BMD was significantly decreased, while bone turnover was elevated, and bone remodeling was accelerated following bariatric surgery. Basal bone metabolism should be evaluated preoperatively. To prevent secondary hyperparathyroidism and bone loss, calcium and vitamin D should be monitored closely and supplemented accordingly after the surgery.

Highlights d Blocking PPARg S273 phosphorylation protects mice from insulin resistance in obesity d These mice do not show the side effects associated with TZD-based PPARg agonism d These mice have reduced expression of Gdf3 mainly in macrophages d Gdf3 is sufficient to cause impaired glucose homeostasis in vivo and in vitro

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ContextThyroid hormone influences glucose homeostasis through central and peripheral regulations. To date, the link between sensitivity to thyroid hormones and prediabetes remains unknown. We aimed to investigate the association between thyroid hormones sensitivity and risk of prediabetes in both general and euthyroid populations.MethodsParticipants with serum free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) measurements from the health checkup programs of the First Hospital of China Medical University were collected. We measured the parameters representing central and peripheral sensitivities to thyroid hormones (central sensitivity, assessed by calculating Thyroid Feedback Quantile-based Index (TFQI), TSH Index (TSHI), and Thyrotroph Thyroxine Resistance Index (TT4RI); peripheral sensitivity, evaluated by FT3/FT4 ratio). Associations between thyroid hormones sensitivities and risk of prediabetes were assessed with logistic regression.ResultsA total of 4378 participants (mean age ± SD, 49 ± 11 years) were included, with 1457 (33%) subjects had prediabetes. The risk of prediabetes was negatively associated with levels of TSHI (odds ratio [OR] 0.91; 95% confidence interval [CI], 0.85–0.97), TT4RI (OR 0.91; 95% CI, 0.84–0.99) and Parametric TFQI (PTFQI) (OR 0.89; 95% CI, 0.83–0.95) among all subjects. The association remained significant in euthyroid subjects and euthyroid subjects with negative thyroid autoimmunity. Higher FT3/FT4 ratio was associated with a mild increased risk of prediabetes (95% CI 1.09; 1.02–1.16). Compared with subjects in the lowest quartile of PTFQI, those in the highest quartile had lower risk of prediabetes (0.70; 95% CI, 0.58–0.84).ConclusionsDecreased central sensitivity to thyroid hormones is associated with lower risk of prediabetes. This demonstrates the complex interaction between thyroid system and glucose metabolism. Future studies are warranted to confirm our findings and underlying mechanisms.

ObjectiveThe inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity.Methods and ResultsWe provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the β3-adrenergic receptor (β3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type β3AR exhibited β3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of β3AR was mutated to alanine.ConclusionTaken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the β3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.

Lysosomes are the stomachs of the cells that degrade endocytosis and intracellular biomacromolecules and participate in various other cellular processes, such as apoptosis and cell migration. The ability of long-term tracking of lysosomes is very important to understand the details of lysosomal functions and to evaluate drug and gene delivery systems. For studying lysosomes, we designed and synthesized a water-soluble triscyclometalated iridium(III) complex (Ir-lyso) attaching morpholine moieties. The phosphorescent intensity of Ir-lyso is responsive to pH and decreases with an increase in the pH but not quenching in high pH. With excellent two-photon properties, Ir-lyso was used to light up the lysosomes in living cells and 3D tumor spheroids. Moreover, Ir-lyso could label lysosomes more than 4 days, so we developed this complex to act as a long-term probe for tracking lysosomes during cell migration and apoptosis. To the best of our knowledge, this is the first paradigm of metal complexes as the two-photon phosphorescent probe for long-term lysosomes tracking.

BackgroundPulmonary arterial hypertension (PAH) is a progressive and fatal disorder associated with high pulmonary artery pressure. Genetic testing enables early diagnosis and offers an opportunity for family screening. To identify genetic mutations and help make a precise diagnosis, we performed genetic testing in 191 probands with PAH and tried to analyze the genotype-phenotype correlation.MethodsInitially, PAH samples (n = 119) were submitted to BMPR2 screening using Sanger sequencing. Later, we developed a PAH panel test to identify causal mutations in 13 genes related to PAH and tried to call BMPR2 copy number variations (CNVs) with the panel data. Multiplex ligation-dependent probe amplification (MLPA) was used to search for CNVs in BMPR2, ACVRL1 and ENG. Notably, EIF2AK4 gene was also involved in the panel, which allowed to distinguish pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) patients from idiopathic PAH (IPAH). Characteristics of patients were compared using t test for continuous variables.ResultsPathogenic BMPR2 mutations were detected most frequently in 32 (17.9%) IPAH and 5 (41.7%) heritable PAH (HPAH) patients by sequencing, and 12 BMPR2 CNVs called from the panel data were all successfully confirmed by MLPA analysis. In addition, homozygous or compound heterozygous EIF2AK4 mutations were identified in 6 patients, who should be corrected to a diagnosis of PVOD/PCH. Genotype-phenotype correlation analysis revealed that PAH patients with BMPR2 mutations were younger at diagnosis (27.2y vs. 31.6y, p = 0.0003) and exhibited more severe pulmonary hemodynamic impairment and a worse cardiac index compared with those without BMPR2 mutations.ConclusionsThe panel assay represented a highly valuable tool in PAH genetic testing, not only for the detection of small sequence alterations, but also for an indication of BMPR2 CNVs, which had implications for the specific samples to perform further MLPA assay. Analyses of PAH causal genes have a great help to clinical diagnosis and deep implications in disease treatment.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0789-9) contains supplementary material, which is available to authorized users.

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