Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

Talukdar, Saswata; Oh, Da Young; Bandyopadhyay, Gautam; Li, Dongmei; Xu, Jianfeng; McNelis, Joanne; Lü, Min; Li, Pingping; Yan, Qi; Zhu, Y.; Ofrecio, Jachelle M.; Lin, Michael; Brenner, Martin; Olefsky, Jerrold M.

doi:10.1038/nm.2885

Cited by 769 publications

(733 citation statements)

References 26 publications

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“…However, the role of other myeloid cells such as dendritic cells or granulocytes that are target cells of Cre-mediated gene deletion in Atg7 cKO mice 49 cannot be totally eliminated, as both granulocytes and dendritic cells participate in the insulin resistance associated with obesity. 50,51 The development of T2D in Atg7 cKO-ob/ob mice but not in lean Atg7 cKO mice suggests that autophagy-deficient myeloid cells do not display significant inflammatory phenotypes in the basal state, but show proinflammatory features in the presence of activators of inflammation or metabolic stress. Thus, autophagy-deficient Mfs appear to be susceptible to inflammasome activators such as lipids, which is the reason Atg7 cKO mice show increased inflammatory features and overt T2D when they become obese.…”

Section: Discussionmentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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Section: Discussionmentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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“…Recently, significant accumulation of neutrophils has been demonstrated in adipose tissue and degradation of the signaling molecule IRS-1 was attributed to neutrophil-derived elastase [104].…”

Section: Participation Of Pmn In Vital Function Other Than Defense Agmentioning

confidence: 99%

Changing world of neutrophils

Tímár

Lörincz

Ligeti

2013

Pflugers Arch - Eur J Physiol

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“…In the past decade it has been reported that obesity is underlying chronic low-grade inflammation that causes various metabolic disorders, including insulin resistance (2). Under obese conditions, a variety of inflammatory cells, including macrophages, neutrophils, T-cells, and eosinophils, are activated, stimulating infiltration, in adipose tissue (3)(4)(5)(6). Among these inflammatory cells, classically activated macrophages (M1-type macrophages) in adipose tissue secrete proinflammatory cytokines (TNF-␣ and IL-1␤), which induce insulin resistance (7)(8)(9)(10)(11).…”

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confidence: 99%

Deficiency of Oncostatin M Receptor β (OSMRβ) Exacerbates High-fat Diet-induced Obesity and Related Metabolic Disorders in Mice

Komori

Tanaka

Senba

et al. 2014

Journal of Biological Chemistry

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Background: Obesity is associated with adipose tissue inflammation, insulin resistance, and hepatic steatosis. Results: OSM receptor ␤ (OSMR␤)-deficient mice fed a high-fat diet exhibited severe obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis. Conclusion: OSM signaling has suppressive effects on the deterioration of obesity-induced metabolic disorders. Significance: These results indicate that OSM signaling may be a promising therapeutic target of obesity-induced metabolic disorders.

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Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

Cited by 769 publications

References 26 publications

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Changing world of neutrophils

Deficiency of Oncostatin M Receptor β (OSMRβ) Exacerbates High-fat Diet-induced Obesity and Related Metabolic Disorders in Mice

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