Tohru Uchida's research while affiliated with University of Hyogo and other places

... These microbiota-specific changes highlight the ability of the GF mouse to sense/utilize/store iron in a different way, which may suggest a mechanism for protection from fatty liver development on a low-iron diet. To identify mechanistically how lipid accumulation in the liver is altered in response to a low-iron diet, we measured liver transcripts for long-chain FA uptake (CD36) [50], de novo FA biosynthesis (Fasn) [51,52], and hepatic lipase (Lipc), which helps keep fat-transporting molecules in balance by regulating the formation of low-density lipoproteins (LDLs) and the transport of high-density lipoproteins (HDLs) [53]. CD36 transcripts were increased in response to the low-iron diet only in the SPF mice but were not significantly increased in the GF animals ( Figure 2E). ...

... Furthermore, Rac1-null mice exhibited impaired glucose tolerance and hypoinsulinemia, suggesting key regulatory roles for Rac1 in normal insulin function. 104 Taken together, the literature data suggest an important role of Rac1 in islet function. ...

... TNF-α and monocyte chemoattractant protein 1 (MCP1) play important roles in this process. TNF-α is involved in insulin resistance by activating inflammatory kinases, including c-Jun N-terminal kinase (JNK) [53] and inhibitor kappa B kinase (IKK) [54]. Previous studies have shown that increased TNF-α and macrophage levels in the adipose tissue (AT) of obese mice and humans are associated with insulin resistance [55][56][57]. ...

... 37 In line with this, whole-body deletion of ATF6 impaired glucose intolerance and blunted insulin secretion, 249 whereas ATF6 induction improved β cell insulin secretion and viability under ER stress conditions. 286 Furthermore, inhibiting ATF6 could result in embryonic lethality and β cell receding by arresting cell cycle entry, 287 while upregulating ATF6α activity is able to markedly expand β cell mass in db/db mice, 288 suggesting its importance in the fate dysfunction and failure. Chronical PERK activation results in translational suppression of required genes, including chaperones, insulin, and ER enzymes, as well as induction of cell death through CHOP. ...

... The mechanism of ER stress induced impairment of insulin action includes stress responses and signaling cascades. ER stress diminishes insulin signaling (12) by serinephosphorylated IRS-1, inhibition of Akt activity by CHOP induction (13), and activation of JNK through via the IRE1or the PERK/CHOP pathways, all of which result in impaired insulin receptor signaling (14). Taken together, in the state of hyperglycemia, both reduced insulins signaling, and ER stress occur and may influence each other, culminating in the further development of diabetic complications. ...

... In addition to directly binding to certain receptor tyrosine kinases, p85α can also indirectly bind to receptors through adaptor proteins such as the insulin receptor substrates, IRS-1 and IRS-2. Following activation of the IR or IGF-1 (insulinlike growth factor 1) receptors, IRS-1 or IRS-2 is recruited through a phosphotyrosine-binding domain (Yenush et al., 1998). The C-termini of IRS-1 and IRS-2 contain tyrosine phosphorylation sites that enable the binding and activation of PI3K through the SH2 domains in p85α (Taniguchi et al., 2006). ...

... [30][31][32] Growth and metabolic effects of IR/IGF-1R receptors are elicited through IRS phosphorylation and activation of PI3K. [33][34][35][36] Human IR/IGF-1R kinases have been shown to phosphorylate several YxxM-containing synthetic IRS-1 peptides with varying specificities. 14,21,29 CHICO, which is the Drosophila homolog of IRS1-4 and a substrate for D-IR, contains two YxxM motifs ( Figure 4A) that are potential docking sites for Drosophila PI3K. ...

... For instance, STAT6 is involved in T cell proliferation [14]. Also, its activation prevents apoptotic cell death in B cells [15]. It is also involved in the fusion of macrophages to generate multinucleated giant cells in response to inflammation [16]. ...

... Total and phosphorylated AMPK levels were measured using specific primary antibodies (Cell Signaling #2531 (Koh et al., 2022); Cell Signaling #2535 (Bartolacci et al., 2022)-recognizes phosphorylated Threonine 172). Total raptor (Cell Signaling #2280 (Sanders et al., 2022)) and phosphorylated raptor (S792, Cell Signaling #2083 (Sanders et al., 2022)) levels were also measured alongside total P70S6K (Cell Signaling #9202 ), phosphorylated P70S6K (Santa Cruz SC-11759 (Xiao et al., 2002)), total ULK (Cell signaling #8054 (Wu et al., 2020)), and ULK S555 (cell signaling #5869 (Wu et al., 2020)). Synaptophysin (Cell Signaling #5461 (Wu et al., 2018)), NeuN (Cell Signaling #24307 (Tang et al., 2021)), PSD-95 (post-synaptic marker, Cell Signaling #36233 (Shui et al., 2022)), Homer-1 (post-synaptic marker, SC-136358 (Wang et al., 2014)), SNAP-25 (Cell signaling #5308 (Polishchuk et al., 2023)), VAMP2 (Cell signaling #13508 (Arrojo et al., 2019)) were measured as synaptic and neuronal markers. ...

... Their efficacy in part may reflect β−cell proliferative effects of GLP-1 that are mediated by activation of aPKC, 31 and, indeed, PKC-λ/ι is required for maintenance of mouse β-cell integrity. 32 However, these agents may additionally improve insulin resistance via weight loss owing to effects on the gastrointestinal function and appetite suppression. 33 Also, in DIO/MetS/T2DM, we presently do not know if β-cell aPKC activity is altered downward (as in muscle-see below), or upward (as in liver), in which case, it may participate in mediating compensatory increases in insulin secretion. ...