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

Syed F.Hassnain Waqas, Anh Cuong Hoang, Ya Tin Lin, Grace Ampem, Hind Azegrouz, Lajos Balogh, Julianna Thuróczy, Jin Chung Chen, Ivan 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 & 2 others Christine M. Seroogy, Tamás Röszer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2842-2854
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number7
DOIs
StatePublished - Jun 30 2017

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Adipose Tissue
Macrophages
Appetite
Obesity
Basic-Leucine Zipper Transcription Factors
phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide
Interleukin-4 Receptors
Arginase
Caloric Restriction
Ubiquitin-Protein Ligases
Metabolic Diseases
High Fat Diet
Mixed Function Oxygenases
Interleukin-4
Interleukin-10
Cell Cycle
Maintenance
Hormones
Cytokines
Gene Expression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Waqas, S. F. H., Hoang, A. C., Lin, Y. T., Ampem, G., Azegrouz, H., Balogh, L., ... Röszer, T. (2017). Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages. Journal of Clinical Investigation, 127(7), 2842-2854. https://doi.org/10.1172/JCI90152

Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages. / Waqas, Syed F.Hassnain; Hoang, Anh Cuong; Lin, Ya Tin; Ampem, Grace; Azegrouz, Hind; Balogh, Lajos; Thuróczy, Julianna; Chen, Jin Chung; Gerling, Ivan; Nam, Sorim; Lim, Jong Seok; Martinez-Ibañez, Juncal; Real, José T.; Paschke, Stephan; Quillet, Raphaëlle; Ayachi, Safia; Simonin, Frédéric; Schneider, E. Marion; Brinkman, Jacqueline A.; Lamming, Dudley W.; Seroogy, Christine M.; Röszer, Tamás.

In: Journal of Clinical Investigation, Vol. 127, No. 7, 30.06.2017, p. 2842-2854.

Research output: Contribution to journalArticle

Waqas, SFH, Hoang, AC, Lin, YT, Ampem, G, Azegrouz, H, Balogh, L, Thuróczy, J, Chen, JC, Gerling, I, Nam, S, Lim, JS, Martinez-Ibañez, J, Real, JT, Paschke, S, Quillet, R, Ayachi, S, Simonin, F, Schneider, EM, Brinkman, JA, Lamming, DW, Seroogy, CM & Röszer, T 2017, 'Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages', Journal of Clinical Investigation, vol. 127, no. 7, pp. 2842-2854. https://doi.org/10.1172/JCI90152
Waqas, Syed F.Hassnain ; Hoang, Anh Cuong ; Lin, Ya Tin ; Ampem, Grace ; Azegrouz, Hind ; Balogh, Lajos ; Thuróczy, Julianna ; Chen, Jin Chung ; Gerling, Ivan ; Nam, Sorim ; Lim, Jong Seok ; Martinez-Ibañez, Juncal ; Real, José T. ; Paschke, Stephan ; Quillet, Raphaëlle ; Ayachi, Safia ; Simonin, Frédéric ; Schneider, E. Marion ; Brinkman, Jacqueline A. ; Lamming, Dudley W. ; Seroogy, Christine M. ; Röszer, Tamás. / Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 7. pp. 2842-2854.
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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.",
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T1 - Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages

AU - Waqas, Syed F.Hassnain

AU - Hoang, Anh Cuong

AU - Lin, Ya Tin

AU - Ampem, Grace

AU - Azegrouz, Hind

AU - Balogh, Lajos

AU - Thuróczy, Julianna

AU - Chen, Jin Chung

AU - Gerling, Ivan

AU - Nam, Sorim

AU - Lim, Jong Seok

AU - Martinez-Ibañez, Juncal

AU - Real, José T.

AU - Paschke, Stephan

AU - Quillet, Raphaëlle

AU - Ayachi, Safia

AU - Simonin, Frédéric

AU - Schneider, E. Marion

AU - Brinkman, Jacqueline A.

AU - Lamming, Dudley W.

AU - Seroogy, Christine M.

AU - Röszer, Tamás

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N2 - 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.

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