Tumor Necrosis Factor (TNF)-α-induced Repression of GKAP42 Protein Levels through cGMP-dependent Kinase (cGK)-Iα Causes Insulin Resistance in 3T3-L1 Adipocytes

Ando, Yumiko; Shinozawa, Yusuke; Iijima, Yoshimi; Yu, Bu Chin; Sone, Meri; Ooi, Yuko; Watanaka, Yusuke; Chida, Kazuhiro; Hakuno, Fumihiko; Takahashi, Shin‐Ichiro

doi:10.1074/jbc.m114.624759

Cited by 27 publications

(24 citation statements)

References 55 publications

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“…M1 macrophages are a prominent source of chemotactic and pro-inflammatory factors. Pro-inflammatory cytokines, such as TNF-α and IL-6, blocked insulin signalling [33][34][35]. Exosomes derived from activated macrophages could be vectors for pro-inflammatory cytokines that mediate adipocyte insulin resistance [36].…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Song

Han

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adipocyte-derived exosomes (ADEs) stimulate the activation of macrophages and contribute to the development of insulin resistance. Sonic Hedgehog (Shh) is an exosome-carrying protein and stimulates macrophages to secrete inflammatory cytokines. However, the impact of ADEs carrying Shh on the pro-inflammatory activation of macrophages and consequently, adipocyte insulin resistance is unclear. Methods: 3T3-L1 adipocytes were cultured with high glucose and insulin to imitate the pathogeny of insulin resistance. ADEs were isolated from conditioned media of 3T3-L1 adipocytes via differential ultracentrifugation. We explored the role of ADEs carrying Shh in the polarization of macrophages by flow cytometry. Western blot and electrophoretic mobility shift assay (EMSA) were performed to determine the activation of Shh-mediated signalling pathways. The effects of ADE-treated macrophages on adipocyte insulin signalling were studied by Western blot. Results: We found that circulating Shh-positive exosomes were increased in type 2 diabetes patients. High glucose and insulin increased the secretion of Shh-positive ADEs. The ADEs carrying Shh induced pro-inflammatory or M1 polarization of bone marrow-derived macrophages (BMDM) and RAW 264.7 macrophages. Inhibitors of Ptch and PI3K blocked the M1 polarization induced by ADEs, which suggests that ADEs carrying Shh mediated M1 macrophage polarization through the Ptch/PI3K signalling pathway. ADE-treated RAW 264.7 macrophages were subsequently used to assess the effect on insulin signalling in adipocytes. Using a co-culture assay, we showed that both ADE-treated macrophages and exosomes from these macrophages could decrease the expression of insulin-resistant substrate-1 (IRS-1) and hormone-sensitive lipase (HSL) in adipocytes. Inhibitors of Ptch and PI3K blocked the down-regulation of IRS-1 and HSL induced by ADE-treated macrophages. Conclusion: Together, these data indicate that ADEs carrying Shh induce the M1 polarization of macrophages, which contributes to insulin resistance in adipocytes through the Ptch/PI3K pathway.

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Section: Discussionmentioning

confidence: 99%

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Song

Han

Chen

et al. 2018

Cell Physiol Biochem

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“…41 Moreover, these proinflammatory adipokines may induce insulin resistance; 41 TNFa impairs insulin-stimulated glucose uptake by repressing the protein levels of a 42-kDa cyclic guanosine monophosphatedependent protein kinase-anchoring protein, required for insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 and translocation of glucose transporter 4 in adipocytes. 42 Though cardiometabolic diseases are more frequently associated with younger psoriatic patients, 30 the psoriatic patients with younger onset did not show differences in dietary habits compared with age-and sex-matched normal controls except for the increased BMI, possibly due to the small number of cases. Further studies should evaluate the dietary habits in increased numbers of psoriatic patients with younger onset, and detect certain dietary characteristics related to cardiometabolic diseases.…”

