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Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis

Nature Metabolism volume 4, pages 1166–1184 (2022)Cite this article

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Abstract

Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or β3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic β3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes’ thermogenic capacity to combat obesity and metabolic disorders.

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Fig. 1: Adipocyte IRE1α ablation results in promotion of cold-induced WAT browning.
Fig. 2: IRE1α deficiency leads to augmented β3-adrenergic stimulation of iWAT browning and lipolysis.
Fig. 3: Adipocyte IRE1α abrogation augments CL316,243-stimulated activation of thermogenic beige adipocytes.
Fig. 4: Adipocyte IRE1α deficiency enhances the adaptive thermogenic gene program.
Fig. 5: Adipocyte IRE1α suppresses the thermogenic regulator PGC1α.
Fig. 6: IRE1α’s RIDD activity downregulates Ppargc1a expression in beige adipocytes.
Fig. 7: Adipocyte IRE1α abrogation ameliorates diet-induced obesity, insulin resistance and metabolic dysfunction.
Fig. 8: Adipocyte IRE1α abrogation augments β3-AR agonist-induced weight loss and metabolic improvements in obese mice.

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Data availability

There are no restrictions as to the availability of materials reported in the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. The RNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus and are accessible through accession number GSE180524. Source data are provided with this paper.

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Acknowledgements

We thank L. Qi and J. Lin from University of Michigan Medical School and Z. Meng from Zhejiang University for insightful discussions. This work was supported by grants from the National Natural Science Foundation of China (31690102, 91857204, 32021003, 31922033, 91857105, 82170891 and 91739303) to Y.L., Z.G., M. Shao and J.L.; from the Ministry of Science and Technology of China (National Key R&D Program of China 2018YFA0800700) to Y.L. and Z.G.; from Fundamental Research Funds for the Central Universities (021414380511 and 2042020kf1056) to Z.G. and Y.L.; and from Shanghai Pujiang Program (21PJ1414600) and Shanghai Municipal Science and Technology Major Project (2019SHZDZX02) to M. Shao.

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Author notes

  1. These authors contributed equally: Yong Chen, Zhuyin Wu.

Authors and Affiliations

  1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; The Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China

    Yong Chen, Zhuyin Wu, Shijia Huang, Sijia He, Yurong Hu, Li Chen, Peng Chen, Songzi Liu, Shengqi He, Ling Zheng, Zhiyin Song, Bao-Liang Song & Yong Liu

  2. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Xiaoxia Wang

  3. State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China

    Lin Liu & Zhenji Gan

  4. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Bo Shan

  5. Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Sheng-Zhong Duan

  6. National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China

    Sheng-Zhong Duan

  7. Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA

    Lei Jiang & Qiong A. Wang

  8. Department of Molecular & Cellular Endocrinology, Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, USA

    Lei Jiang & Qiong A. Wang

  9. Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China

    Jianmiao Liu

  10. Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, MI, USA

    Liangyou Rui

  11. The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Mengle Shao

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  1. Yong Chen
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Contributions

Y.C. and Y.L. conceived and designed the studies. Y.C. and Z. Wu performed most of the experiments and analyzed the data. S. Huang, X. Wang, Y. Hu, L.C., P.C., S.L. and S. He performed some of the animal and cell experiments. L.L. and Z.G. conducted the bioinformatics analysis. L.Z., S.D., B. Shan, Z. Song, L.J., Q. Wang, B. Song, J.L., L.R. and M. Shao provided essential reagents and assisted with the experimental design and data analysis. Y.C., M. Shao and Y.L. wrote the manuscript.

Corresponding author

Correspondence to Yong Liu.

