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Jessica A Deis, Hong Guo, Yingjie Wu, Chengyu Liu, David A Bernlohr and Xiaoli Chen

Lipocalin-2 (LCN2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for LCN2 in the recruitment and retinoic acid-induced activation of brown-like or ‘beige’ adipocytes. We found LCN2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2 −/− mice. Lcn2 −/− inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2 −/− inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both WT and Lcn2 −/− inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2 −/− adipocytes is able to recruit beige adipocytes at a normal level, however, further activation of beige adipocytes by insulin and RA is impaired in the absence of LCN2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1α expression is markedly reduced in Lcn2 −/− inguinal adipocytes. Most intriguingly, LCN2 and the retinoic acid receptor-alpha (RAR-α) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-α translocation is absent in adipocytes deficient in LCN2. Our data suggest a novel LCN2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action.

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Ting-Ting Zhou, Fei Ma, Xiao-Fan Shi, Xin Xu, Te Du, Xiao-Dan Guo, Gai-Hong Wang, Liang Yu, Vatcharin Rukachaisirikul, Li-Hong Hu, Jing Chen and Xu Shen

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.

Open access

Kamran Ullah, Tanzil Ur Rahman, Hai-Tao Pan, Meng-Xi Guo, Xin-Yan Dong, Juan Liu, Lu-Yang Jin, Yi Cheng, Zhang-Hong Ke, Jun Ren, Xian-Hua Lin, Xiao-Xiao Qiu, Ting-Ting Wang, He-Feng Huang and Jian-Zhong Sheng

Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10−9 M or 10−7 M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10−7 M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC–MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10−7 M estradiol. Differential expression of C3, plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C3, plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation.