Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPRmt) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPRmt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.Chylomicrons and very-low-density lipoproteins (VLDLs) are large, complex cargos that may require specific chaperones for efficient transport from the ER to Golgi. In this issue of Cell Metabolism, Wang et al. (2020) identify SURF4, in coordination with SAR1B, as an essential player in COPII transport of VLDLs from ER to Golgi, suggesting that SURF4 may be a target for approaches aimed at reducing secretion of triglyceride-rich, atherogenic lipoproteins from the liver.Endoplasmic reticulum (ER) stress is essential in the development of obesity, insulin resistance, and hepatosteatosis. In the latest issue of Cell Metabolism, Tirosh et al. (2020) demonstrate that intracellular ER stress can be transmitted to neighboring hepatocytes via connexin 43, thus propagating ER stress and promoting hepatosteatosis and insulin resistance.In this letter, Dalenberg et al. provide a point-by-point response to the critique offered by Kahn and Sievenpiper. They also offer new evidence to support their original finding from a study they conducted in mice.The lack of appropriate comparator can lead to incorrect interpretation of results regarding low-calorie sweeteners. The result of a re-analysis of the study by Dalenberg et al. shows that the impairment of insulin sensitivity by sucralose in combination with carbohydrate may be explained by the carbohydrate component rather than the low-calorie sweetener.RNA binding proteins (RBPs) are a large and diverse class of proteins that regulate all aspects of RNA biology. As RBP dysregulation has been implicated in a number of human disorders, including cancers and neurodegenerative disease, small molecule chemical probes that target individual RBPs represent useful tools for deciphering RBP function and guiding the production of new therapeutics. While RBPs are often thought of as tough-to-drug, the discovery of a number of small molecules that target RBPs has spurred considerable recent interest in new strategies for RBP chemical probe discovery. Here we review current and emerging technologies for high throughput RBP-small molecule screening that we expect will help unlock the full therapeutic potential of this exciting protein class.Mast cells, which express the high-affinity IgE receptor (FcεRI) on their surface, play a crucial role in inducing allergic inflammation. Since mast cells are activated by crosslinking of FcεRI with IgE and allergens, the cell surface expression level of FcεRI is an important factor in determining the sensitivity to allergens. Recently, the involvement of gut microbiota in the prevalence and regulation of allergy has attracted attention but the precise underlying mechanisms are not fully understood. In this study, the effect of intestinal bacteria on cell surface expression of FcεRI was examined. Bacteroides acidifaciens type A 43 specifically suppressed cell surface expression of FcεRI on mouse bone marrow-derived mast cells (BMMCs) without reduction in FcεRI α and β-chain mRNA and total protein expression. The suppressive effect required sustained exposure to this bacterium, with a corresponding reduction in Erk activation. Inhibition of Erk decreased cell surface distribution of FcεRI in BMMCs, at least in part, through facilitated endocytosis of FcεRI. find more These results indicate that B. acidifaciens type A 43 suppresses cell surface expression of FcεRI on mast cells in a post-translational manner via inhibition of Erk. The suppression of FcεRI expression on mast cells by specific bacteria might be the underlying mechanism involved in the regulation of allergy by gut microbiota.

To study the correlation between TSLP gene SNPs and RA in a Han Chinese population.

The genotypes of TSLP genes rs11466749, rs11466750 and rs10073816 among 197 RA patients and 197 controls were analysed by direct sequencing. ELISA was used to detect the plasma TSLP level. Logistic regression analysis was also conducted to identify risk factors for RA.

The rs11466749 locus GG genotype (OR=5.30, 95% CI 1.76-15.95, P<0.01), dominant model (OR=1.68, 95% CI 1.03-2.73, P=0.04), recessive model (OR=5.15, 95% CI 1.72-15.43, P<0.01), and G allele (OR=2.02, 95% CI 1.33-3.09, P<0.01) were associated with an increased risk of RA. The rs1073816 locus AA genotype (OR=4.58, 95% CI 1.49-14.01, P<0.01), dominant model (OR=1.75, 95% CI 1.09-2.79, P=0.03), recessive model (OR=4.27, 95% CI 1.40-13.00, P=0.03) and A allele (OR=1.94, 95% CI 1.29-2.91, P<0.01) were associated with an increased risk of RA. The rs1073816 locus GA genotype (OR=0.29, 95% CI 0.18-0.45, P<0.01), dominant model (OR=0.32, 95% CI 0.21-0.49, P<0.01) and A allele (OR=0.45, 95% CI 0.32-0.63, P<0.01) were related to a decreased risk of RA susceptibility. The rs1466749 locus GG genotype, rs11466750 AA genotype, and rs10073816 GG genotype were independent risk factors for RA (P<0.05). The AUC of plasma TSLP level in the diagnosis of RA was 0.8661 (95% CI 0.8301-0.9002, P<0.001). There were statistically significant differences in plasma TSLP levels among subjects with different genotypes at rs11466749, rs11466750, and rs10073816 in the TSLP gene (P<0.05).

Plasma TSLP levels are a potential molecular marker of RA. SNPs at rs11466749, rs11466750 and rs10073816 of the TSLP gene are related to the susceptibility of the Han Chinese population to RA.

Plasma TSLP levels are a potential molecular marker of RA. SNPs at rs11466749, rs11466750 and rs10073816 of the TSLP gene are related to the susceptibility of the Han Chinese population to RA.