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Extended data

Extended Data Fig. 1 Metabolic phenotyping of Ern1AKO and Ern1BKO mice at thermoneutrality.

a, Immunoblot analysis of IRE1α protein in fractionated adipocytes and stromal vascular fraction (SVF) cells from interscapular brown adipose tissue (BAT), inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) of Ern1fl/fl littermates and Ern1AKO mice. VCL protein was used as the loading control. b-g, Male Ern1fl/fl and Ern1AKO (Ern1fl/fl;Adipoq-Cre) mice at 4 weeks of age were housed at 30oC for 6 weeks. (b) Body weight at the indicated time (n = 20 for Ern1fl/fl, n = 17 for Ern1AKO). (c) Averaged daily food intake (n = 20 for Ern1fl/fl, n = 17 for Ern1AKO). (d-g) Physical activity (d), oxygen consumption (VO2) (e), heat production (f) and respiratory exchange ratio (RER) (g) over a 24-hour period at 30oC. Shown also is regression-based analysis of absolute oxygen consumption (e) and heat production (f) against body weight (n = 10 per genotype). h, Immunoblot analysis of IRE1α in BAT, iWAT and eWAT from Ern1fl/fl and Ern1BKO (Ern1fl/fl;Ucp1-iCre) mice. i-n, Male Ern1fl/fl littermates and Ern1BKO mice were kept at room temperature (22oC) until 4 weeks of age, followed by 6 weeks of acclimation at thermoneutrality (30oC). (i,j) Body weight monitoring (i) and averaged daily food intake (j) (n = 19 per genotype). (k-n) Physical activity (k), oxygen consumption (VO2) (l), heat production (m) and RER (n) over a 24-hour period at 30oC. Shown also is regression-based analysis of absolute oxygen consumption (l) and heat production (m) against body weight (n = 8 per genotype). Quantitative results are shown as mean ± s.e.m.

Source data

Extended Data Fig. 2 Metabolic analyses of Ern1AKO and Ern1BKO mice in response to 3-day cold exposure.

Male Ern1fl/fl littermates and Ern1AKO or Ern1BKO mice were kept at room temperature (22oC) until 4 weeks of age, followed by 6 weeks of acclimation at thermoneutrality (30oC). Mice were then maintained at 30oC or subjected to cold exposure at 8oC for 3 days. a,b, Oxygen consumption (VO2) (a) and heat production (b) of Ern1fl/fl and Ern1BKO mice were monitored over a 24-hour period on day 2 of cold exposure at 8oC. Shown also is regression-based analysis of absolute oxygen consumption (a) and heat production (b) against body weight (n = 10-11 per genotype). c, Physical activity of Ern1AKO (left) and Ern1BKO (right) mice over a 24-hour period on day 2 of cold exposure at 8oC. d, RER of Ern1AKO (left) and Ern1BKO (right) mice over a 24-hour period on day 2 of cold exposure at 8oC. e, Relative iWAT weight of Ern1fl/fl and Ern1BKO mice housed at 30oC or following 3 days of cold exposure (30oC, n = 13 for Ern1fl/fl, n = 10 for Ern1BKO; 8oC, n = 13 per genotype). f-i, Relative weight and representative H&E staining of eWAT (f,g) and BAT (h,i), respectively, from Ern1fl/fl and Ern1AKO mice housed at thermoneutrality (30oC) or after 3 days of cold exposure (n = 16 for Ern1fl/fl and n = 15 for Ern1AKO at 30oC, n = 18 for Ern1fl/fl and n = 18 for Ern1AKO at 8oC). j,k, Representative images of H&E staining (j) and UCP1 immunostaining (k) of full iWAT sections (left) with indicated amplified regions (right) from Ern1fl/fl and Ern1BKO mice housed at thermoneutrality (30oC) or after 3 days of cold exposure. Scale bar, 1 mm (left) or 200 μm (right). l, Representative images of DAPI and UCP1 immunostaining of iWAT sections from Ern1fl/fl and Ern1BKO mice housed at thermoneutrality (30oC) or after 3 days of cold exposure. Scale bar, 100 μm. m, Immunoblot analysis of IRE1α-Ser724 phosphorylation and IRE1α protein levels in iWAT (top) or BAT (bottom) from Ern1fl/fl and Ern1AKO mice housed at 30oC or after 1 hour or 3 days of cold exposure at 8oC. n,o, Immunoblot analysis of IRE1α and UCP1 protein (left) with quantification (right) of UCP1 protein levels in iWAT (n) or BAT (o) of Ern1fl/fl and Ern1BKO mice housed at 30oC or after 3 days of cold exposure at 8oC (n = 3 per genotype at 30oC; n = 5-6 per genotype at 8oC for quantification). p,q, Ern1fl/fl or Ern1BKO mice housed at 30oC for 6 weeks were cold exposed for 3 days at 8oC. (p) qRT–PCR analysis of exon 2-containing mRNA abundance of Ern1 in iWAT and BAT (n = 9-10 per genotype). (q) Agarose gel analysis of RT–PCR products corresponding to the region spanning the targeted exon 2 within Ern1 mRNA in iWAT and BAT (n = 3 per genotype). r-t, Immunostaining analysis of IRE1α protein in UCP1-expressing adipocytes using Rosa26mTmG reporter mice. (r) Representative confocal images of fixed iWAT (top) or BAT (bottom) sections from Ucp1-iCre;Rosa26mTmG mice housed for 7 days at 30oC or following 3 days of cold exposure at 8oC. Scale bar, 25 μm. Cellular membranes of UCP1-expressing beige or brown adipocytes are visualized by the membrane-targeted EGFP (mEGFP, green). (s,t) Ucp1-iCre;Rosa26mTmG or Ern1fl/fl;Ucp1-iCre;Rosa26mTmG mice maintained at 30oC for 6 weeks were subjected to cold exposure at 8oC for 3 days. (s) Representative immunostaining of IRE1α protein along with DAPI staining of fixed iWAT (top) and BAT (bottom) sections. Scale bar, 25 μm. (t) Quantification of the percentage of IRE1α-expressing adipocytes in mEGFP-positive adipocytes from iWAT and BAT sections (n = 15 images from 3 mice per genotype). Quantitative results are shown as mean ± s.e.m.; *P < 0.05, ***P < 0.001 by two-tailed Student’s t-test (p,t) or two-way ANOVA (h).

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Extended Data Fig. 3 Energy expenditure analyses of Ern1AKO mice following CL316,243 stimulation.

Male Ern1fl/fl or Ern1AKO mice at 10 weeks of age were housed at room temperature and injected i.p. daily with saline or CL316,243 (1 mg/kg/day) for 3 days. (a) Heat production, (b) physical activity and (c) RER were monitored on day 3 in response to CL316,243 treatment. Shown also is the regression-based analysis (a) of CL316,243-stimulated absolute heat production against body weight. P = 0.009 when comparing the effect of genotype upon heat production (n = 15-16 per genotype). Data are shown as mean ± s.e.m.; *P < 0.05 by two-tailed Student’s t-test (a).

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Extended Data Fig. 4 Stimulated lipolysis of iWAT from Ern1fl/fl and Ern1BKO mice.

iWAT explants from Ern1fl/fl and Ern1BKO mice at 10 weeks of age were treated with PBS or CL316,243 (1 μM). Glycerol (a) and FFA (b) levels were determined from the supernatant medium at the indicated stimulation intervals. Shown also is the release rate of glycerol (a) or FFA (b). Results represent 2 independent experiments (PBS, n = 24 explants from 2 mice per genotype; CL316,243, n = 48 explants from 2 mice per genotype). Data are presented as mean ± s.e.m.

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Extended Data Fig. 5 Analysis of Adiponectin-Cre versus Ucp1-iCre-mediated IRE1α ablation during beige adipocyte differentiation from iWAT SVF cells.

SVF cells isolated from iWAT of Ern1fl/fl, Ern1AKO or Ern1BKO mice were differentiated for 8 days into beige adipocytes in vitro. a-d, Oil-red O staining and quantification of Oil-red O in differentiated beige adipocytes from Ern1fl/fl and Ern1AKO (a,b) or Ern1fl/fl and Ern1BKO (c,d) mice at indicated time point. Scale bar (a,c), 200 μm. e, Immunoblot analysis of IRE1α, ATGL and C/EBPβ during Ern1fl/fl and Ern1AKO beige adipocyte differentiation. f, Immunoblot analysis of IRE1α, UCP1, ATGL and C/EBPβ during Ern1fl/fl and Ern1BKO beige adipocyte differentiation. g, Immunoblot analysis of the indicated proteins in differentiated Ern1fl/fl and Ern1BKO beige adipocytes after treatment with PBS or CL316,243 (1 μM, 6 hours). Quantitative results are shown as mean ± s.e.m.

