IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling

Abstract

Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

“…ICV cannulation was performed as previously described (Timper et al, 2017). In brief, mice were anesthetized using a ketamine-dexmedetomidine combination and were placed into a stereotaxic apparatus.…”

“…Western blot analysis was conducted as previously described (Timper et al, 2017). In brief, membranes were blocked with 10% WB-blocking reagent (Roche, Switzerland) in Tris-buffered saline containing 0.1% Tween-20 (TBS-T), and incubated with primary antibodies, made up in TBS-T (0.1% Tween 20) and 5% Western Blotting-Reagent, at 4°C overnight.…”

“…Afterward 30 μm thick sections were cut on a cryostat. Every fourth section throughout the ARH was processed for POMC immunohistochemistry and for pSTAT3 immunohistochemistry using a commercially available TSA Plus Fluorescence kit (#NEL741001KT, Perkin Elmer) as previously described (Timper et al, 2017). To ensure comparable immunostaining, sections were processed simultaneously under identical conditions.…”

“…The total number of POMC neurons as well as the number of pSTAT3-positive POMC neurons was quantified unilaterally in images from every fourth section of every animal throughout the ARH using ImageJ analysis software (NIH) as previously reported (Timper et al, 2017). For quantification, only nuclei that were clearly immunoreactive were counted and only pSTAT3 nuclei that depicted a corresponding DAPI-positive staining were included in the analysis.…”

Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

“…Furthermore, upon HFD challenge, numerous events trigger metabolic changes that could in fine increase basal pSTAT3 levels in the ARC independently of leptin action. For instance, central chronic inflammation and gliosis are associated with increased hypothalamic IL-6 levels [79, 80], and IL-6 is known to activate the STAT3 pathway [81, 82]. Low expression of ObRb at the plasma membrane in DIO, with a subsequent decreased response to leptin, and the higher basal STAT3 activation in the ARC of DIO mice likely involve parallel and independent mechanisms.…”