Inter-relation between interleukin (IL)-1, IL-6 and body fat regulating circuits of the hypothalamic arcuate nucleus

Interleukin (IL)-1 and IL-6 are immune modulating cytokines that also affect metabolic function because both IL-1 receptor I deficient (IL-1RI⁻/⁻) and IL-6 deficient (IL-6⁻/⁻) mice develop late-onset obesity and leptin resistance. Both IL-1 and IL-6 appear to target the central nervous system (CNS) to increase energy expenditure. The hypothalamic arcuate nucleus (ARC) is a major relay between the periphery and CNS in body fat regulation (e.g. by being a target of leptin). The present study aimed to investigate the possible mechanisms responsible for the effects exerted by endogenous IL-1 and IL-6 on body fat at the level of the ARC, as well as possible interactions between IL-1 and IL-6. Therefore, we measured the gene expression of neuropeptides of the ARC involved in energy balance in IL-1RI⁻/⁻ and IL-6⁻/⁻ mice. We also investigated the interactions between expression of IL-1 and IL-6 in these mice, and mapped IL-6 receptor α (IL-6Rα) in the ARC. The expression of the obesity promoting peptide neuropeptide Y (NPY), found in the ARC, was increased in IL-1RI⁻/⁻ mice. The expression of NPY and agouti-related peptide (AgRP), known to be co-expressed with NPY in ARC neurones, was increased in cold exposed IL-6⁻/⁻ mice. IL-6Rα immunoreactivity was densely localised in the ARC, especially in the medial part, and was partly found in NPY positive cell bodies and also α-melanocyte-stimulating hormone positive cell bodies. The expression of hypothalamic IL-6 was decreased in IL-1RI⁻/⁻ mice, whereas IL-1ß expression was increased in IL-6⁻/⁻ mice. The results of the present study indicate that depletion of the activity of the fat suppressing cytokines IL-1 and IL-6 in knockout mice can increase the expression of the obesity promoting neuropeptide NPY in the ARC. Depletion of IL-1 activity suppresses IL-6 expression, and IL-6Rα-like immunoreactivity is present in neurones in the medial ARC, including neurones containing NPY. Therefore, IL-6, IL-1 and NPY/AgRP could interact at the level of the hypothalamic ARC in the regulation of body fat.