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Extended Data Fig. 6 Effects of adipocyte IRE1α abrogation upon iWAT transcriptome and BAT thermogenic program.

a-f, Temperature-dependent effects of adipocyte IRE1α abrogation upon iWAT transcriptome. Bulk RNA-seq analysis of iWAT RNAs was performed for Ern1fl/fl and Ern1AKO mice housed at 30oC or following 3 days of cold exposure at 8oC as described in Fig. 4a (n = 3 mice per group). (a) Volcano plot highlighting significantly upregulated and downregulated genes (fold change >1.5 and ANOVA p-value <0.05) in Ern1AKO iWAT relative to Ern1fl/fl iWAT when housed at 30oC. (b,c) Gene ontology (GO) biological process (BP) analysis of downregulated (b) and upregulated genes (c) resulting from IRE1α abrogation in mice at 30oC. (d) Volcano plot highlighting significantly upregulated and downregulated genes (fold change >1.5 and ANOVA p-value <0.05) in Ern1AKO iWAT relative to Ern1fl/fl iWAT after cold exposure at 8oC. (e,f) GO biological process analysis of downregulated (e) and upregulated genes (f) resulting from IRE1α abrogation after cold exposure. g-j, Adipocyte IRE1α deficiency does not significantly affect the adaptive thermogenic gene program in BAT. (g,h) qRT-PCR analysis of Xbp1 mRNA splicing (g) and mRNA abundance of the indicated thermogenic genes (h) in BAT of mice following 3 days of cold exposure or at thermoneutrality (n = 5 per genotype at 30oC; n = 10 per genotype at 8oC). (i,j) qRT-PCR analysis of Xbp1 mRNA splicing (i) and mRNA abundance of the indicated thermogenic genes (j) in BAT of mice following 3 days of daily saline or CL316,243 injection (saline control, n = 6 each genotype; CL316,243 treatment, n = 9 for each genotype). Data are presented as mean ± s.e.m.; *P < 0.05, **P < 0.01 by two-way ANOVA (g,i).

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Extended Data Fig. 7 Adipocyte IRE1α suppresses PGC1α through its RIDD activity.

a-c, Immortalized iWAT SVF cells from C57BL/6 J mice were transduced with retroviruses expressing the indicated transgenes and were then differentiated for 8 days into beige adipocytes in vitro. (a) Representative Oil-red O staining of differentiated beige adipocytes with relative absorbance at OD510 shown from 3 independent experiments. (b) qRT-PCR analysis of the mRNA abundance of Ppargc1a and the indicated PGC1α-activated thermogenic genes (n = 3 independent experiments). (c) Immunoblot analysis (left) and quantification (right) of the indicated proteins. d-f, Immortalized iWAT SVF cells from C57BL/6 J mice were transduced with retrovirus expressing IRE1α WT or its RNase-defective mutant (K907A) and were then differentiated into beige adipocytes. (d) Representative Oil-red O staining of differentiated beige adipocytes with relative absorbance at OD510 shown from 3 independent experiments. (e) qRT-PCR analysis of Xbp1 mRNA splicing and the mRNA abundance of the indicated thermogenic genes, RIDD target genes and transcription factors (n = 4 independent experiments). (f) Immunoblot analysis of p-IRE1α, IRE1α, XBP1s and UCP1 proteins in differentiated beige adipocytes. g, Fluorescence-based analysis of IRE1α cleavage of mouse Ppargc1a (mPpargc1a) mRNA in vitro. Synthetic wild-type (WT) or G-to-C mutant (mut) mPpargc1a mRNA substrates possessing the indicated 5’-FAM and 3’-BQH1 chemical groups were incubated for 2.5 hours with purified recombinant human IRE1α protein (18 nM) that were pre-mixed for 1 hour with DMSO or 4μ8C (20 μM). Relative fluorescence unit (RFU) was monitored. h, Gel analysis of Ppargc1a mRNA cleavage. In vitro transcription-derived mRNA fragments of human Ppargc1a (1-1000 nt) were incubated with recombinant human IRE1α protein (37oC, 60 min) in the presence of DMSO or 4μ8C (20 μM), followed by 6% TBE-Urea PAGE gel analysis. Human Xbp1 mRNA (full coding region) were used as a positive control. Arrows indicate the probable major RNA cleavage products. Results represent 2 independent experiments. Data are shown as mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 by one-way ANOVA (b,c,e).

