TY - JOUR
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 C.
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
PY - 2017/6/30
Y1 - 2017/6/30
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.
AB - 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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U2 - 10.1172/JCI90152
DO - 10.1172/JCI90152
M3 - Article
C2 - 28581443
AN - SCOPUS:85021739476
SN - 0021-9738
VL - 127
SP - 2842
EP - 2854
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -