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Article ; Online: The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

Izumi, Tetsuro

2023 Volume 70, Issue 8, Page(s) 761–770

Abstract: ALK7, a type I receptor for the transforming growth factor-β superfamily, is known to be predominantly expressed in adipocytes in both mice and humans. The present review describes recent findings suggesting that ALK7 plays a major role in regulating ... ...

Abstract	ALK7, a type I receptor for the transforming growth factor-β superfamily, is known to be predominantly expressed in adipocytes in both mice and humans. The present review describes recent findings suggesting that ALK7 plays a major role in regulating lipid metabolism and fat mass. Furthermore, the ligands and upstream regulators that activate ALK7 signaling are discussed. The focus is on findings in mice and their derivative tissues and cells that harbor the mutations of ALK7 and related molecules. Particular attention is paid to the contradictory nature of the current literature about the loss-of-function phenotypes and the relationship with insulin secretion and sensitivity. Additional attention is paid to the ALK7 gene variants found in humans and their associated traits. The goal is to seek a parsimonious, and preferably singular and unified, description of the underlying mechanism. This review also introduces recent promising findings about ALK7 neutralizing treatment to obese mice.
MeSH term(s)	Humans ; Mice ; Animals ; Obesity/genetics ; Obesity/metabolism ; Adiposity ; Adipocytes/metabolism ; Diabetes Mellitus/metabolism ; Signal Transduction/genetics ; Adipose Tissue/metabolism ; Activin Receptors, Type I/genetics ; Activin Receptors, Type I/metabolism
Chemical Substances	Activin Receptors, Type I (EC 2.7.11.30)
Language	English
Publishing date	2023-04-19
Publishing country	Japan
Document type	Review ; Journal Article
ZDB-ID	1151918-6
ISSN	1348-4540 ; 0918-8959
ISSN (online)	1348-4540
ISSN	0918-8959
DOI	10.1507/endocrj.EJ23-0112
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Article ; Online: Multiple pathways and independent functional pools in insulin granule exocytosis.

Izumi, Tetsuro

Genes to cells : devoted to molecular & cellular mechanisms

2023 Volume 28, Issue 7, Page(s) 471–481

Abstract: In contrast to synaptic vesicle exocytosis, secretory granule exocytosis follows a much longer time course, and thus allows for different prefusion states prior to stimulation. Indeed, total internal reflection fluorescence microscopy in living ... ...

Abstract	In contrast to synaptic vesicle exocytosis, secretory granule exocytosis follows a much longer time course, and thus allows for different prefusion states prior to stimulation. Indeed, total internal reflection fluorescence microscopy in living pancreatic β cells reveals that, prior to stimulation, either visible or invisible granules fuse in parallel during both early (first) and late (second) phases after glucose stimulation. Therefore, fusion occurs not only from granules predocked to the plasma membrane but also from those translocated from the cell interior during ongoing stimulation. Recent findings suggest that such heterogeneous exocytosis is conducted by a specific set of multiple Rab27 effectors that appear to operate on the same granule; namely, exophilin-8, granuphilin, and melanophilin play differential roles in distinct secretory pathways to final fusion. Furthermore, the exocyst, which is known to tether secretory vesicles to the plasma membrane in constitutive exocytosis, cooperatively functions with these Rab27 effectors in regulated exocytosis. In this review, the basic nature of insulin granule exocytosis will be described as a representative example of secretory granule exocytosis, followed by a discussion of the means by which different Rab27 effectors and the exocyst coordinate to regulate the entire exocytic processes in β cells.
MeSH term(s)	Insulin/metabolism ; rab GTP-Binding Proteins/metabolism ; rab27 GTP-Binding Proteins/metabolism ; Vesicular Transport Proteins/metabolism ; Exocytosis
Chemical Substances	Insulin ; rab GTP-Binding Proteins (EC 3.6.5.2) ; rab27 GTP-Binding Proteins ; Vesicular Transport Proteins
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1330000-3
ISSN	1365-2443 ; 1356-9597
ISSN (online)	1365-2443
ISSN	1356-9597
DOI	10.1111/gtc.13029
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Article ; Online: In vivo Roles of Rab27 and Its Effectors in Exocytosis.