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Extended Data Fig. 8 Ern1BKO mice exhibits enhanced thermogenic iWAT remodeling in response to chronic cold exposure of 15 days.

a,b, Ucp1-iCre;Rosa26mTmG or Ern1fl/fl;Ucp1-iCre;Rosa26mTmG mice were subjected to long-term cold exposure at 8oC for 15 days. (a) Representative immunostaining of IRE1α protein along with DAPI staining of fixed iWAT (top) and BAT (bottom) sections. Scale bar, 25 μm. (b) Quantification of the percentage of IRE1α-expressing adipocytes in mEGFP-positive adipocytes from iWAT and BAT sections (n = 15 images from 3 mice per group). c-o, Male Ern1fl/fl and Ern1BKO mice at 8 weeks of age were subjected to chronic cold exposure at 8oC for 15 days. (c) qRT-PCR analysis of exon 2-containing mRNA abundance of Ern1 in iWAT and BAT (n = 14 per genotype). (d) Agarose gel analysis of RT–PCR products corresponding to the region spanning the targeted exon 2 within Ern1 mRNA in iWAT and BAT (n = 3 per genotype). (e) Oxygen consumption, (f) heat production, (g) physical activity and (h) RER were monitored on day 13 of cold exposure at 8oC. Shown also are the regression-based analyses of absolute oxygen consumption (e) or heat production (f) against body weight. P = 0.036 or 0.044 when comparing the effect of genotype upon oxygen consumption or heat production (n = 14 per genotype). (i) Representative H&E staining and (j) UCP1 immunostaining of full iWAT sections (left) with indicated amplified regions (right). Scale bar, 1 mm (left) or 200 μm (right). (k) Immunoblot analysis (left) and quantification (right) of IRE1α and UCP1 proteins in iWAT of mice following 15 days of cold exposure (n = 6 per genotype). (l) qRT-PCR analysis of Xbp1 mRNA splicing and mRNA abundance of Ppargc1a and Ucp1 in iWAT of mice (n = 14 per genotype). (m) Representative H&E staining of BAT sections. Scale bar, 200 μm. (n) Immunoblot analysis (left) and quantification (right) of BAT IRE1α and UCP1 proteins (n = 6 per genotype). (o) qRT-PCR analysis of BAT Xbp1 mRNA splicing and mRNA abundance of Ppargc1a and Ucp1 (n = 14 per genotype). Quantitative results are shown as mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test (b,c,k,l,n,o).

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Extended Data Fig. 9 Adipocyte IRE1α abrogation promotes energy expenditure and ameliorates dietary obesity and metabolic inflammation.

a-c, Hyperactivation of adipocyte IRE1α RNase is accompanied by decreased mRNA level of Ppargc1a and RIDD targets in HFD-fed mice. Male Ern1fl/fl mice were fed a normal chow (NC, 10% fat) or a high-fat diet (HFD, 60% fat) for 14 weeks, starting at 8 weeks of age. Total RNA was extracted from fractionated adipocytes prepared from iWAT, followed by qRT-PCR analysis (n = 10 for NC; n = 9 for HFD). (a) Relative levels of Ern1 mRNA and Xbp1 mRNA splicing. (b) Relative mRNA levels of two typical RIDD target genes. (c) Relative mRNA levels of the indicated thermogenic regulators. d-n, Metabolic effects of adipocyte IRE1α abrogation in HFD-fed mice. Male Ern1fl/fl and Ern1AKO mice at 8 weeks of age were maintained on a normal chow (NC, 10% fat) diet or fed a high-fat diet (HFD, 60% fat) for 14 weeks. (d-f) Body weight gain (d) (NC, n = 20 per genotype; HFD, n = 33 for Ern1fl/fl littermates and n = 31 for Ern1AKO), fat pad weight (e) (NC, n = 12 per genotype; HFD, n = 30 per genotype) and averaged daily food intake (f) (NC, n = 9 for Ern1fl/fl littermates and n = 12 for Ern1AKO; HFD, n = 23 for Ern1fl/fl and n = 21 for Ern1AKO). (g-j) Physical activity (g), oxygen consumption (VO2) (h), heat production (i) and RER (j) were monitored over a 24-hour period (NC, n = 12 per genotype; HFD, n = 19 for Ern1fl/fl and n = 18 for Ern1AKO). Shown also in (i) is the regression-based analysis of heat production against body weight, with P values representing the effect of genotype upon heat production. (k,l) Representative H&E staining (k) and F4/80 IHC staining (l) of eWAT sections. Scale bar, 100 μm. (m) Representative flow cytometry histograms for CD11b- and F4/80-expressing SVF cells from eWAT of HFD-fed animals. Bars represent percentages of CD11b+F4/80+ cells (n = 4 per genotype). (n) qRT-PCR analysis of mRNA abundance of the indicated inflammatory genes in SVF or adipocytes from eWAT (SVF, n = 4 for Ern1fl/fl and n = 3 for Ern1AKO; Adipocytes, n = 6 per genotype). Data are shown as mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test (a,b,c,e,m,n) or two-way ANOVA (d).

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Extended Data Fig. 10 Pharmacological inhibition of IRE1α RNase activity ameliorates diet-induced obesity.

a, Experimental design. Male Ern1fl/fl were fed an HFD for 6 weeks prior to i.p. injection of vehicle (Veh) or 4μ8C every other day for 4 weeks. Male Ern1AKO littermates was likewise fed an HFD and treated with Veh to serve as a control cohort. b, Body weight monitoring every other day (n = 8 for Ern1fl/fl + Veh, n = 8 for Ern1fl/fl + 4μ8C, n = 9 for Ern1AKO + Veh). c, Body fat mass and lean mass (n = 8 for Ern1fl/fl + Veh, n = 8 for Ern1fl/fl + 4μ8C, n = 9 for Ern1AKO + Veh). d, Glucose tolerance test (n = 8 per group). e, Fat pad weight (n = 8 for Ern1fl/fl + Veh, n = 8 for Ern1fl/fl + 4μ8C, n = 9 for Ern1AKO + Veh). f,g, Representative H&E staining (f) and UCP1 immunostaining (g) of iWAT sections. Scale bar, 200 μm. h, qRT-PCR analysis of Xbp1 mRNA splicing and the mRNA abundance of thermogenic genes in iWAT from HFD-fed Ern1fl/fl mice following Veh or 4μ8C treatment (n = 8 per group). All results represent two independent 4μ8C treatment animal experiments, and data are shown as mean ± s.e.m.; #P < 0.05, ##P < 0.01, ###P < 0.001 (Ern1AKO + Veh versus Ern1fl/fl + Veh in d); *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test (b,d,h) or one-way ANOVA (c,e).

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2, Supplementary Methods, Supplementary Tables 1–5 and Supplementary References.

Reporting Summary

Supplementary Table 6

Statistical data (exact P values and sample/cohort sizes for each dataset in the study).

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Chen, Y., Wu, Z., Huang, S. et al. Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis. Nat Metab 4, 1166–1184 (2022). https://doi.org/10.1038/s42255-022-00631-8

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