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Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response

Nature Aging volume 4, pages 839–853 (2024)Cite this article

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Abstract

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.

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Fig. 1: Estrogen ameliorates age-related defects in iWAT beiging.
Fig. 2: Estrogen promotes beige adipogenesis in vitro.
Fig. 3: ER stress blocks beige adipocyte formation in 2-month-old mice.
Fig. 4: Activation of the PERK signaling pathway attenuates E2-induced beiging.
Fig. 5: Sma+ APCs contribute to E2-induced beige adipogenesis.
Fig. 6: The ablation of NAMPT signaling in Sma+ APCs inhibits beige adipocyte formation.
Fig. 7: FK866 abolishes E2-restored beige adipocyte formation in aging mice.
Fig. 8: NMN administration promotes beige adipocyte formation in aging mice.

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Data availability

The RNA-seq dataset generated and analyzed during the current study is available under accession number GSE261481. The rest of the data generated or analyzed during this study are all included in the published article and its supplementary information files. Source data are provided with this paper. All other data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank S. Imai for kindly providing the NAMPT floxed mouse strain. We thank members of the Y.J. laboratory for mouse genotyping and technical help, with special thanks to P. Bhalla and A. Elsabbagh. We thank C. R. Adams and J. Purcell for assistance with mouse husbandry; S. J. Green and the Research Resources Center for RT–PCR analysis; the Metabolic Phenotyping Core for analytical and phenotypical mouse measurements; and members of the Y.J. laboratory for helpful comments on the manuscript. The graphical abstract (Extended Data Fig. 10c) was created using BioRender, and scheme illustrations in Fig. 2a and Extended Data Fig. 5b were adapted from previous work19 and redeveloped using BioRender. This work was supported by National Institutes of Health (NIH) grants K01 DK11177, R03 DK127149 and R01 DK132398 and Pilot Support grant P30DK020595 to Y.J., NIH grant R01HL148756 to S.-G.O. and NIH grant R01DK123098 to P.X.

Author information

Author notes

  1. These authors contributed equally: Jooman Park, Ruoci Hu.

  2. These authors jointly supervised this work: Sang-Ging Ong, Pingwen Xu, Yuwei Jiang.

Authors and Affiliations

  1. Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang & Yuwei Jiang

  2. Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL, USA

    Ruoci Hu & Yuwei Jiang

  3. Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA

    Shaolei Xiong

  4. Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, Chicago, IL, USA

    Ziqiao Xu & Zhengjia Chen

  5. Biostatistics Shared Resource, University of Illinois Cancer Center, Chicago, IL, USA

    Zhengjia Chen

  6. Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA

    Qing Song & Zhenyuan Song

  7. Department of Pharmacology and Regenerative Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Gege Yan & Sang-Ging Ong

  8. Division of Endocrinology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Abeer M. Mahmoud, Brian T. Layden, Pingwen Xu & Yuwei Jiang

  9. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA

    Yanlin He

  10. Jesse Brown Medical VA Medical Center, Chicago, IL, USA

    Brian T. Layden

  11. Division of Pulmonary, Critical Care, Sleep & Allergy, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Jiwang Chen

  12. Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Sang-Ging Ong

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  1. Jooman Park
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Contributions

Y.J. and J.P. conceived and designed the experiments. J.P. and R.H. conducted most of the experiments. Y.Q., S.X., A.S.E.-S., M.I., J.W., Q.S., Z.S., G.Y., A.M., Y.H., B.L., J.C., S.-G.-O. and P.X. contributed to the study design, data interpretation and manuscript writing. Z.X. and Z.C. performed interaction analysis between age and treatment types.

Corresponding author

Correspondence to Yuwei Jiang.

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Extended data

Extended Data Fig. 1 Age-related decline and restoration of serum E2 levels in male mice.

Serum E2 levels were compared between 2-month-old (Young) and 12-month-old (Old) males and assessed 4 and 24 hours after intraperitoneal injections of E2 (10 μg/Kg) to 12-month-old males by one way-ANOVA followed by Tukey’s post-hoc test. Animal number: Young (n = 5), Old (n = 4), Old E2 4 h (n = 5), Cold E2 (n = 4). Data information: All results are presented as means ± SEM.

