The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.

Highlights d Myeloid cell diversity in NASH is associated with distinct microanatomical niches d Reprogramming of LXR activity leads to impaired Kupffer cell identify and survival d ATF3 collaborates with LXRs to promote a scar-associated macrophage phenotype d Altered enhancer landscapes enable inference of disease mechanisms

Highlights d Determinants of Kupffer cell identity are inferred from dynamic enhancer landscapes d DLL4 activates poised enhancers to induce Kupffer cell lineage-determining factors d LXRa induced by DLL4 drives subsequent activation of Kupffer cell enhancers d TGF-b and desmosterol regulate SMADs and LXRs to maintain Kupffer cell identity

SUMMARY The nature of obesity-associated islet inflammation and its impact on β cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating β cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair β cell function in a cell-cell contact-dependent manner. Increased engulfment of β cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote β cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet β cells.

Highlights d Oxidized phospholipids (OxPLs) accumulate in non-alcoholic steatohepatitis (NASH) d OxPLs induce oxidative stress and mitochondrial damage, in part by modifying MnSOD d Neutralizing OxPLs improved mitochondrial function and biogenesis in NASH d Neutralizing OxPLs ameliorates NASH Authors

SignificanceThe beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/− cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/− cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/− animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/− adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

The bacterial tmRNA⅐SmpB system facilitates recycling of stalled translational complexes in a process termed "ribosome rescue." During ribosome rescue, the nascent chain is tagged with the tmRNA-encoded ssrA peptide, which targets the tagged polypeptide for degradation. Translational pausing also induces a variety of recoding events such as frameshifts, ribosome hops, and stop codon readthrough. To examine the interplay between recoding and ribosome rescue, we determined the various fates of ribosomes that pause during translation termination. We expressed a model protein containing the C-terminal Asp-Pro nascent peptide motif (which interferes with translation termination) and quantified the protein chains produced by recoding and ssrA-peptide tagging. The nature and extent of translational recoding depended upon the codon for the C-terminal Pro residue, with CCU and CCC promoting efficient ؉1 frameshifting. In contrast, ssrA-peptide tagging was unaffected by C-terminal Pro coding. Moreover, ؉1 frameshifting was not suppressed by tmRNA⅐SmpB activity, suggesting that recoding and ribosome rescue are not competing events. However, cells lacking ribosomal protein L9 (⌬L9) exhibited a significant increase in recoding and a concomitant decrease in ssrA-peptide tagging. Pulse-chase analysis revealed that pre-termination ribosomes turn over more rapidly in ⌬L9 cells, suggesting that increased recoding alleviates the translational arrest. Together, these results indicate that tmRNA⅐SmpB does not suppress transient ribosome pauses, but responds to prolonged translational arrest.