Interleukin 6 Deficiency Modulates the Hypothalamic Expression of Energy Balance Regulating Peptides during Pregnancy in Mice

Patricia Pazos,Felipe F Casanueva,Carlos Diéguez,Luis Lima,María C García,Raul M Luque

doi:10.1371/journal.pone.0072339

Abstract

Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central regulation of body fat in this physiological state.

Highlights

Energy balance is largely regulated by the central nervous system (CNS) via a homeostatic system
The body weight gain was similar in WT and IL6 tm1kopf/J (Il6-KO) mice whether pregnant or not in all time points studied, with values for virgin groups at the end of the 18 days-study period of: WT mice = 1.02460.242 g versus Il6-KO mice = 0.67660.150; and pregnant groups of: WT mice = 16.67260.619 g versus Il6-KO mice = 15.85460.835 g (Figure 1B)
We report that interleukin 6 (IL6), an adipokine produced by the expanding adipose tissue, the hypothalamus and perhaps from other maternal sources like the placenta [50,51], contributes to the neuroendocrine adaptation that occur in the dam’s brain during this physiological demanding time

Summary

Introduction

Energy balance is largely regulated by the central nervous system (CNS) via a homeostatic system. Central regulatory networks, located mainly in the hypothalamus and brainstem, sense metabolic status from widely divergent afferent signals (hormones, nutrients and neural signals) and modify the expression and release of specific neurotransmitters/neuromodulators with potent effects on energy intake and expenditure [1,2]. The other produces cocaine and amphetamine regulated transcript (CART) and proopiomelanocortin (POMC)-derived peptides, such as alpha melanocyte stimulating hormone (aMSH), that promote anorexia by inhibiting food intake and increasing catabolic processes. AGRP/NPY neurons block the aMSH effects by activating NPY receptors (Y1-Y5) on the MC4-R bearing cells and through direct and indirect GABA-ergic inhibitory inputs [6]

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Conclusion