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Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice

Nature Metabolism volume 3, pages 496–512 (2021)Cite this article

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Abstract

Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.

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Fig. 1: Digoxin prevents DIO and metabolic disorders.
Fig. 2: Digoxin suppresses DIO and metabolic disorders.
Fig. 3: RORγt inhibitors suppress DIO and metabolic disorders.
Fig. 4: Deletion of IL-17RA prevents DIO and metabolic disorders.
Fig. 5: Inhibition of the IL-17A axis promotes browning and thermogenesis.
Fig. 6: Genetic ablation of Il17ra in adipocytes prevents DIO.
Fig. 7: IL-17A phosphorylates PPARγ in adipocytes to promote obesity.

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Data availability

All data in this study are available in the text and its Supplementary Information files, which include Extended Data Figs. 1–8 and Source Data Figs. 1 and 2. The data that support the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.

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Acknowledgements

We are very thankful to R. Elosua and I. Subirana for collecting and analysing the epidemiological data (Hospital del Mar Medical Research Institute, Barcelona). We particularly thank the biostatistician C. Coscia for discussing the statistical analysis of EE. We are grateful to the CNIO Biobank for helping us to collect WAT from patients and associated clinical data. We particularly acknowledge the patients enroled in this study for their participation and the Aragon Health Sciences Institute in the framework of the Biobank of the Aragon Health System for its collaboration. We are also thankful to M. Malumbres for critical reading of this manuscript, and to the CNIO Mouse Genome Editing Core Unit and Animal Facility for the mouse re-derivation and maintenance, respectively. This work was funded by the European Foundation for the Study of Diabetes (EFSD) award supported by EFSD/JRDF/Lilly programme (EASD 96103), the Pfizer Foundation, and the State Research Agency (AEI, 10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2016-76598-R, SAF2017-92733-EXP and RTI2018-094834-B-I00), cofunded by European Regional Development Fund (ERDF). This work was developed at the CNIO funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and Innovation. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, Spain

    Ana Teijeiro, Amanda Garrido, Anna Ferre & Nabil Djouder

  2. Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain

    Cristian Perna

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Contributions

A.T. and N.D. designed the experiments. A.T. performed most of the experiments and statistical analyses. A.G. helped to process and analyse human WAT samples. A.F. helped with some experiments performed in 3T3-L1 cells. C.P. histopathologically analysed mouse tissues. A.T. and N.D. analysed the data. N.D. conceived, developed and wrote the project and study. N.D. and A.T. wrote the manuscript. N.D. secured all funding.

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Correspondence to Nabil Djouder.

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Peer review information Nature Metabolism thanks Bruno Silva-Santos and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: George Caputa; Pooja Jha.

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Extended data

Extended Data Fig. 1 Digoxin prevents DIO and metabolic disorders.

a, Gating strategy for flow cytometry analysis of IL-17A-producing cells in ND- or HFD-fed-C57BL/6 mice (beginning at 8 weeks) for 2 months, treated with or without digoxin for 1 week. b, qRT-PCR in spleen of 38-week-old C57BL/6 mice fed with HFD (beginning at 8 weeks) treated with or without digoxin (n = 5 mice per group). c, qRT-PCR of RORγt target genes in spleen and RORγ target genes in WAT of mice from b (n = 5 mice per group; P = 0.0008; 0.0358; 0.0028; 0.0033; 0.0683; 0.0115, from left to right). d, Total lean mass in ND- or HFD-fed-24-week-old C57BL/6 mice treated with or without digoxin (beginning at 8 weeks) (n = 5 mice per group; P = 0.0168; <0.0001; 0.0007, from left to right). e, Liver weight in mice from d (n = 5 mice per group; P = 0.0064; 0.0013; 0.0014, from left to right). f, Bone mineral density (BMD) in mice from d (n = 5 mice per group). Unpaired two-tailed Student’s t test was used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Extended Data Fig. 2 Digoxin suppresses DIO and metabolic disorders.