Izumi, Tetsuro

Cell structure and function

2021 Volume 46, Issue 2, Page(s) 79–94

Abstract: The monomeric GTPase Rab27 regulates exocytosis of a broad range of vesicles in multicellular organisms. Several effectors bind GTP-bound Rab27a and/or Rab27b on secretory vesicles to execute a series of exocytic steps, such as vesicle maturation, ... ...

Abstract	The monomeric GTPase Rab27 regulates exocytosis of a broad range of vesicles in multicellular organisms. Several effectors bind GTP-bound Rab27a and/or Rab27b on secretory vesicles to execute a series of exocytic steps, such as vesicle maturation, movement along microtubules, anchoring within the peripheral F-actin network, and tethering to the plasma membrane, via interactions with specific proteins and membrane lipids in a local milieu. Although Rab27 effectors generally promote exocytosis, they can also temporarily restrict it when they are involved in the rate-limiting step. Genetic alterations in Rab27-related molecules cause discrete diseases manifesting pigment dilution and immunodeficiency, and can also affect common diseases such as diabetes and cancer in complex ways. Although the function and mechanism of action of these effectors have been explored, it is unclear how multiple effectors act in coordination within a cell to regulate the secretory process as a whole. It seems that Rab27 and various effectors constitutively reside on individual vesicles to perform consecutive exocytic steps. The present review describes the unique properties and in vivo roles of the Rab27 system, and the functional relationship among different effectors coexpressed in single cells, with pancreatic beta cells used as an example.Key words: membrane trafficking, regulated exocytosis, insulin granules, pancreatic beta cells.
MeSH term(s)	Cell Membrane/metabolism ; Exocytosis ; Secretory Vesicles/metabolism ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; rab27 GTP-Binding Proteins
Chemical Substances	rab27 GTP-Binding Proteins ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2021-09-04
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	197293-5
ISSN	1347-3700 ; 0386-7196
ISSN (online)	1347-3700
ISSN	0386-7196
DOI	10.1247/csf.21043
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Zs.A 1294: Show issues

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Article ; Online: Munc13-4 regulates asthma and obesity in mice by controlling functions of CD11c

Okunishi, Katsuhide / Kochi, Yuta / Zhao, Min / Wang, Hao / Nakagome, Kazuyuki / Izumi, Tetsuro

Allergy

2024

Language	English
Publishing date	2024-03-01
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.16087
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Uh III Zs.150: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Response to Comment on Bu et al. Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages. Diabetes 2018;67:1761-1772.

Izumi, Tetsuro

Diabetes

2018 Volume 67, Issue 12, Page(s) e2–e3

MeSH term(s)	Adipose Tissue ; Growth Differentiation Factor 3 ; Insulin ; Lipolysis ; Macrophages
Chemical Substances	Growth Differentiation Factor 3 ; Insulin
Language	English
Publishing date	2018-11-17
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/dbi18-0037
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Article ; Online: Munc13b stimulus-dependently accumulates on granuphilin-mediated, docked granules prior to fusion.

Mizuno, Kouichi / Izumi, Tetsuro

Cell structure and function

2022 Volume 47, Issue 1, Page(s) 31–41

Abstract: The Rab27 effector granuphilin plays an indispensable role in stable docking of secretory granules to the plasma membrane by interacting with the complex of Munc18-1 and the fusion-incompetent, closed form of syntaxins-1~3. Although this process prevents ...

