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 7

NPFF/NPFFR2 inhibits IFN signaling.

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NPFF/NPFFR2 inhibits IFN signaling. (A) Effect of a 4-hour treatment wit...
(A) Effect of a 4-hour treatment with 0.5 nM NPFF, 2.5 ng/ml IFN-γ, or their combination on Il6 and Nos2 transcription in mouse ATMs. (B) Effect of 500 μM Br-cAMP on the transcriptional changes in mouse ATMs evoked within 0.5 hours by treatment with 0.5 nM NPFF. (C) STAT3 phosphorylation within 20 minutes in mouse ATMs following treatment with 0.5 nM NPFF and 500 μM Br-cAMP (left). Effect of a 1-hour treatment with 0.5 nM NPFF and 100 ng/ml IL-6 on Rnf128 transcription in mouse ATMs. The effect of NPFF was also tested following a 20-minute preincubation with IL-6 (right). (D) Proliferation of ATMs treated for 18 hours with 0.5 nM NPFF, 500 μM Br-cAMP, or their combination. (E) Effect of 500 μM Br-cAMP and 0.5 nM NPFF on Ndrg2 and Ifi203 transcription in ATMs and Ifi202b transcription in J774A.1 macrophages. In A–E, each data point represents pooled ATMs from 3 to 5 mice. In E, triplicates of J774A.1 cultures were used. *P < 0.05 and **P < 0.01 for the indicated comparisons and #P < 0.05 and ##P < 0.01 versus vehicle control; 1-way ANOVA with Dunnett’s post-hoc test. (F) NPFF action in macrophages (simplified scheme): (i) NPFF/NPFFR2 blocks adenylate cyclase (AC); (ii) NPFF reduces cAMP levels; (iii)  STAT3 signaling is inhibited; (iv) Reduced Rnf128 transcription delays p-STAT6 decay; and (v) Inhibition of IFN-inducible (IFI) genes. (G) Role of NPFF/NPFFR2 signaling in ATMs. Morbid obesity reduces plasma NPFF to levels below the effective dose of NPFF in ATMs.