PLC‐β exerts biologic influences through GPCR. GPCRs are involved in regulating glucose‐stimulated insulin secretion (GSIS). Previous studies have suggested that PLC‐βs might play an important role in pancreatic β cells. However, because of a lack of the specific inhibitors of PLC‐β isozymes and appropriate genetic models, the in vivo function of specific PLC‐β isozymes in pancreatic β cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC‐β1 was crucial for β‐cell function by generation of each PLC‐β conditional knockout mouse. Mice lacking PLC‐β1 in β cells exhibited a marked defect in GSIS, leading to glucose intolerance. In ex vivo studies, the secreted insulin level and Ca2+ response in Plcb1f/f; pancreas/duodenum homeobox protein 1 (Pdx1)‐Cre recombinase‐estrogen receptor T2 (CreERt2) islets was lower than those in the Plcb1f/f islets under the high‐glucose condition. PLC‐β1 led to potentiate insulin secretion via stimulation of particular Gq‐protein–coupled receptors. Plcb1f/f; Pdx1‐CreERt2 mice fed a high‐fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC‐β1 as an important molecule that regulates β cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.—Hwang, H.‐J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.‐S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Coceo, L., Berggren, P.‐O., Jang, H.‐J., Suh, P.‐G. Phospholipase Cβ1 potentiates glucose‐stimulated insulin secretion. FASEB J. 33, 10668–10679 (2019). http://www.fasebj.org

Abbreviations: A/B, N-terminal regulatory domain; AIM, adipogenic induction medium; ALP, alkaline phosphatase; AMP-DNM, N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin; aP2, adipocyte protein 2; ATF2, activating transcription factor 2; BMP2, bone morphogenetic protein 2; BV, bone volume; C/EBPα, CCAAT-enhancer binding protein α AbstractDysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

The zafirlukast has been reported to be anti-inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic β-cells has not been investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration-dependent manner in both low and high glucose conditions and elevated the level of [Ca ] , further activating Ca /calmodulin-dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) signaling. These effects were nearly abolished by the L-type Ca channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca rather than intracellular Ca from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes.

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Stresses and various infectious reagents caused multiple inflammatory diseases in swine in a livestock industrial environment. Therefore, there is a need for an effective therapeutic or preventive agent that could alleviate chronic and acute inflammation. We found that lysophosphatidic acid (LPA), a stress-induced potent endogenous inflammatory molecule, causes a broad range-regulation of inflammation related genes inflammation in swine macrophages. We further investigated the genome scaled transcriptional regulatory effect of a novel LPA-signaling antagonist, KA-1002 on swine macrophages, inducing the alleviated LPA-mediated inflammation related gene expression. Therefore, KA-1002 could potentially serve as a novel therapeutic or preventive agent to maintain physiologically healthy and balanced conditions of pigs.