PI3-kinase mutation linked to insulin and growth factor resistance in vivo

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85alpha regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism

Leptin receptor signaling regulates protein synthesis pathways and neuronal differentiation in pluripotent stem cells

The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.publishedVersio

Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Kif26b, a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. Kif26b expression is restricted to the metanephric mesenchyme, and its transcription is regulated by a zinc finger transcriptional regulator Sall1. However, the mechanism(s) by which Kif26b protein is regulated remain unknown. Here, we demonstrate phosphorylation and subsequent polyubiquitination of Kif26b in the developing kidney. We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. Furthermore, Kif26b lacks ATPase activity but does associate with microtubules. Nocodazole treatment not only disrupts the localization of Kif26b to microtubules but also promotes phosphorylation and polyubiquitination of Kif26b. These results suggest that the function of Kif26b is microtubule-based and that Kif26b degradation in the metanephric mesenchyme via the ubiquitin-proteasome pathway may be important for proper kidney development

Estimating Preferences for Wood Products with Environmental Attributes

Tropical deforestation and forest degradation are serious problems for the global environment; as a result, sustainable forest management and forest certification have become important. In this study, using a choice experiment, we investigated, on the demand side, consumers’ preferences and willingness to pay (WTP) for certified wood products that attempt to address public concerns regarding deforestation and forest degradation. Specifically, we investigated how estimates of consumers’ preferences and WTP were influenced by product attributes such as quality, certification, and price. To the authors’ knowledge, few studies of this kind have been conducted, particularly in Japan. The study’s main finding was that Japanese consumers were willing to pay a premium for certified wood products with attributes related to sustainable forest management; most preferred were products with attributes related to preserving biodiversity. These findings indicate that consumers are willing to pay a premium for products that contribute to solving the problems of deforestation and forest degradation

Estimating Preferences for Wood Furniture in Terms of Sustainable Forest Management

The world’s forest area decreased to three point nine billion hectares in 2015, a net annual loss of 3.3 million hectares, and large-scale deforestation is occurring in the tropics. Furthermore, greenhouse gas emissions are increasing as forests are converted to other uses such as agricultural land. Against this backdrop, sustainable forest management is becoming increasingly important. This study attempts to quantify people’s general awareness and values concerning for on-line shopping habits (in this study, for wooden furniture) in terms of sustainable forest management in Japan by estimating the acceptable price premium or willingness of consumers to pay for wood-related products made using wood produced under sustainable forest management as the raw material. The study proceeds to quantify the awareness and values of consumers concerning sustainable forest management and conservation of forest environments. Consumers were found to have a certain willingness to pay for wooden furniture made from wood produced through sustainable forest management. As a consequence of this analysis, it was revealed that consumers place a high value on sustainable forest management and environmental conservation, and that they are willing to act on these values when purchasing wood-related products

カンゾウ ハッセイ ニ ヒッス デ アル キネシン Kif26b ノ ブンシ キコウ ノ カイセキ

Kif26bによる後腎間葉細胞の機能制御とその分子機構の解明を目的とした

Potential of a glucagon‐like peptide‐1 receptor/glucose‐dependent insulinotropic polypeptide receptor/glucagon receptor triagonist for the treatment of obesity and type 2 diabetes

Triagonists of GLP‐1R/ GIPR /GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus result in weight loss and glycemic control in obese T2D animal models.[Image: see text

Membrane metallo-endopeptidase (Neprilysin) regulates inflammatory response and insulin signaling in white preadipocytes

Objective: Accumulation of visceral white adipose tissue (WAT) associates with insulin resistance, adipose tissue inflammation, and metabolic syndrome, whereas accumulation of subcutaneous WAT may be protective. We aimed to identify molecular mechanisms that might provide mechanistic insights underlying the phenotypic differences in these tissues. Membrane Metallo-Endopeptidase (MME/Neprislyin) is an extracellular, membrane-bound protease enriched in subcutaneous WAT that can target degradation of a variety of peptides, including insulin, IL6, and β-amyloids. We hypothesized that MME contributes to adipose depot-specific metabolic properties. Methods: We performed RNA sequencing on human subcutaneous and visceral preadipocytes and array gene expression profiling in murine subcutaneous and visceral preadipocytes. We conducted several insulin signaling and inflammatory response experiments on different cellular states of MME expression. Results: MME in white preadipocytes is expressed at a higher level in subcutaneous compared to visceral WAT and favors insulin signaling and a low inflammatory response. Thus, knockdown of MME in subcutaneous preadipocytes increased the inflammatory response to substance P and amyloid β aggregates. This associated with increased basal insulin signaling and decreased insulin-stimulated signaling. Moreover, MME differentially regulates the internalization and turnover of the α/β subunits of the insulin receptor. Conclusion: MME is a novel regulator of the insulin receptor in adipose tissue. Given the clinical significance of both chronic inflammation and insulin sensitivity in metabolic disease, these results show a potentially new target to increase insulin sensitivity and decrease inflammatory susceptibility. Keywords: Insulin receptor, Adipose, Neprilysin, Visceral, Insulin signaling, Inflammatio

The phosphatase Dullard negatively regulates BMP signalling and is essential for nephron maintenance after birth

Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period