Inter‐relation between Interleukin (IL)‐1, IL‐6 and Body Fat Regulating Circuits of the Hypothalamic Arcuate Nucleus

Abstract

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.

Interleukin-6 is important for regulation of core body temperature during long-term cold exposure in mice

“…The decreased levels of Ucp2 in the hypothalamus of IL6Rα NesCre mice may have been a method for increasing the body temperature of these mice. In a previous study by our group an increase in the mRNAs of the orexigenic genes Agrp and Npy was noted in the hypothalamus of IL6-/mice compared with Wt mice after 4 weeks at cold ambient temperature (32). This was not as evident after 6 days of cold exposure, but was close to reaching significance for Npy in this present study.…”

The impact of exenatide (a GLP‑1 agonist) on markers of inflammation and oxidative stress in normal human astrocytes subjected to various glycemic conditions

“…In our study, which was conceived without strong proinflammatory stimulus, we showed that exenatide increased the expression of IL-1β, which, in paracrine way, may be responsible for altered feeding behaviors. Previously, it was shown that IL-1β had anorexigenic properties and could affect body weight at the hypothalamic level (35). Of note, we noted that exenatide had the ability to elevate the level of IL-1β under normoglycemic culture conditions, which is concordant with the extended therapeutic indications of GLP-1 agonists to treat obesity even without coexisting diabetes.…”

The expression of interleukin-6 and its receptor in various brain regions and their roles in exploratory behavior and stress responses

“…In support of this hypothesis, mice lacking IL-6 developed late-onset obesity; injections of IL-6 to IL-6 −/− mice partially reversed this obesity (Wallenius et al, 2002). Although the mechanisms are not understood, neurons of the hypothalamic arcuate nucleus, primarily in the ventromedial region of the nucleus, express the obesity promoting Neuropeptide Y (NPY), which increases food intake (Schele et al, 2013;Senaris et al, 2011). The authors concluded that IL-6 might act directly on neurons of the hypothalamic arcuate nucleus, inhibiting the expression of NPY and thus reducing food intake.…”