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Catestatin Improves Insulin Sensitivity by Promoting M1‐M2 Polarization and Inhibiting Obesity‐Induced Macrophage Infiltration and Gluconeogenesis in Liver
Author(s) -
Mahata Sushil Kumar,
Ying Wei,
Muntjewerff Elke M,
Mahata Sumana,
Nicolasen Mara J.T.,
Das Soumita,
Bandyopadhyay Gautam Kumar,
Bogaart Geert
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.834.13
Subject(s) - proinflammatory cytokine , inflammation , insulin resistance , endocrinology , cd14 , medicine , macrophage polarization , insulin , monocyte , biology , immune system , immunology , gene , phenotype , biochemistry
Objective Components of the innate and adaptive immune system are affected in obesity and Type 2 diabetes (T2D) and inflammation participates in the pathogenesis of T2D. The activation of the resident Kupffer cells and monocyte (Mc)‐derived recruited macrophages (McMΦs) in the liver contributes to obesity‐induced insulin resistance (IR) and T2D. Here, we sought to determine whether the Chromogranin A (CgA) peptide Catestatin (CST: human CgA 352–372 ) regulates recruitment of macrophages and modulates metabolism in insulin‐resistant diet‐induced obese (DIO) mice as well as M1–M2 polarization in human monocytes. Methods and Results CST treatment of DIO mice diminished the expression of gluconeogenic genes, attenuated expression of pro‐inflammatory genes, increased expression of anti‐inflammatory genes in McMΦs, and inhibited infiltration of McMΦs, leading to improvement of insulin sensitivity. To gain better insights into the mechanism of action of CST, we isolated CD14 + subsets of monocytes from buffy coats from healthy individuals. The monocytes were cultured with M‐CSF towards undifferentiated MΦs and subsequently polarized towards pro‐inflammatory and anti‐inflammatory phenotypes with GM‐CSF, IFN‐γ and LPS or M‐CSF and IL4, respectively. RNA sequencing of proinflammatory MΦs revealed that CST decreased expression of proinflammatory genes in proinflammatory (e.g., IL23A, FCRLA, and IL1A) as well as in anti‐inflammatory MΦs (e.g., IL11RA, SP140, NLRCS, and TRIM34). In anti‐inflammatory macrophages, CST increased expression of anti‐inflammatory genes. Consistent with gene expression, CST exposure to anti‐inflammatory MΦs enhanced IL‐10 production but not in pro‐inflammatory MΦs, whereas CST inhibited TNFα and IL‐6 production in both cultures. Conclusion We conclude that (i) CST attenuated macrophage mediated inflammation, resulting in improved insulin sensitivity in obese mice. (ii) CST promoted M1–M2 polarization by decreasing expression of proinflammatory cytokines and increasing expression of ant‐iinflammatory cytokines. Support or Funding Information Supported by grants from the VA (I01BX000323 to S.K.M.), and the NWO Gravitation Programme 2013 (ICI‐024.002.009 to G.v.d.B.), and a Vidi grant from the Netherlands Organization for Scientific Research (NWO‐ALW VIDI 864.14.001 to G.v.d.BG.v.d.B.). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .