roles under pathological conditions.
IL-1 reportedly suppresses intestinal lipid absorption and lipid accumulation in vivo, although the mechanism has not been completely elucidated (51
). Although serum TAG levels are low in IL-1Ra−/−
mice, this is not a result of defects in intestinal lipid absorption, because TAG levels in the chylomicron fraction of serum lipoproteins in IL-1Ra−/−
mice are similar to those in wild-type mice (unpublished data). On the other hand, lipid accumulation is inhibited in mutant mice, because these mice show decreased fat accumulation in adipose tissue even when fed a high-fat diet, which leads to serum TAG levels similar to wild-type mice. The ability of embryonic fibroblasts to differentiate into mature adipocytes in vitro, however, is normal in IL-1Ra−/−
mice, indicating that the ability of adipocyte progenitor cells to differentiate into mature adipocytes is normal in mutant mice (unpublished data). Furthermore, fatty acid uptake by in vitro–differentiated adipocytes from IL-1Ra−/−
mice is also normal. Therefore, these observations suggest that IL-1 does not directly affect the differentiation or function of adipocytes, but rather affects adipocyte function by an indirect mechanism.
In this context, it is noteworthy that serum insulin levels in IL-1Ra−/−
mice are significantly low under free-fed conditions and during recovery from starvation. Impaired insulin secretion is also observed after glucose administration. Furthermore, insulin secretion upon glucose administration is suppressed by the administration of IL-1 in wild-type mice (unpublished data), in agreement with previous works (52
). These findings indicate that excess IL-1 signaling suppresses insulin secretion from the pancreas.
Insulin is a major regulator of lipid metabolism in adipocytes, and it promotes adipocyte TAG store by fostering the differentiation of preadipocytes, stimulating glucose transport and TAG synthesis, and inhibiting lipolysis (54
). Insulin also increases the uptake of fatty acids derived from circulating lipoproteins by stimulating LPL activity (55
) and promoting the trafficking of fatty acid transporters in adipose tissue (58
). Actually, we showed that PHP lipase activity is reduced in IL-1Ra−/−
mice. Thus, decreased insulin may cause reduced fat accumulation in adipose tissue of IL-1Ra−/−
mice. It is also possible that excess IL-1 signaling affects LPL activity resulting in the suppression of fat accumulation.
However, normal serum glucose levels are maintained in IL-1Ra−/−
mice under physiological conditions, despite decreased insulin levels. This is because insulin sensitivity is increased in IL-1Ra−/−
mice as monitored by insulin tolerance tests. In contrast, the sensitivity of serum FFA to insulin is not increased in IL-1Ra−/−
mice, and the expression of adiponectin and resistin, which are involved in the insulin sensitivity of adipose tissue (59
), are not changed. These results indicate that the sensitivities of serum glucose and FFAs to insulin are different, and only lipid metabolism may be affected by the deficiency of insulin levels in IL-1Ra−/−
It is known that MSG-sensitive neurons are involved in the peripheral lipid metabolism because disruption of these neurons causes obesity in wild-type mice, probably by activating the vagus nerves without affecting food intake (62
). It is also known that MSG treatment activates insulin secretion in wild-type mice (63
). In contrast, disruption of the ARH neurons by MSG treatment did not cause obesity in IL-1Ra−/−
mice. Serum insulin levels were also not increased in these MSG-treated mutant mice, indicating that excess IL-1 signaling antagonizes the effects of the ARH neuron damage. However, it remains to be elucidated whether IL-1 acts on the pancreas so as to antagonize the effect of vagus nerve activation or directly suppresses vagus nerve activation. Nonetheless, these observations support the notion that IL-1 suppresses lipid accumulation in peripheral tissues by reducing blood insulin levels.
We reported previously that IL-1Ra−/−
mice on a BALB/cA background spontaneously develop chronic inflammatory arthropathy resembling rheumatoid arthritis, after weaning (64
). On the C57BL/6J background, these mutant mice, however, scarcely develop arthritis even at an older age (>24 wk old; reference 64
). Because no IL-1Ra−/−
mice on this genetic background develop arthritis at 5 wk old, whereas the lean phenotype develops as early as 5 wk old, leanness is not likely to be caused by autoimmunity or inflammation.
In summary, we have shown that the lean phenotype of IL-1Ra−/− mice is not caused by feeding suppression, but rather by impaired lipid accumulation. We showed that IL-1Ra−/− mice exhibit defects in postprandial insulin secretion and lipid metabolism. These results indicate that the IL-1 system plays a pivotal role in maintaining insulin homeostasis under physiological conditions. The IL-1Ra−/− mouse is a unique model for leanness and should be of use to further investigate obesity, diabetes, and lipid metabolism disorders.