On the site and mechanism of action of the anti-obesity effects of interleukin-6

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Abstract

We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus.

Section snippets

Interleukin-6 (IL-6) in the immune system

IL-6 has widespread actions in many systems in the body, playing physiological and even pathophysiological roles. Perhaps its best known role relates to its effects on immune function. IL-6 is released from immune cells during inflammation and elicits pro-inflammatory effects, such as induction of the acute-phase reaction, and also proliferation of B lymphocytes [1], [2]. In one of the first articles describing IL-6 knockout mice, Kopf and co-workers [3] showed that endogenous IL-6 is essential

IL-6 in non-immune organs

In the absence of inflammation, a large proportion of the circulating IL-6 is derived from adipose tissue [5], and IL-6 levels in blood correlate with adipose tissue mass [5], [6] in a manner similar to that of leptin. Both short-term and long-term changes in food intake influence the amount of IL-6 in both fat tissue and in the circulation [7], [8].

Circulating levels of IL-6, but not of TNFα and interleukin 1β (IL-1β), increase 100-fold during exercise. This finding reflects increased

Endogenous IL-6 suppresses body fat in mice

Recently, we demonstrated that IL-6-deficient mice develop mature-onset obesity and obesity-related metabolic disorders. Administration of low-dose IL-6 replacement therapy partly reversed many of these disorders, indicating that the phenotypical changes were indeed due to the IL-6 deficiency [13]. However, the low doses of IL-6 that partly reversed the obesity seen in IL-6-deficient mice did not induce acute-phase reaction and did not affect body weight or the amount of fat mass in the lean

IL-6 and obesity-related metabolic disturbances

Older IL-6 knockout mice displayed leptin insensitivity and decreased glucose tolerance, and older females displayed increased circulating triglyceride levels [13]. These metabolic perturbations and the leptin insensitivity may be secondary to obesity [14]. Moreover, our findings show that the obese mice lacking IL-6 still develop impaired glucose tolerance. This suggests that IL-6 from adipose tissue is not an essential mediator of obesity-associated glucose intolerance in mice, a hypothesis

Central nervous system (CNS) IL-6 treatment suppresses obesity

To investigate a possible site of action for the anti-obesity action of endogenous IL-6 in rodents, we investigated the effects of long-term central IL-6 treatment. Rats were administered daily intracerebroventricular (ICV) injections of either IL-6 or saline. The results showed that the IL-6 injections suppressed body weight between days 5–10 of treatment, and this difference was maintained throughout the 14-day study. In contrast, saline injections had no effect on body weight by the end of

Effects of IL-6 on the hypothalamus

Results of our study indicate that IL-6 suppresses obesity via an effect on the CNS. The exact site of action for IL-6 is unknown. However, it seems reasonable to assume that, at least in part, it is exerted on the hypothalamus, which is an important centre for the regulation of body fat [14], [17]. Several lines of evidence indicate that the action of both IL-6 and its receptor are expressed in the hypothalamus. Possibly, the site of action is found in hypothalamic nuclei involved in the

Effects of central IL-6 on food intake

In our study, average daily food intake was decreased in rats treated with IL-6 ICV for 2 weeks compared with that of animals in the saline-treated group, although the food intake was not consistently decreased on all days during the treatment period. Moreover, daily food intake per unit of body weight was not significantly lower in the IL-6 treated group compared with the saline-treated group [16]. Recently, Li et al. [21] confirmed that chronic exposure of the hypothalamus to an

Effects of central IL-6 on energy expenditure

To investigate the site and mechanism of action of IL-6, we compared the effect of a single low dose of IL-6 given centrally or peripherally on energy expenditure and food intake in rats. A single ICV IL-6 injection in the lateral ventricle increased oxygen consumption (VO2) and carbon dioxide production (VCO2) in male rats. The respiratory exchange ratio (RER), which is a measure of nutrient partitioning of fat and carbohydrates, was not changed. Saline treatment did not affect (VO2), (VCO2)

IL-6 in the CNS of humans

As mentioned above, serum IL-6 is, to a large extent, like leptin, released from adipose tissue in individuals without inflammation. Not surprisingly, the levels of IL-6 correlate positively with body mass index [5], [6], in a way that is similar to that shown for leptin [14]. However, as our results indicate that IL-6 can affect body fat and energy expenditure via the CNS [13], [16], [25], [26], it was of interest to study the correlation between IL-6 levels in the cerebrospinal fluid (CSF)

A comparison between IL-6 and ciliary neurotrophic factor (CNTF)

Recently, the cytokine ciliary neurotrophic factor (CNTF), which shares many properties with IL-6, has been demonstrated to decrease obesity in mice [28], [29]. Subsequently, clinical phase 2 studies also showed CNTF to have the same effect in humans [30]. Consequently, clinical phase 3 studies are now being conducted with CNTF for treatment of obesity.

Conclusion

Some of our present knowledge about the metabolic effects of IL-6 is summarized in Fig. 2. IL-6 seems to increase energy expenditure and decrease fat mass via effects at the CNS level [13], [16], possibly the hypothalamus [11], [12]. The stimulatory effect on energy expenditure may be exerted, at least in rodents, via stimulation of the sympathetic nervous system that in turn induces increased expression of uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT) and thereby increased heat

Acknowledgements

We thank the Swedish Medical Research Council (9894), the Bergvall Foundation, the Swedish Medical Society, the Swedish Society for Medical Research, the Novo-Nordisk Foundation and the European Commission (Framework 5, QLRT-1999-02038).

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