to mass spectrometry related experiments and analysis; R.H., Z.Y. and B.R. performed the library construction and next-generation sequencing for ChIP-seq and RNA-seq; M.H. and Y.G.Z. synthesized L-lactyl-CoA. H.H. and D.Z. analyzed ChIP-seq and RNA-seq data. G.Z. provided all primary BMDM cell cultures. D.M.C. carried out the bacterial infection experiments, C.C. carried out TAM experiments. Author Information. Y.Z. is a founder, board member, advisor to, and inventor on patents licensed to PTM Bio Inc. L.B. is co-founder and CSO of rMark Bio Inc., and founder and CEO of Onchilles Pharma Inc. Readers are welcome to comment on the online version of the paper. Data availability. The ChIP-seq and RNA-seq data have been made available at the Gene Expression Omnibus (GEO) repository under the accession number GSE115354. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE 31 partner repository with the dataset identifier PXD014870. All other data are available from the authors upon reasonable request.

SUMMARY During obesity, adipose tissue macrophages (ATMs) adopt a ‘metabolically-activated’ (MMe) phenotype. However, the functions of MMe macrophages are poorly understood. Here we combine proteomic and functional methods to demonstrate that in addition to potentiating inflammation, MMe macrophages also promote dead adipocyte clearance through lysosomal exocytosis. We identify NADPH-oxidase-2 (NOX2) as a driver of the inflammatory and adipocyte-clearing properties of MMe macrophages, and show that compared to wild-type, Nox2−/− mice exhibit a time-dependent metabolic phenotype during diet-induced obesity. After 8-weeks of high-fat feeding, Nox2−/− mice exhibit attenuated ATM inflammation and mildly improved glucose tolerance. After 16-weeks of high-fat feeding, Nox2−/− mice develop severe insulin resistance, hepatosteatosis, and visceral lipoatrophy characterized by dead adipocyte accumulation and defective ATM lysosomal exocytosis, a phenotype reproduced in myeloid cell-specific Nox2−/− mice. Collectively, our findings suggest that MMe macrophages perform detrimental and beneficial functions, whose contribution to metabolic phenotypes during obesity is determined by disease progression.

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Background and Purpose-We and others have previously reported that bone morphogenetic protein-7 (BMP-7), given before middle cerebral artery occlusion (MCAO), reduces ischemic injury in brain. Recent studies have indicated that receptors for BMP are upregulated after brain ischemia. It is possible that this upregulation may facilitate endogenous neurorepair in the ischemic brain. The purpose of this study was to determine the neuroregenerative effects of BMP-7 given parenterally after ischemia/reperfusion injury. Methods-Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The middle cerebral artery was transiently occluded by a filament inserted through the right internal carotid artery. The filament was removed after 60-minute ischemia to allow reperfusion. Some animals were killed 24 hours after MCAO to examine BMP-7 mRNA expression. Other animals received a single dose of intravenous BMP-7 or vehicle at 24 hours after MCAO and were used for subsequent behavioral studies and BMP-7 immunostaining. Results-BMP-7 mRNA was upregulated 24 hours after MCAO in untreated animals. BMP-7 immunoreactivity was dose-dependently increased on the ischemic side of the hippocampus/dentate on day 6 after MCAO in animals receiving intravenous injection of BMP-7. Animals receiving BMP-7 also showed a decrease in body asymmetry from day 7 to day 14 and an increase in locomotor activity on day 14 after MCAO. Conclusions-Our data indicate that BMP-7, given parenterally after stroke, can pass through the blood-brain barrier on the ischemic side and induce behavioral recovery in stroke animals at longer testing times. (Stroke. 2003;34:558-564.)

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