SUMMARY Adipose tissue (AT) of obese mice and humans accumulates immune cells, which secrete cytokines that can promote insulin resistance. AT macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Here we show that a major fraction of macrophages unexpectedly undergo cell division locally within AT, as detected by Ki67 expression and 5-ethynyl-2′-deoxyuridine incorporation. Macrophages within the visceral AT (VAT), but not those in other tissues, including liver and spleen, displayed increased proliferation in obesity. Importantly, depletion of blood monocytes had no impact on ATM content, while their proliferation in situ continued. Treatment with monocyte chemotactic protein 1 (MCP-1) induced macrophage cell division in AT explants, while MCP-1 deficiency in vivo decreased ATM proliferation. These results reveal that proliferation in situ driven by MCP-1 is an important process by which macrophages accumulate in the VAT in obesity, in addition to blood monocyte recruitment.

Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT)1. In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs)2,3. In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance4,5, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity6–8. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

BackgroundThe de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood.Methods & resultsHere we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT.ConclusionsThese results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.

The direct synthesis of an acid-labile polyphosphoramidate by organobase-catalyzed ring-opening polymerization and an overall two-step preparation of polyphosphodiester ionomers (PPEI) by acid-assisted cleavage of the phosphoramidate bonds along the backbone of the polyphosphoramidate were developed in this study. The ultrafast organobase-catalyzed ring-opening polymerization of a cyclic phospholane methoxyethyl amidate monomer initiated by benzyl alcohol allowed for the preparation of well-defined polyphosphoramidates (PPA) with predictable molecular weights, narrow molecular weight distributions (PDI<1.10), and well-defined chain ends. Cleavage of the acid-labile phosphoramidate bonds on the polyphosphoramidate repeat units was evaluated under acidic conditions over a pH range of 1–5, and the complete hydrolysis produced polyphosphodiesters. The thermal properties of the resulting polyphosphoester ionomer acid and polyphosphoester ionomer sodium salt exhibited significant thermal stability. The parent PPA and both forms of the PPEIs showed low cytotoxicities toward HeLa cells and RAW 264.7 mouse macrophage cells. The synthetic methodology developed here has enriched the family of water-soluble polymers prepared by rapid and convenient organobase-catalyzed ring-opening polymerizations and straightforward chemical medication reactions, which are designed to be hydrolytically degradable and have promise for numerous biomedical and other applications.

OBJECTIVE To reveal more data on the epidemiologic and clinical characteristics of coronavirus disease 2019 (COVID-19) patients outside of Wuhan, from five hospitals in east of Zhejiang province, China. DESIGN Retrospective case series. SETTING Five hospitals in east of Zhejiang province, China. PARTICIPANTS 88 cases of laboratory-confirmed and 3 cases of clinical-confirmed COVID-19 were : medRxiv preprint RESULTSOf all 91 patients, 88 (96.70%) were laboratory-confirmed COVID-19 pneumonia with throat swab samples that tested positive for SARS-Cov-2 while 3 (3.30%) were clinical-diagnosed COVID-19 pneumonia cases. The median age of the patients was 50 (36.5-57) years, and female accounted for 59.34%. In this sample 40 (43.96%) patients had contracted the diseases from local cases, 31 (34.07%) patients had been to Wuhan/Hubei, 8 (8.79%) cases had contacted with people from Wuhan, 11 (12.09%) cases were confirmed aircraft transmission.In particular within the city of Ningbo, 60.52% cases can be traced back to an event held in a temple.The most common symptoms were fever (71.43%), cough (60.44%) and fatigue (43.96%).The median of incubation period was 6 (IQR, 3-8) days and the median time from first visit to a doctor to confirmed diagnosis was 1 (1-2) days. According to the Chest computed tomography scans, 67.03% cases had bilateral pneumonia, and 27.47% cases showed unilateral pneumonia. CONCLUSIONSocial activity cluster, family cluster and travel by airplane were how COVID-19 patients get transmitted and could be rapidly diagnosed COVID-19 in Zhejiang.