a, Weights of HFD-fed-C57BL/6 mice (beginning at 8 weeks) treated with digoxin (beginning at 16 weeks) and injected with rIL-17C, rIL-17E or rIL-17F (beginning at 21 weeks) (n = 4 mice per group). b, Scheme of Rorc-Cre-DTR mouse model in which RORγt-positive cells are depleted with DT. c, Weights of ND- or HFD-fed-C57BL/6 mice (beginning at weeks) treated with vehicle or ouabain (beginning at 8 weeks) (n = 5 mice per group). d, Total lean mass in ND- or HFD-fed-38-week-old C57BL/6 mice (beginning at 8 weeks) treated with or without digoxin (beginning at 20 weeks) (n = 10, 5, 8, and 15 mice; P = 0.0457; 0.0001, from left to right). e, Liver weight in mice from d (n = 9, 5, 10, and 8 mice; p <0.0001). f, BMD in mice from d (n = 10, 5, 8, and 15 mice). g, Scheme representing digoxin treatment over 4 weeks in HFD-fed-C57BL/6 mice. h, ORO in livers of HFD-fed-24-week-old-C57BL/6 (beginning at 8 weeks) treated with or without digoxin (beginning at 20 weeks). i, ORO quantification from mice from h (n =5 mice per group; P = 0.0084). Scale bar, 50 μm. j, Cholesterol in plasma from ND- or HFD-fed-C57BL/6 mice (beginning at 8 weeks) treated with or without digoxin (beginning at 20 weeks) for 1 week, 2 weeks or 4 weeks (n = 4 mice per group; P = 0.0006; 0.0245; 0.023; 0.0015; 0.001; 0.017; 0.0025; 0.0467, from left to right). k, Fasting glucose levels in mice from j (n = 4 mice per group; p = 0.0053; 0.021; 0.05; 0.0012; 0.0115; 0.003; 0.0009, from left to right). l, m, Results from the GTT (l) (p = 0.0354; <0.0001; 0.0016; 0.0067, from left to right) and ITT (m) (P = 0.001; 0.0003; 0.0328; 0.0038, from left to right) in mice from j (n = 4 mice per group). n, H&E in mice from d. 3V: Third ventricle. Scale bars,100μm, 200μm and 500 μm. o, p, Creatinine (o) and NH3 (p) in plasma from mice from d (n = 4 mice per group). q, Success in the tightrope test in mice from h (n = 4, 4, 5, and 4 mice; P = 0.0394; 0.0395, from left to right). r, Rotarod test in mice from h (n = 4, 4, 10, 4 mice; P = 0.0175; 0.0005, from left to right). s, Open-field test in mice from h (n = 4, 4, 5, and 4 mice). t, Object recognition test in in mice from h (n = 4, 4, 5, and 4 mice). Unpaired two-tailed Student’s t test (d-f, i-k, o-t) or two-way ANOVA (a, c, l, m) were used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Extended Data Fig. 3 RORγt inhibitors suppress DIO and metabolic disorders.

a-d, gWAT (a) (P = 0.0001), iWAT (b) (P = 0.0206), BAT (c) (P = 0.0062), and liver (d) (pP = 0.0434) weights in HFD-fed-20-week-old C57BL/6 mice, treated with vehicle or GSK805 (beginning at 8 weeks) (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice). e, Cholesterol in plasma from mice from a-d (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.001). f, Percentage of total fat in HFD-fed-26-week-old C57BL/6 mice (beginning at 8 weeks) treated with vehicle or GSK805 (beginning at 20 weeks) (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.0234). g, Total fat mass in mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.0257). h-j, gWAT (h) (P = 0.0443), iWAT (i) (P = 0.0122), BAT (j) (P = 0.0475) weights in mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice). k, Total lean mass in mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.0321). l, Liver weight in mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.0136). m, BMD in mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice). n, Cholesterol in plasma from mice from f (n = 5 (HFD + vehicle) and 3 (HFD + GSK805) mice; P = 0.0325). o-r, gWAT (o) (P = 0.0338), iWAT (p) (P = 0.0061), BAT (q) (P = 0.0192), and liver (r) (P = 0.0065) weights in HFD-fed-18-week-old C57BL/6 mice, treated with vehicle or TMP778 (beginning at 6 weeks) (n = 4 (HFD + vehicle) and 5 (HFD + TMP778) mice). s, Cholesterol in plasma from mice from o-r (n = 4 (HFD + vehicle) and 5 (HFD + TMP778) mice; P = 0.0018). t, Table summarizing the effects of anti-obesity compounds in preclinical mouse models. 1Time: administration time needed for weight stabilization described. 2Length: Long-term administration described. ND: Not determined. IP: intraperitoneal administration. SC: subcutaneous administration. Weight loss was adjusted to ND- or HFD-fed mice as indicated in Methods. Unpaired two-tailed Student’s t test was used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.Data are represented as means ± s.e.m.

