No abstract

Chemerin, an adipokine, has been reported to reduce the production of pro-inflammatory cytokines and neutrophil infiltration. This study investigated the role of Chemerin and its natural receptor, ChemR23, as well as its downstream mediator calmodulin-dependent protein kinase kinase 2 (CAMKK2)/adenosine monophosphate-activated protein kinase (AMPK) /Nuclear factor erythroid 2-related factor 2 (Nrf2) following germinal matrix hemorrhage (GMH) in neonatal rats, with a specific focus on inflammation. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. The results demonstrated that human recombinant Chemerin (rh-Chemerin) improved neurological and morphological outcomes after GMH. Rh-Chemerin promoted accumulation and proliferation of M2 microglia in periventricular regions at 72 h. Rh-Chemerin increased phosphorylation of CAMKK2, AMPK and expression of Nrf2, and decreased IL-1beta, IL-6 and TNF-alpha levels. Selective inhibition of ChemR23/CAMKK2/AMPK signaling in microglia via intracerebroventricular delivery of liposome-encapsulated specific ChemR23 (Lipo-alpha-NETA), CAMKK2 (Lipo-STO-609) and AMPK (Lipo-Dorsomorphin) inhibitor increased the expression levels of IL-1beta, IL-6 and TNF- alpha, demonstrating that ChemR23/CAMKK2/AMPK signaling in microglia suppressed inflammatory response after GMH. Cumulatively, these data showed that rh-Chemerin ameliorated GMH-induced inflammatory response by promoting ChemR23/CAMKK2/AMPK/Nrf2 pathway, and M2 microglia may be a major mediator of this effect. Thus, rh-Chemerin can serve as a potential agent to reduce the inflammatory response following GMH.

Background Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by 18-F fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). We recently described a novel non-invasive and non-ionizing imaging method to assess BAT in mice using contrast enhanced ultrasound (CEUS). Here, we report the application of this method in healthy humans. Methods Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas filled lipid microbubbles and triggered imaging of the supraclavicular space. The first 5 subjects received microbubbles at a lower infusion rate than the subsequent 8 subjects, and are analyzed as a separate group. Blood flow was estimated by the product of the plateau (A) and the slope (β) of microbubble replenishment curves. All underwent 18F-FDG PET-CT after cold exposure. Results An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS co-localized with BAT, as detected by 18F-FDG PET-CT. In a cohort of 8 subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared to basal BAT blood flow in warm conditions (Aβ 3.3 [0.5–5.7] AU/s vs. 1.25 [0.5–2.6] AU/s; p=0.02). Of these 8 subjects, 5 had a >2-fold increase in their blood flow after cold exposure; these responders had higher BAT activity measured by 18F-FDG PET-CT (SUVmax 2.25 [1.53–4.57] vs. 0.51 [0.47–0.73]; p=0.02). Conclusions The present study demonstrates the feasibility of using CEUS as a non-invasive, non-ionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies.

No abstract