Section: Discussionmentioning

confidence: 86%

“…Taken together, the high intake of confection may lead to the exacerbation of psoriatic symptoms and the promotion of insulin resistance: the high intake of confection may promote the secretion from adipose tissues of pro‐inflammatory adipokines like TNF‐α or resistin, which may act on dendritic cells, T cells or keratinocytes, and aggravate the inflammation in the skin . Moreover, these pro‐inflammatory adipokines may induce insulin resistance; TNF‐α impairs insulin‐stimulated glucose uptake by repressing the protein levels of a 42‐kDa cyclic guanosine monophosphate‐dependent protein kinase‐anchoring protein, required for insulin‐induced tyrosine phosphorylation of insulin receptor substrate 1 and translocation of glucose transporter 4 in adipocytes …”

Section: Discussionmentioning

confidence: 99%

Dietary habits in Japanese patients with psoriasis and psoriatic arthritis: Low intake of meat in psoriasis and high intake of vitamin A in psoriatic arthritis

Yamashita

Morita

Ito

et al. 2019

The Journal of Dermatology

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Psoriasis is characterized by T‐helper 17 cell‐dominant abnormal immunity, and hyperproliferation and abnormal differentiation of epidermal keratinocytes. Some patients are associated with arthritis. Dietary habits can modulate the pathogenesis of psoriasis. Previous studies in Western countries showed higher body mass indices, higher intake of fat and lower intake of fish or vegetables in psoriatic patients compared with the reference groups. We evaluated dietary habits in adult Japanese psoriatic patients, using a validated brief‐type self‐administered dietary history questionnaire, and compared the results to those of age‐ and sex‐matched healthy controls. The results in psoriatic patients with arthritis were compared with those in the patients without. Japanese psoriatic patients showed higher body mass indices, higher intake of fish/shellfish, pulses, sugar/sweeteners, vitamin B12 and vitamin D, and lower intake of meat, compared with those of healthy controls. The logistic regression analysis showed that psoriasis was associated with high body mass index and low intake of meat. The intake of confection in patients with high Psoriasis Area and Severity Index was higher than that in those with low index. The intake of β‐carotene, vitamin A and green/yellow vegetables in psoriatic patients with arthritis were higher than those in the patients without. The dietary habits in Japanese psoriatic patients are rather different from those in Western patients. This is the first study showing the differences in dietary habits between psoriatic patients with arthritis and those without. Further studies should elucidate the relationships of these results with skin and joint lesions in psoriatic patients.

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“…Three patients, two of which were from the same cluster, shared the missense mutation c.1197C > G (p.Asp266His) in GKAP1 . GKAP1 regulates insulin‐dependent signals and GLUT4 translocation and has been suggested to have a role in male germ cell development . The gene has not previously been linked to cancer.…”

Section: Discussionmentioning

confidence: 99%

“…regulates insulin-dependent signals and GLUT4 translocation 40 and has been suggested to have a role in male germ cell development. 41 The gene has not previously been linked to cancer.…”

Section: Discussionmentioning

confidence: 99%

Candidate susceptibility variants for esophageal squamous cell carcinoma

Donner

Katainen

Tanskanen

et al. 2017

Genes Chromosomes & Cancer

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Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life-time risk of ESCC, but no other well-established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth. We collected archival tissue material and exome sequenced a total of 30 ESCC cases. We prioritized shared, deleterious and rare variants that were significantly enriched in our sample set compared to Finnish and population subset specific controls. Six variants passed filtering, the most frequent being a nonsense mutation in DNAH9 (p.Tyr1573Ter) found in four unrelated patients. DNAH9 has been reported to be frequently lost in ESCC tumors. In this study, one patient's tumor showed loss of the wild type allele of DNAH9 suggesting a tumor suppressive function. A missense variant in GKAP1 was shared by three patients, and missense variants in BAG1, NFX1, FUK, and DDOST by two each. EP300 which has previously been implicated in the genesis of ESCC had a missense variant segregating in three affected individuals in a single family. If validated in independent patient sets, these variants could serve as a tool towards prevention and early diagnosis of ESCC.

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Tumor Necrosis Factor (TNF)-α-induced Repression of GKAP42 Protein Levels through cGMP-dependent Kinase (cGK)-Iα Causes Insulin Resistance in 3T3-L1 Adipocytes

Cited by 27 publications

References 55 publications

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Dietary habits in Japanese patients with psoriasis and psoriatic arthritis: Low intake of meat in psoriasis and high intake of vitamin A in psoriatic arthritis

Candidate susceptibility variants for esophageal squamous cell carcinoma

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