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Final Activity Report Summary - IL-6 AND PREGNANCY (Role of IL-6 in the increased food intake and adiposity during pregnancy)

Pregnancy is a hypermetabolic state with a great increase in maternal body fat and weight, and it is associated with numerous neuroendocrine changes. During gestation, there is no increase in energy efficiency, and the energy balance becomes positive at this stage, primarily because of a marked increase in food intake, which is necessary to prevent the depletion of maternal energy stores. Interleukin (IL-6) is a multifunctional immune-modulating cytokine that has been suggested to have important functions in glucose and lipid metabolism. IL-6 is secreted from adipose tissue to the circulation, and its expression is positively correlated with BMI and total fat tissue. IL-6 deficient (IL-6-/-) mice develop obesity, which could partly be reversed by IL-6 replacement, suggesting a role for IL-6 in long-term regulation of adipose tissue mass. Furthemore, intracerebroventricular (ICV) injections of a low dose of IL-6 decreased food intake and increased energy expenditure in rats, suggesting a central site of action of IL-6.

By using the IL-6 deficient mice as a tool, we have carefully analysed the long-term effects of lack IL-6 on body weight, fat mass distribution, food intake and metabolism during late pregnancy (gestational age 18). IL-6 ko at 12-14 weeks of age were used in these studies, an age when they were significantly leaner than wt mice. Our results indicate that IL-6 ko mice, despite having lower absolute fat mass content and lower body weight, had a trend to higher fat accretion during gestation than wt mice and similar leptin levels. This effect was not mediated by an increase in food intake levels, which were somewhat lower in IL-6 ko mice. Glucose levels after short term fasting were similar in non-pregnant IL-6 ko and wt mice and remained at similar level in late pregnant animals. In the present study we have observed a slight increase in triglycerides levels in pregnant IL-6 knockout mice and a significant decrease in total serum cholesterol in pregnant wt mice but not in IL-6-/-, suggesting an altered lipid metabolism during pregnancy in IL-6 ko mice. However further studies will be needed to evaluate the pattern of specific serum lipoprotein levels in our experimental model.

During this project we have also attempted to identify at the level of the hypothalamus the site and possible mechanism of action of endogenous IL-6 on food intake and body weight regulation in this physiological setting. We aimed to point out possible factors involved in these complex regulatory mechanisms by studying the pattern of expression of different hypothalamic orexigenic (NPY, AgRP, MCH and orexins) and anorexigenic (POMC) neuropeptides in female IL-6 ko and wild-type mice (virgin and pregnant). Late pregnancy caused a marked decrease in hypothalamic POMC mRNA content in wt mice but not in IL-6 ko mice. NPY mRNA levels in the arcuate nucleus of the hypothalamus were significantly increased in pregnant IL-6 ko mice in relation to their corresponding non-pregnant IL-6 ko controls. The expression of AgRP in the arcuate nucleus and, MCH and prepro-orexin in the lateral hypothalamus was not affected by pregnancy in IL-6 knockout mice. Taking together this data suggest a drive to an orexigenic and anabolic pattern at the level of the hypothalamus in pregnant IL-6 knockout mice, which could explain the observed trend to an increased fat accumulation observed in this study.

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