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 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
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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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 3

Metabolic phenotyping of HFD-fed mice after NPFF treatment.

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Metabolic phenotyping of HFD-fed mice after NPFF treatment. (A) HFD-fed ...
(A) HFD-fed mice were treated with vehicle or NPFF daily, as shown in Figure 2H. Basal blood glucose level (BGL) after a 4-hour fast, glucose tolerance test (GTT), and insulin sensitivity test (ITT) (n = 6). (B) Insulin-induced AKT phosphorylation in liver, quadriceps muscle, eWAT, and iWAT. Total AKT and p-AKT (Ser308 and Thr473) levels were measured by ELISA (n = 6). (C) Plasma insulin, glucagon, and adiponectin levels (n = 6). (D) Body weight, weight gain, food consumption, eWAT and iWAT weight, and body temperature (measured at 9:00 am) (n = 6). (E) PTT (n = 6). (F) Oil red O staining of liver sections. Scale bars: 100 μm. Liver weights and liver triglycerol (TG) content. As a comparison, NCD liver TG content is also shown (n = 6). (G) Plasma lipid profile (n = 6). *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test and 2-way ANOVA (A) and 1-way ANOVA with Dunnett′s post-hoc test (B).