Abstract	The Rab27 effector granuphilin plays an indispensable role in stable docking of secretory granules to the plasma membrane by interacting with the complex of Munc18-1 and the fusion-incompetent, closed form of syntaxins-1~3. Although this process prevents spontaneous granule exocytosis, those docked granules actively fuse in parallel with other undocked granules after stimulation. Therefore, it is postulated that the closed form of syntaxins must be converted into the fusion-competent open form in a stimulus-dependent manner. Although Munc13 family proteins are generally thought to prime docked vesicles by facilitating conformational change in syntaxins, it is unknown which isoform acts in granuphilin-mediated, docked granule exocytosis. In the present study, we show that, although both Munc13a and Munc13b are expressed in mouse pancreatic islets and their beta-cell line MIN6, the silencing of Munc13b, but not that of Munc13a, severely affects glucose-induced insulin secretion. Furthermore, Munc13b accumulates on a subset of granules beneath the plasma membrane just prior to fusion during stimulation, whereas Munc13a is translocated to the plasma membrane where granules do not exist. When fluorescently labeled granuphilin was introduced to discriminate between molecularly docked granules and other undocked granules in living cells, Munc13b downregulation was observed to preferentially decrease the fusion of granuphilin-positive granules immobilized to the plasma membrane. These findings suggest that Munc13b promotes insulin exocytosis by clustering on molecularly docked granules in a stimulus-dependent manner.Key words: docking, insulin, live cell imaging, priming, TIRF microscopy.
MeSH term(s)	Animals ; Exocytosis/physiology ; Insulin/metabolism ; Mice ; Qa-SNARE Proteins/metabolism ; Secretory Vesicles/metabolism ; Vesicular Transport Proteins/metabolism
Chemical Substances	Insulin ; Qa-SNARE Proteins ; Vesicular Transport Proteins
Language	English
Publishing date	2022-04-06
Publishing country	Japan
Document type	Journal Article
ZDB-ID	197293-5
ISSN	1347-3700 ; 0386-7196
ISSN (online)	1347-3700
ISSN	0386-7196
DOI	10.1247/csf.22005
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Article ; Online: Munc13b stimulus-dependently accumulates on granuphilin-mediated, docked granules prior to fusion

Kouichi Mizuno / Tetsuro Izumi

Cell Structure and Function, Vol 47, Iss 1, Pp 31-

2022 Volume 41

Abstract	The Rab27 effector granuphilin plays an indispensable role in stable docking of secretory granules to the plasma membrane by interacting with the complex of Munc18-1 and the fusion-incompetent, closed form of syntaxins-1~3. Although this process prevents spontaneous granule exocytosis, those docked granules actively fuse in parallel with other undocked granules after stimulation. Therefore, it is postulated that the closed form of syntaxins must be converted into the fusion-competent open form in a stimulus-dependent manner. Although Munc13 family proteins are generally thought to prime docked vesicles by facilitating conformational change in syntaxins, it is unknown which isoform acts in granuphilin-mediated, docked granule exocytosis. In the present study, we show that, although both Munc13a and Munc13b are expressed in mouse pancreatic islets and their beta-cell line MIN6, the silencing of Munc13b, but not that of Munc13a, severely affects glucose-induced insulin secretion. Furthermore, Munc13b accumulates on a subset of granules beneath the plasma membrane just prior to fusion during stimulation, whereas Munc13a is translocated to the plasma membrane where granules do not exist. When fluorescently labeled granuphilin was introduced to discriminate between molecularly docked granules and other undocked granules in living cells, Munc13b downregulation was observed to preferentially decrease the fusion of granuphilin-positive granules immobilized to the plasma membrane. These findings suggest that Munc13b promotes insulin exocytosis by clustering on molecularly docked granules in a stimulus-dependent manner. Key words: docking, insulin, live cell imaging, priming, TIRF microscopy
Keywords	docking ; insulin ; live cell imaging ; priming ; tirf microscopy ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Japan Society of Cell Biology
Document type	Article ; Online
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Article ; Online: Internal limiting membrane peeling and inverted flap technique in macular hole: postoperative metamorphopsia and optical coherence tomography.

Murakami, Tomoya / Okamoto, Fumiki / Sugiura, Yoshimi / Izumi, Iori / Iioka, Aoi / Morikawa, Shohei / Hiraoka, Takahiro / Oshika, Tetsuro

Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde

2024

Abstract: Introduction: We compared postoperative metamorphopsia and optical coherence tomography (OCT) findings between eyes that underwent internal limiting membrane (ILM) peeling and the inverted flap (IF) technique for macular hole (MH).: Methods: This ... ...

Abstract	Introduction: We compared postoperative metamorphopsia and optical coherence tomography (OCT) findings between eyes that underwent internal limiting membrane (ILM) peeling and the inverted flap (IF) technique for macular hole (MH). Methods: This retrospective analysis included 64 eyes of 64 patients with idiopathic MH whose MH was closed after initial surgery. Thirty-nine patients were treated with pars plana vitrectomy (PPV) with ILM peeling, and 25 patients were treated with PPV with the IF technique. Best corrected visual acuity (BCVA), severity of metamorphopsia, and OCT images were collected before and 3, 6, and 12 months postoperatively. Based on the OCT images, the status of the external limiting membrane (ELM) and ellipsoid zone and the presence of hyperreflective plugs were assessed. Results: At baseline and 3, 6, and 12 months postoperatively, BCVA and severity of metamorphopsia were not significantly different between groups. The status of the ELM was significantly worse in the IF group than in the ILM peeling group at 3 and 6 months postoperatively. Significantly more hyperreflective plugs were observed in the IF group than in the ILM peeling group at 3 and 6 months postoperatively. Stepwise multi-regression analysis revealed that hyperreflective plugs were significantly associated with the severity of metamorphopsia at 12 months postoperatively. Discussion/conclusion: The alterations on the OCT were fewer in the ILM peeling group than in the IF group, while no significant differences were observed in postoperative severity of metamorphopsia between groups. Metamorphopsia was worse in eyes with hyperreflective plugs.
Language	English
Publishing date	2024-02-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	209735-7
ISSN	1423-0267 ; 0030-3755
ISSN (online)	1423-0267
ISSN	0030-3755
DOI	10.1159/000537846
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Article ; Online: Functional hierarchy among different Rab27 effectors involved in secretory granule exocytosis.

Zhao, Kunli / Matsunaga, Kohichi / Mizuno, Kouichi / Wang, Hao / Okunishi, Katsuhide / Izumi, Tetsuro

eLife

2023 Volume 12

Abstract: The Rab27 effectors are known to play versatile roles in regulated exocytosis. In pancreatic beta cells, exophilin-8 anchors granules in the peripheral actin cortex, whereas granuphilin and melanophilin mediate granule fusion with and without stable ... ...

Abstract	The Rab27 effectors are known to play versatile roles in regulated exocytosis. In pancreatic beta cells, exophilin-8 anchors granules in the peripheral actin cortex, whereas granuphilin and melanophilin mediate granule fusion with and without stable docking to the plasma membrane, respectively. However, it is unknown whether these coexisting effectors function in parallel or in sequence to support the whole insulin secretory process. Here, we investigate their functional relationships by comparing the exocytic phenotypes in mouse beta cells simultaneously lacking two effectors with those lacking just one of them. Analyses of prefusion profiles by total internal reflection fluorescence microscopy suggest that melanophilin exclusively functions downstream of exophilin-8 to mobilize granules for fusion from the actin network to the plasma membrane after stimulation. The two effectors are physically linked via the exocyst complex. Downregulation of the exocyst component affects granule exocytosis only in the presence of exophilin-8. The exocyst and exophilin-8 also promote fusion of granules residing beneath the plasma membrane prior to stimulation, although they differentially act on freely diffusible granules and those stably docked to the plasma membrane by granuphilin, respectively. This is the first study to diagram the multiple intracellular pathways of granule exocytosis and the functional hierarchy among different Rab27 effectors within the same cell.
MeSH term(s)	Mice ; Animals ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism ; Insulin/metabolism ; Actins/metabolism ; Secretory Vesicles/metabolism ; Exocytosis/physiology
Chemical Substances	Vesicular Transport Proteins ; Insulin ; Actins
Language	English
Publishing date	2023-02-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.82821
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Article ; Online: Targeting activin receptor-like kinase 7 ameliorates adiposity and associated metabolic disorders.

Zhao, Min / Okunishi, Katsuhide / Bu, Yun / Kikuchi, Osamu / Wang, Hao / Kitamura, Tadahiro / Izumi, Tetsuro

JCI insight

2023 Volume 8, Issue 4

Abstract: Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to ... ...

Abstract	Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
MeSH term(s)	Animals ; Mice ; Activin Receptors/metabolism ; Activin Receptors, Type I/immunology ; Activin Receptors, Type I/metabolism ; Adiposity ; Antibodies, Neutralizing ; Fatty Acids ; Metabolic Diseases/metabolism ; Obesity/metabolism ; Disease Models, Animal
Chemical Substances	Activin Receptors (EC 2.7.11.30) ; Activin Receptors, Type I (EC 2.7.11.30) ; Acvr1c protein, mouse (EC 2.7.11.30) ; Antibodies, Neutralizing ; Fatty Acids
Language	English
Publishing date	2023-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.161229
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