Protection from diet-induced obesity and insulin resistance in mice lacking CCL19-CCR7 signaling

Sano, Tomomi; Iwashita, Misaki; Nagayasu, Shintaro; Yamashita, Akiko; Shinjo, Takanori; Hashikata, Atsushi; Asano, Tomohiko; Kushiyama, Akifumi; Ishimaru, Naozumi; Takahama, Yousuke; Nishimura, Fusanori

doi:10.1002/oby.21127

Cited by 34 publications

(30 citation statements)

References 35 publications

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“…Our observation of protection from insulin resistance in Ccr7 −/− mice agrees with recent reports and identifies loss of the ATDC population as a primary mechanism for this effect (42). CCR7 was identified in a module of signal transduction genes that were downregulated with weight loss after bariatric surgery that was disconnected from T cell signaling genes (43).…”

Section: Discussionsupporting

confidence: 93%

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance

Cho

Zamarron

Muir

et al. 2016

The Journal of Immunology

118

149

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Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDC) contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we utilize CD64 to distinguish ATM and ATDC and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+ cells overlaps with other leukocytes and that CD45+CD64+ is specific for ATM. The expression of core DC genes were enriched in CD11c+CD64− cells (ATDC), while core macrophage genes were enriched in CD45+CD64+ cells (ATM). CD11c+CD64− ATDC expressed MHCII and co-stimulatory receptors and had similar capacity to stimulate CD4+ T cell proliferation as ATM. ATDC were predominantly CD11b+ conventional DCs and made up the bulk of CD11c+ cells in adipose tissue with moderate high fat diet exposure. Mixed chimeric experiments with Ccr2−/− mice demonstrated that high-fat diet (HFD) induced ATM accumulation from monocytes was dependent on CCR2; while ATDC accumulation was less CCR2-dependent. ATDC accumulation during obesity was attenuated in Ccr7−/− mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ ATM and CD45+CD64−CD11c+ ATDC were identified in human obese adipose tissue and ATDC were increased in subcutaneous adipose tissue compared to omental. These results support a revised strategy for unambiguous delineation of ATM and ATDC and suggests that ATDC are independent contributors to adipose tissue inflammation during obesity.

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Section: Discussionsupporting

confidence: 93%

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance

Cho

Zamarron

Muir

et al. 2016

The Journal of Immunology

118

149

View full text Add to dashboard Cite

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“…TREM-1 over-expression along with M1 macrophage markers (CD86, CCR7 and iNOS) expression was found in the omentum biopsies of both obese diabetics and non-diabetics, supporting the hypothesis that chronic inflammation and macrophage phenotype change happens early in obese patients with or without diabetes [37]. Increased over-expression of CCR7 [38] and iNOS [39] in the obese diabetic group in a higher number of patients in omentum tissues compared to obese non-diabetics, suggests that the predominance of M1 macrophage markers in ATMs regulates the amplitude of adipose tissue inflammation. However, we found significantly increased overexpression of all three M1 macrophage markers (CD86, CCR7, and iNOS) in obese diabetic group in a higher number of patients in liver tissues compared to obese non-diabetics.…”

Section: Discussionmentioning

confidence: 64%

RETRACTED ARTICLE: TREM-1 associated macrophage polarization plays a significant role in inducing insulin resistance in obese population