Extended Data Fig. 4 Deletion of IL-17RA prevents DIO and metabolic disorders.

a, Scheme of Il17raΔ/Δ mouse model in which Il17ra deletion is controlled by hUBC-CreERT2. b, qRT-PCR of tissues from ND- or HFD-fed-Il17ra+/+ and -Il17raΔ/Δ mice, after deletion of Il17ra (n = 3 mice per group; P = 0.05; 0.0018; 0.0383; 0.047, from left to right). c, Total lean mass in ND- or HFD-fed-38-week-old Il17ra+/+ and Il17raΔ/Δ mice (n = 4, 4, 6, and 5 mice; P = 0.002; 0.017, from left to right). d, Liver weight in mice from c (n = 5, 6, 9, and 6 mice; P = 0.001; 0.0003, from left to right). e, BMD in mice from c (n = 4, 4, 6, and 5 mice). Unpaired two-tailed Student’s t test was used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Extended Data Fig. 5 Inhibition of IL-17A axis promotes browning and thermogenesis.

a, b, Cumulative food intake of ND- or HFD-fed-C57BL/6 mice (beginning at 8 weeks), treated with or without digoxin (beginning at 20 weeks) for 1 month (a) (n = 4 mice per group; P = 0.0245) and of ND- or HFD-fed-Il17ra+/+ and -Il17raΔ/Δ mice (beginning at 8 weeks) for 1 month (b) (n = 3, 4, 6, and 4 mice; P = 0.0397). c, d, Cumulative food intake of ND- or HFD-fed-38-week-old C57BL/6 mice (beginning at 8 weeks) treated with or without digoxin (beginning at 20 weeks) (c) (n = 10, 5, 4 and 8 mice; P = 0.0415; 0.0037, from left to right) (c), and of ND- or HFD-fed-38-week-old Il17ra+/+ and Il17raΔ/Δ mice (beginning at 8 weeks) (d) (n = 6, 6, 6 and 4 mice; P = 0.0043). e, Cumulative drink intake of mice from a (n = 4 mice per group). f, Cumulative drink intake of mice from b (n = 3, 4, 6 and 4 mice). g, Hematocrit (HCT), hemoglobin (HGB) and red blood cells (RBC) measured by haemogram in mice from c (n = 9, 5, 10, and 5 mice). h, Weights of ND- or HFD-fed-C57BL/6 mice, treated with or without digoxin in drinking water or intraperitoneally (i.p) (beginning at 8 weeks) (n = 5 mice per group; p <0.0001). i, Locomotor activity in mice from c (n = 10, 9, 8, and 12 mice). j, Locomotor activity in mice from d (n = 7, 6, 7, and 4 mice). k, Respiratory exchange ratio (RER) in mice from c (n = 10, 9, 8, and 12 mice; p <0.0001). l, RER in mice from d (n = 7, 6, 7, and 4 mice; P = 0.0002; <0.0001; 0.0022, from left to right). m, n, EE normalized to body weight and monitored for 3 days (m) and total EE normalized to body weight (n) (P = 0.0004; 0.0009, from left to right) in ND- or HFD-fed-13-week-old C57BL/6 mice (beginning at 8 weeks) treated with or without digoxin (beginning at 12 weeks) for 1 week (n = 10, 8, 9, 8 mice). Grey squares denote night periods. o, p, EE normalized to body weight and monitored for 3 days (o) and total EE normalized to body weight (p) (P = 0.004; 0.0043; 0.0002, from left to right) in mice from c (n = 10, 9, 8, and 12 mice). q, r, EE normalized to body weight and monitored for 3 days (q) and total EE normalized to body weight (r) (P = 0.0117; 0.0002; 0.0035, from left to right) in mice from d (n = 7, 6, 7, and 6 mice). s, t, EE monitored for 3 days (s) and total EE (t) in mice from c (n = 10, 9, 8, and 12 mice). u, Regression plot of total EE from t and body weight from each mouse from c (n = 10, 9, 8, and 12 mice). v, WB of gWAT from mice from c (n = 1, 3, 4, and 4 samples). w, qRT-PCR of β oxidation target genes in BAT of mice from c (n = 6, 3, 6, and 5 mice; P = 0.0253; 0.0091; 0.0003; 0.0109; 0.0329; <0.0001; 0.0074; 0.0364; 0.0029; 0.0055, from left to right). x, H&E and IHC in gWAT, iWAT, and BAT of ND- or HFD-fed-12-week-old C57BL/6 mice, treated with or without digoxin (beginning at 8 weeks) for 1 month after 24 hours of cold exposure. Scale bars, 100 μm in WAT and 50 μm in BAT. Unpaired two-tailed Student’s t test (g, i-l, n, p, r, t, w), two-way ANOVA with interaction (u), “conventional” two-way ANCOVA (t) and two-tailed Tukey’s post-hoc test (t), or two-way ANOVA (a-f, h) were used. Each dot in (u) represents one mouse. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Source data

