Immunohistochemical Analysis of IA-2 Family of Protein Tyrosine Phosphatases in Rat Gastrointestinal Endocrine Cells

Gomi, Hiroshi; Kubota-Murata, Chisato; Yasui, Tadashi; Tsukise, Azuma; Torii, Seiji

doi:10.1369/0022155412466872

Cited by 17 publications

(16 citation statements)

References 25 publications

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“…The product of relaxin receptor 2 (RXFP2) mediates G-protein dependent stimulation of adenylate cyclase and an increase of cAMP levels [61]. Receptor-type tyrosine-protein phosphatase N2 (PTPRN2) was shown to be required for the accumulation of insulin-containing vesicles preventing their degradation [62] and accumulation of norepinephrine, dopamine and serotonin [63]. Ephrin type-A receptor 5 (EPHA5) which has a role in regulation of insulin secretion [64] was also highly expressed in DN as compared to SC brown adipocytes.…”

Section: Discussionmentioning

confidence: 99%

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

Tóth

Arianti

Shaw

et al. 2020

Preprint

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AbstractBrown adipocytes, abundant in deep-neck (DN) area in humans, are thermogenic with anti-obesity potential. FTO pro-obesity rs1421085 T-to-C SNP shifts differentiation program towards white adipocytes in subcutaneous fat. Human adipose-derived stromal cells were obtained from subcutaneous neck (SC) and DN fat of 9 donors, of which 3-3 carried risk-free (T/T), heterozygous or obesity-risk (C/C) FTO genotypes. They were differentiated to white and brown (long-term PPARγ stimulation) adipocytes, then global RNA sequencing was performed and differentially expressed genes (DEGs) were compared. DN and SC progenitors had similar adipocyte differentiation potential but differed in DEGs. DN adipocytes displayed higher browning features according to ProFAT or BATLAS scores and characteristic DEG patterns revealing associated pathways which were highly expressed (thermogenesis, interferon, cytokine, retinoic acid, with UCP1 and BMP4 as prominent network stabilizers) or downregulated (particularly extracellular matrix remodelling) compared to SC ones. Part of DEGs in either DN or SC browning was PPARγ-dependent. Presence of the FTO obesity-risk allele suppressed the expression of mitochondrial and thermogenesis genes with a striking resemblance between affected pathways and those appearing in ProFAT and BATLAS, underlining the importance of metabolic and mitochondrial pathways in thermogenesis. Among overlapping regulatory influences which determine browning and thermogenic potential of neck adipocytes, FTO genetic background has a so far not recognized prominence.

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Section: Discussionmentioning

confidence: 99%

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

Tóth

Arianti

Shaw

et al. 2020

Preprint

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“…Mice that are specifically deficient in IRS2 in ␤ cells and the hypothalamus exhibit an age-dependent reduction in the ␤-cell mass (42,43), whereas IRS2 is crucially involved in ␤-cell proliferation in response to high-fat diet-induced insulin resistance (44). A possible explanation of the unchanged ␤-cell mass in phogrin-knockout mice is that phogrin regulates ␤-cell growth only as a compensatory response.…”

Section: Phogrin Connects Insulin Secretion and Signalingmentioning

confidence: 99%

The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic β cells

Torii

Kubota

Saito

et al. 2018

Journal of Biological Chemistry

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Autocrine insulin signaling is critical for pancreatic β-cell growth and activity and is at least partially controlled by protein-tyrosine phosphatases (PTPs) that act on insulin receptors (IRs). The receptor-type PTP phogrin primarily localizes on insulin secretory granules in pancreatic β cells. We recently reported that phogrin knockdown decreases the protein levels of insulin receptor substrate 2 (IRS2), whereas high-glucose stimulation promotes formation of a phogrin-IR complex that stabilizes IRS2. However, the underlying molecular mechanisms by which phogrin affects IRS2 levels are unclear. Here, we found that relative to wildtype mice, IRS2 levels in phogrin-knockout mice islets decreased by 44%. When phogrin was silenced by shRNA in pancreatic β-cell lines, glucose-induced insulin signaling led to proteasomal degradation of IRS2 via a negative feedback mechanism. Phogrin overexpression in a murine hepatocyte cell line consistently prevented chronic insulin treatment-induced IRS2 degradation. , phogrin directly bound the IR without the assistance of other proteins and protected recombinant PTP1B from oxidation to potentiate its activity toward the IR. Furthermore, phogrin expression suppressed insulin-induced local generation of hydrogen peroxide and subsequent PTP1B oxidation, which allowed progression of IR dephosphorylation. Together, these results suggest that a transient interaction of phogrin with the IR enables glucose-stimulated autocrine insulin signaling through the regulation of PTP1B activity, which is essential for suppressing feedback-mediated IRS2 degradation in pancreatic β cells.

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“…Pilot experiments also have shown changes in the level of norepinephrine and epinephrine in the serum and changes in the number of white blood cells in the peripheral circulation (unpublished data). Because of the high expression of IA-2 and IA-2β in the brain and in the gastrointestinal tract [26, 27], we would expect to find a number of other pathophysiologic changes in these organs if appropriately tested. Thus the alterations in the half-life and number of DCV in the IA-2/IA-2β null mice represent a unique model for studying the effect of hormones and neurotransmitters on known targets and on still unrecognized targets.…”

Section: Concluding Commentsmentioning

confidence: 99%

Pathophysiologic changes in IA-2/IA-2β null mice are secondary to alterations in the secretion of hormones and neurotransmitters

Cai

Notkins

2015

Acta Diabetol

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IA-2 and IA-2β are transmembrane proteins of dense core vesicles (DCV). The deletion of these proteins results in a reduction in the number of DCV and the secretion of hormones and neurotransmitters. As a result this leads to a variety of pathophysiologic changes. The purpose of this review is to describe these changes, which are characterized by glucose intolerance, female infertility, behavior and learning abnormalities and alterations in the diurnal circadian rhythms of blood pressure, heart rate, spontaneous physical activity and body temperature. These findings show that the deletion of IA-2 and IA-2β results in multiple pathophysiologic changes and represents a unique in vivo model for studying the effect of hormone and neurotransmitter reduction on known and still unrecognized targets.

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Immunohistochemical Analysis of IA-2 Family of Protein Tyrosine Phosphatases in Rat Gastrointestinal Endocrine Cells

Cited by 17 publications

References 25 publications

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic β cells

Pathophysiologic changes in IA-2/IA-2β null mice are secondary to alterations in the secretion of hormones and neurotransmitters

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