et al. 2017

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BackgroundTREM-1 acts as an amplifier of inflammation expressed on macrophages. The objective of this study was to evaluate the relationship between TREM-1 and macrophage polarization, and association of TREM-1 and M1 macrophage polarization with insulin resistance (IR) in obese population compared to non-obese population.MethodsWe enrolled 38 patients after obtaining IRB approval for this study. We evaluated the mRNA and protein expression levels of general macrophage marker (CD68), M1 marker (CD86, CCR7, iNOS, IFNγ, TNF-α and IL-6,), M2 marker (CD206, CD163, IL-10, IL-4) and chemokine axis (MCP-1, CCR2 and CCR5) along with TREM-1 and TREM-2 in omentum fat, subcutaneous fat, and liver biopsy tissues of non-obese (N = 5), obese non-diabetics, (N = 16) and obese diabetics (N = 17).ResultsThe results of our study showed over-expression of TREM-1, M1 markers and down-regulation of TREM-2 and M2 markers in the omentum, subcutaneous and liver biopsies of obese patients (diabetics and non-diabetics) compared to non-obese patients. Overall, the obese diabetic group showed a significant (p < 0.05) higher number of patients with over expression of M1 markers (TREM-1, CD68, CD86, CCR-7, iNOS, IFN-γ, TNF-α, IL-6, MCP-1, CCR-2 and CCR-5) and down-regulation of M2 markers (CD206, CD163 and IL-4) in liver biopsy compared to obese non-diabetics.ConclusionsTREM-1 expression is significantly increased along with the M1 markers in liver biopsy of obese diabetic (17/17) and obese non-diabetic patients (9/16). Our data suggests that TREM-1 overexpression and M1 macrophage polarization are associated with obesity-induced IR.

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“…TREM-1 over-expression along with M1 macrophage markers (CD86, CCR7 and iNOS) expression was found in the omentum biopsies of both obese diabetics and non-diabetics, supporting the hypothesis that chronic in ammation and macrophage phenotype change happens early in obese patients with or without diabetes [38]. Increased over-expression of CCR7 [39] and iNOS [40] in the obese diabetic group in a higher number of patients in omentum tissues compared to obese non-diabetics, suggests that the predominance of M1 macrophage markers in ATMs regulates the amplitude of adipose tissue in ammation. However, we found signi cantly increased overexpression of all three M1 macrophage markers (CD86, CCR7, and iNOS) in obese diabetic group in a higher number of patients in liver tissues compared to obese non-diabetics.…”

Section: Discussionsupporting

confidence: 61%

TREM-1 Associated Macrophage Polarization Plays a Significant Role in Inducing Insulin Resistance in the Obese Population

Subramanian

Agrawal

Pallati

et al. 2020

Preprint

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Background: TREM-1 acts as an amplifier of inflammation expressed on macrophages. The objective of this study was to evaluate the relationship between TREM-1 and macrophage polarization, and association of TREM-1 and M1 macrophage polarization with insulin resistance (IR) in the obese population compared to the non-obese population.Methods: We enrolled 34 patients after obtaining IRB approval for this study. We evaluated the mRNA and protein expression levels of general macrophage marker (CD68), M1 marker (CD86, CCR7, iNOS, IFNγ, TNF-α, and IL-6,), M2 marker (CD206, CD163, IL-10, IL-4) and chemokine axis (MCP-1, CCR2, and CCR5) along with TREM-1 and TREM-2 in omentum fat, subcutaneous fat, and liver biopsy tissues of non-obese (N=4), obese non-diabetics, (N=16) and obese diabetics (N=14).Results: The results of our study showed over-expression of TREM-1, M1 markers, and down-regulation of TREM-2 and M2 markers in the omentum, subcutaneous and liver biopsies of obese patients (diabetics and non-diabetics) compared to non-obese patients. Overall, the obese diabetic group showed a significant (p<0.05) higher number of patients with overexpression of M1 markers (TREM-1, CD68, CD86, CCR-7, iNOS, IFN-γ, TNF-α, IL-6, MCP-1, CCR-2, and CCR-5) and down-regulation of M2 markers (CD206, CD163, IL-10, and IL-4) in liver biopsy compared to obese non-diabetics. Conclusion: TREM-1 expression is significantly increased along with the M1 markers in liver biopsy of obese diabetic (14/14) and obese nondiabetic patients (9/16). Our data suggest that TREM-1 overexpression and M1 macrophage polarization are associated with obesity-induced IR.

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Protection from diet-induced obesity and insulin resistance in mice lacking CCL19-CCR7 signaling

Cited by 34 publications

References 35 publications

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance

RETRACTED ARTICLE: TREM-1 associated macrophage polarization plays a significant role in inducing insulin resistance in obese population

TREM-1 Associated Macrophage Polarization Plays a Significant Role in Inducing Insulin Resistance in the Obese Population

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