Extended Data Fig. 6 IL-17A mediates obesity independently of the leptin axis or myeloid cells’ activation.

a, Weights of Lep+/+(ob) and Lep-/-(ob) mice treated with or without digoxin (beginning at12 weeks) (n = 7, 11 and 12 mice; p <0.0001). b, Pictures of 24-week-old Lep+/+(ob) and Lep-/-(ob) mice treated with or without digoxin (beginning at 12 weeks). Scale bar, 1 cm. c, Weights of mice from b relative to the weight of Lep+/+(ob) mice (n = 7, 11, and 12 mice; p <0.0001). d, Weights of Lepr+/-(db) and Lepr-/-(db) mice treated with or without digoxin (beginning at 12 weeks) (n = 13, 8, and 7 mice; p <0.0001). e, Scheme of tamoxifen treatment for 2 weeks at 10 weeks of age in Lep+/+(ob);Il17ra+/+, Lep-/-(ob);Il17ra+/+ and Lep-/-(ob);Il17raΔ/Δ mice (upper panel), and weights of Lep+/+(ob);Il17ra+/+, Lep-/-(ob);Il17ra+/+ and Lep-/-(ob);Il17raΔ/Δ mice (lower panel) (n = 8, 5, and 6 mice; p <0.0001). f, Percentage of weight change after 1 month of rLeptin in ND- or HFD-fed-28-week-old C57BL/6 mice (beginning at 8 weeks), treated with or without digoxin (beginning at 20 weeks), relative to 24-week-old weight (n = 4, 5, 4, and 4 mice; P = 0.0135). g, Percentage of weight change after 1 month of rLeptin in 20-week-old Lep-/-(ob) mice treated with or without digoxin (beginning at 12 weeks), relative to 16-week-old weight. (n = 4, 5, 5, and 5 mice; P = 0.0002; 0.0001, from left to right). h, Weights of ND- or HFD-fed-Lep+/+(ob) and Lep-/-(ob) mice (beginning at 6 week)s, treated with or without digoxin (beginning at 12 weeks) (n = 4, 11, 9, and 6 mice; P = 0.0421). i, IHC in gWAT of ND- or HFD-fed-38-week-old C57BL/6 mice (beginning at 8 weeks), treated with or without digoxin (beginning at 20 weeks). Scale bars, 20 μm and 100 μm. j-m B220 (j) (n = 4, 5, 6, and 7 mice; P = 0.0381; 0.0072, from left to right), CD3 (k) (n = 4, 4, 5, and 5 mice; P = 0.044; 0.0115, from left to right), F4/80 (l) (n = 4, 5, 8, and 8 mice; P = 0.0321; 0.0006, from left to right) and MPO (m) (n = 4, 4, 8, and 7 mice; P = 0.0314; 0.0211, from left to right) quantification from gWAT of mice from i. n, Scheme of Il17raΔ/Δ(Myeloid) mouse model in which Il17ra deletion is controlled by LysM-Cre. o, Gating strategy and representative flow cytometry from Il17ra+/+(Myeloid) and Il17raΔ/Δ(Myeloid) mice. p, Quantification of IL-17RA+ CD11b+ cells in Il17ra+/+(Myeloid) and Il17raΔ/Δ(Myeloid) mice (n = 4 and 8 mice; p <0.0001). q, Weights of ND- or HFD-fed-Il17ra+/+(Myeloid) and -Il17raΔ/Δ(Myeloid) mice, treated with or without digoxin (beginning at 8 weeks) (n = 4, 5, 8, and 4 mice; P = 0.0003). Unpaired two-tailed Student’s t test (c, f, g, j-m, p) or two-way ANOVA (a, d, e, h, q) were used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Extended Data Fig. 7 IL-17A phosphorylates PPARγ in adipocytes to promote obesity.

a, FITC-dextran in plasma from ND- or HFD-fed-38-week-old C57BL/6 mice (beginning at 8 weeks), treated wit or /without digoxin (beginning at 20 weeks) (n = 5 mice per group; P = 0.0019). b, Daily faecal mass in mice from a (n = 3, 4, 5, and 6 mice; p <0.0001). c, Faecal caloric density measured by bomb calorimetry in mice from a (n = 4 mice per group). d, Faecal trycerides (TGs) (n = 6, 5, 6, and 5 mice per group), proteins (n = 5 mice per group) and carbohydrates (n = 5, 4, 4, and 5 mice) in mice from a. e, Plasma free fatty acids (FFA) in mice from a (n = 5, 6, 5, and 7 mice). f, qRT-PCR of target genes for hepatic β oxidation in livers of mice from a (n = 5, 4, 5, and 7 mice). g, H&E in gWAT of mice from a (upper panel) and of ND- or HFD-fed-38-week-old Il17ra+/+ and -Il17raΔ/Δ mice (lower panel). Scale bar, 100 μm. h, Adipocyte size of mice from a (n = 7, 4, 8, and 7 mice; P = 0.0005; 0.0178; 0.0238, from left to right). i, Adipocyte size of ND- or HFD-fed-38-week-old Il17ra+/+ and Il17raΔ/Δ mice (n = 4, 4, 5, and 3 mice; P = 0.0463; 0.0043; 0.0029, from left to right). j, Scheme of fasting-refeeding and sample collection in ND- or HFD-fed-24-week-old C57BL/6 mice (beginning at 8 weeks, treated with or without digoxin (beginning at 20 weeks) for 1 month. k, l, Pc j after 24 hours of fasting and refeeding represented as ng/ml (k) (p <0.0001; 0.0053) or normalized to fasted levels (T0) (l) (P = 0.0083; 0.0181; 0.0047; 0.0475; 0.0176; 0.0376; 0.0478, from left to right) (n = 5 mice per group). m, Scheme of Il17raΔ/Δ(Adipoq) mouse model in which IL17ra deletion is controlled by Adipoq-Cre. n, Il17ra mRNA levels in WAT from HFD-fed-20-week-old Il17ra+/+(Adipoq) and Il17raΔ/Δ(Adipoq) mice (beginning at 8 weeks) (n = 5 mice per group; P = 0.05; 0.0218, from left to right). o, Weights of HFD-fed-20-week-old Il17ra+/+, Il17raΔ/Δ, Il17ra+/+(Adipoq) and Il17raΔ/Δ(Adipoq) mice (beginning at 8 weeks) (n = 8, 7, 8, and 6 mice; p <0.0001; 0.0026, from left to right). p, Total lean mass in mice from n (n = 6, 4, 8, and 4 mice; P = 0.0092; 0.0244, from left to right). q, Liver weight in mice from n (n = 6, 4, 8, and 6 mice; P = 0.028; 0.0007, from left to right). r, BMD in mice from n (n = 6, 4, 8, and 6 mice). s, qRT-PCR in gWAT from mice from n (n = 4 mice per group). t, u, qRT-PCR of target genes for lipogenesis (t) (P = 0.008; 0.0408; 0.0128; 0.0064, from left to right) and differentiation (u) (P = 0.0228; 0.0462, from left to right) in gWAT of mice from a (n = 6, 4, 7, and 7 mice). v, qRT-PCR of genes modulated by the CDK5-mediated phosphorylation of PPARγ on Ser273 in differentiated 3T3-L1 adipocytes (n = 3 independent experiments; P = 0.0442; 0.0129; 0.0033, from left to right). w, qRT-PCR of genes modulated by the CDK5-mediated phosphorylation of PPARγ on Ser273 in gWAT from mice from a (n = 6, 4, 7, and 7 mice; p <0.0001; 0.0094; 0.0002; 0.0007; <0.0001; 0.0086; 0.0004; 0.0284; 0.0002; 0.0489; <0.0001; 0.0216; 0.0001; 0.0038; 0.0002; 0.0386, from left to right). Unpaired two-tailed Student’s t test (a-f, h, i, l, n-w) or two-way ANOVA (k) were used. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Data are represented as means ± s.e.m.

Extended Data Fig. 8 IL-17A signalling correlates with obese genes in human WAT.

a, b, Linear regression analysis of ADIPOQ (a) and CFD (b) with BMI in visceral WAT from patients with morbid obesity (n = 75). c, Linear regression analysis of IL17A with LCN2 in visceral WAT from patients with morbid obesity (n = 75). d, e, Linear regression analysis of IL17A (d) and LCN2 (e) with BMI in visceral WAT from patients with morbid obesity (n = 75). f, g, Linear regression analysis of ADIPOQ (f) and CFD (g) with IL17A in visceral WAT from patients with morbid obesity (n = 75). h, i, Linear regression analysis of ADIPOQ (h) and CFD (i) with LCN2 in visceral WAT from patients with morbid obesity (n = 75). j, k, Linear regression analysis of ADIPOQ (j) and CFD (k) with BMI in visceral WAT from women with morbid obesity (n = 41). l, Linear regression analysis of IL17A with LCN2 in visceral WAT from women with morbid obesity (n = 41). m, n, Linear regression analysis of IL17A (m) and LCN2 (n) with BMI in visceral WAT from women with morbid obesity (n = 41). o, p, Linear regression analysis of ADIPOQ (o) and CFD (p) with IL17A in visceral WAT from women with morbid obesity (n = 41). q, r, Linear regression analysis of ADIPOQ (q) and CFD (r) with LCN2 in visceral WAT from women with morbid obesity (n = 41). s-u, Linear regression analysis of IL17C (s), IL17E (t), and IL17F (u) with BMI in visceral WAT from patients with morbid obesity (n = 75). v, w, Association of digoxin use with BMI, cholesterol and LDL levels in a cross-sectional population-based survey. Each dot in (a-u) represents one patient. Red dots denote women patients. Linear regression analyses were used.

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Supplementary Tables 1–8

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Source Data Fig. 7

Unprocessed Western Blots from Fig. 7

Source Data Extended Data Fig. 5

Unprocessed Western Blots from Extended Data Fig. 5

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Teijeiro, A., Garrido, A., Ferre, A. et al. Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nat Metab 3, 496–512 (2021). https://doi.org/10.1038/s42255-021-00371-1

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