Source data

Extended Data Fig. 2 Estrogen treatment ameliorates some metabolic dysfunctions associated with aging.

a, Body lean mass composition. Animal number: RT Veh (n = 4), RT E2 (n = 4), Cold Veh (n = 9), Cold E2 (n = 10). b-c, Weight of adipose tissues (b), ANOVA summary (IGW; Interaction P = 0.039, Temperature P = 0.103, Treatment P < 0.0001, PGW; Interaction P = 0.862, Temperature P = 0.056, Treatment P = 0.0002, by two way-ANOVA followed by Tukey’s post-hoc test), and other tissues (c). Animal number: RT Veh (n = 4), RT E2 (n = 4), Cold Veh (n = 9), Cold E2 (n = 10). d-e, Serum and hepatic triglyceride by two-tailed unpaired Student’s t-test (D), and serum and hepatic cholesterol (e). Animal number: Cold Veh (n = 9), Cold E2 (n = 10). f-j, Oxygen consumption and quantification (f), ANOVA summary (Time, Treatment and Temperature; Interaction P = 0.07, Time P < 0.0001, Treatment and Temperature P = 0.006, Light; Interaction P = 0.56, Temperature P = 0.79, Treatment P < 0.0001, Dark; Interaction P = 0.35, Temperature P = 0.011, Treatment P < 0.0001, by two way-ANOVA followed by Tukey’s post-hoc test). Carbone dioxygen consumption and quantification (g), ANOVA summary (Time, Treatment and Temperature; Interaction P = 0.28, Time P = 0.006, Treatment and Temperature P < 0.0001, Light; Interaction P < 0.0001, Treatment P = 0.039, Temperature P < 0.0001, Dark; Interaction P < 0.0001, Treatment P = 0.0019, Temperature P < 0.0001, by two way-ANOVA followed by Tukey’s post-hoc test). RER (H), ANOVA summary (Interaction P < 0.0001, Temperature P < 0.0001, Treatment P < 0.0001), food intake (I), ANOVA summary (Interaction P = 0.51, Temperature P < 0.0001, Treatment P = 0.41, by two way-ANOVA followed by Tukey’s post-hoc test), and physical activity (j), Animal number: RT Veh (n = 5), RT E2 (n = 4), Cold Veh (n = 6), Cold E2 (n = 7). Data information: All results are presented as means ± SEM.

Source data

Extended Data Fig. 3 Estrogen treatment has minimal impact on BAT thermogenesis upon cold exposure.

a, Representative H&E staining of BAT from vehicle (Veh) or E2-treated (10 µg/Kg) groups upon cold exposure. Scale bar, 100 μM. b, qPCR analysis of mRNA expression of thermogenic genes in BAT from vehicle or E2-treated groups by two-tailed unpaired Student’s t-test (n = 7 per group). Data information: All results are presented as means ± SEM.

Source data

Extended Data Fig. 4 Estrogen does not significantly impact cold-induced beige adipocyte formation in aged female mice.

a-b, Body weight and the difference in body fat composition by two-tailed unpaired Student’s t-test. Animal number: Veh (n = 8), E2 (n = 10). c, Representative images of H&E staining and UCP1 immunofluorescence staining in the middle part of iWAT. Scale bar, 100 μm. Data information: All results are presented as means ± SEM.

Source data

Extended Data Fig. 5 ERα but not ERβ antagonist abolishes estrogen-promoted beige adipogenesis in old SVF cells.

a, qPCR analysis of estrogen receptor-related gene expression between young and old SVF cells (n = 3 per group) by two-tailed unpaired Student’s t-test. b, Schematic illustration. SVF cells isolated from iWAT of 12-month-old male mice were pre-treated with either vehicle or E2 (10 nM) or a combination with ERα antagonist MPP (10μM) and E2, or a combination with ERβ antagonist PHTPP (10μM) and E2 before differentiating into beige adipocytes. c, Representative images of UCP1 immunofluorescence staining. Scale bar, 100 μM. d, Quantification of UCP1 by one way-ANOVA followed (n = 5 per group) by Tukey’s post-hoc test. e, qPCR analysis of the thermogenic gene expression (n = 3 per group) by one way-ANOVA followed by Tukey’s post-hoc test. Data information: All results are presented as means ± SEM.

Source data

Extended Data Fig. 6 ER stress inducer tunicamycin reduces energy expenditure in young mice.

a, Downregulated gene ontology (GO) cellular component to E2 by two-tailed unpaired Student’s t-test. b, Downregulated GO reactome pathway to E2 by two-tailed unpaired Student’s t-test. c, The lean mass composition in vehicle and tunicamycin treated group (n = 5 per group). d-h, Oxygen consumption and quantification (d), ANOVA summary (Interaction P = 0.798, Treatment P < 0.0001, Time P = 0.657, by two way-ANOVA followed by Tukey’s post-hoc test), Carbone dioxygen consumption and quantification (e), ANOVA summary (Interaction P = 0.788, Treatment P < 0.0001, Time P = 0.174, by two way-ANOVA followed by Tukey’s post-hoc test), RER (f), food intake (g), and physical activity (h) (n = 7 per group). i, Quantification of basal respiration, ATP-turnover, and maximum respiratory capacity of the samples in panel (n = 7 per group). ANOVA summary (Basal; Interaction P = 0.178, PBS verse Tunicamycin P < 0.0001, Vehicle verse Estrogen P = 0.432, ATP-Linked; Interaction P = 0.505, PBS verse Tunicamycin P < 0.0001, Vehicle verse Estrogen P = 0.763, Maximum; Interaction P = 0.119, PBS verse Tunicamycin P < 0.0001, Vehicle verse Estrogen P = 0.047, by two way-ANOVA followed by Tukey’s post-hoc test). Data information: All results are presented as means ± SEM.

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Extended Data Fig. 7 NAD+ pathway analysis in E2-treated aged iWAT.

a-c, Upregulated gene ontology (GO) cellular component to E2 (a), upregulated gene ontology (GO) molecular function to E2 (b), and heat map of a list of NAD pathway gene expression (c) (n = 3 per group), by two-tailed unpaired Student’s t-test. d, Quantification of the percentage of RFP+ cells. Animal number: Control Veh (n = 8), Control E2 (n = 6), NAMPT Het Veh (n = 8), NAMPT Het E2 (n = 8). ANOVA summary (Interaction P = 0.997, Condition P < 0.0001, Treatment P < 0.0001, by two way-ANOVA followed by Tukey’s post-hoc test). e, Quantification of the percentage of RFP+ cells that express endogenous UCP1 (n = 6 per group). ANOVA summary (Interaction P = 0.896, Condition P < 0.0001, Treatment P < 0.0001, by two way-ANOVA followed by Tukey’s post-hoc test). Data information: All results are presented as means ± SEM.

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Extended Data Fig. 8 FK866 treatment has minimal effect on BAT thermogenesis upon cold exposure.

a, Representative H&E staining of BAT from E2-treated (10 µg/Kg) or combination with FK866 (10 mg/Kg) groups upon cold exposure. Scale bar, 100 μM. b, qPCR analysis of mRNA expression of thermogenic genes in BAT from E2-treated or combination with FK866 groups (n = 4 per group) by two-tailed unpaired Student’s t-test. Data information: All results are presented as means ± SEM.

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Extended Data Fig. 9 NAD+ levels in SVF cells are modulated by NMN or FK866 treatment.

Comparison of NAD+ levels in young versus aged SVF cells, treated with NMN (50 µM) or FK866 (300 nM), shows a decline in the aged cells, an effect that is altered by the treatments. Animal number: Young Veh (n = 5), Young NMN (n = 4), Young FK866 (n = 4), Old Veh (n = 5), Old NMN (n = 4), Old FK866 (n = 4). ANOVA summary (Interaction P < 0.0001, Age P < 0.0001, Treatments P < 0.0001, by two way-ANOVA followed by Tukey’s post-hoc test). Data information: All results are presented as means ± SEM.

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Extended Data Fig. 10 NMN treatment has minimal effect on BAT thermogenesis upon cold exposure.

a, Representative H&E staining of BAT from vehicle or NMN-treated (50 mg/Kg) groups upon cold exposure. Scale bar, 100 μM. b, qPCR analysis of mRNA expression of thermogenic genes in BAT from vehicle or NMN-treated groups by two-tailed unpaired Student’s t-test. Animal number: Veh (n = 5), NMN (n = 4). c, The illustration of the mechanisms of E2-restored beige adipogenesis in aging mice. Data information: All results are presented as means ± SEM.

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Supplementary information

Reporting Summary

Supplementary Table 1

The primer sequences for qPCR in this study.

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Park, J., Hu, R., Qian, Y. et al. Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response. Nat Aging 4, 839–853 (2024). https://doi.org/10.1038/s43587-024-00633-z

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