Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages
Syed F. Hassnain Waqas, … , Christine M. Seroogy, Tamás Röszer
Syed F. Hassnain Waqas, … , Christine M. Seroogy, Tamás Röszer
Published June 5, 2017
Citation Information: J Clin Invest. 2017;127(7):2842-2854. https://doi.org/10.1172/JCI90152.
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Research Article Endocrinology Inflammation

Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages

Abstract

The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet–fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage–associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs.

Authors

Syed F. Hassnain Waqas, Anh Cuong Hoang, Ya-Tin Lin, Grace Ampem, Hind Azegrouz, Lajos Balogh, Julianna Thuróczy, Jin-Chung Chen, Ivan C. Gerling, Sorim Nam, Jong-Seok Lim, Juncal Martinez-Ibañez, José T. Real, Stephan Paschke, Raphaëlle Quillet, Safia Ayachi, Frédéric Simonin, E. Marion Schneider, Jacqueline A. Brinkman, Dudley W. Lamming, Christine M. Seroogy, Tamás Röszer

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Figure 2

Human and mouse plasma contains sufficient NPFF to provoke M2 activation of ATMs.

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Human and mouse plasma contains sufficient NPFF to provoke M2 activation...
(A) Binding of FITC-conjugated NPFF to mouse ATMs. (B) cAMP levels in mouse ATMs treated with NPFF. (C) Plasma NPFF levels were measured in NCD- and HFD-fed mice (n = 6); in nonobese volunteers (n = 21) and morbidly obese patients (n = 16); in obese mice without or with 14 days of CR (n = 6); in morbidly obese patients with or without a CR diet (n = 6); and in nonobese, nonfasted volunteers and nonobese volunteers following 28 days of intermittent fasting (n = 5). (D) Npffr2 and NPFFR2 transcription in response to treatment of mouse and human ATMs for 4 hours with 0.5 nM NPFF (n = 3). (E) Transcription of M2 macrophage activation genes following a 30-minute treatment of mouse ATMs with 10 ng/ml IL-4 or 0.5 nM NPFF. (F) FACS analysis of human ATMs treated with 0.5 nM NPFF for 4 hours. Each data point represents pooled ATMs from 2 donors. (G) Arginase 1 (ARG1) expression of mouse ATMs treated with 10 ng/ml IL-4 or 0.5 nM NPFF for 24 hours. Each data point represents pooled ATMs from 3 to 5 mice. (H) Scheme of NPFF treatment of HFD-fed mice. (I–K) Relative transcription of Npffr2, M2, and M1 genes in ATMs from HFD-fed mice, without or with NPFF treatment (n = 6; each point represents pooled ATMs from 2 mice). (L) Effect of NPFF on palmitic acid–treated ATMs. ATMs were pooled from 3 to 5 mice and treated in triplicate in panels D, E, G, and L. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test.