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Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation

Nature Metabolism volume 4, pages 775–790 (2022)Cite this article

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Abstract

Obesity induces chronic inflammation resulting in insulin resistance and metabolic disorders. Cold exposure can improve insulin sensitivity in humans and rodents, but the mechanisms have not been fully elucidated. Here, we find that cold resolves obesity-induced inflammation and insulin resistance and improves glucose tolerance in diet-induced obese mice. The beneficial effects of cold exposure on improving obesity-induced inflammation and insulin resistance depend on brown adipose tissue (BAT) and liver. Using targeted liquid chromatography with tandem mass spectrometry, we discovered that cold and β3-adrenergic stimulation promote BAT to produce maresin 2 (MaR2), a member of the specialized pro-resolving mediators of bioactive lipids that play a role in the resolution of inflammation. Notably, MaR2 reduces inflammation in obesity in part by targeting macrophages in the liver. Thus, BAT-derived MaR2 could contribute to the beneficial effects of BAT activation in resolving obesity-induced inflammation and may inform therapeutic approaches to combat obesity and its complications.

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Fig. 1: Cold exposure reduces inflammation and insulin resistance and improves glucose tolerance in DIO mice.
Fig. 2: Cold resolves obesity-induced inflammation in BAT and liver of DIO mice.
Fig. 3: Cold increases DHA-derived MaR2 and related structural isomers in BAT and liver of DIO mice.
Fig. 4: Cold specifically enhances the expression of 12-LOX and sEH in BAT, but not in the liver of DIO mice.
Fig. 5: BAT secretes MaR2 isomers in circulation.
Fig. 6: Mirabegron increases maresin pathway products in humans.
Fig. 7: BAT-specific loss of Alox12 increases inflammation in the liver of DIO mice.
Fig. 8: MaR2 resolves inflammation in obesity in part by targeting macrophages.

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and the Supplementary Information files. The raw data that support the findings of this study are available as source data files. Source data are provided with this paper.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants R01DK122808 (to Y.-H.T. and M.S.), R01DK077097 and R01DK102898 (to Y.-H.T.), R01HL106173 (to M.S.), R01DK099511 and R01DK112283 (to L.J.G.), P30DK036836 (to Joslin Diabetes Center’s Diabetes Research Center) and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). S.S. was supported by the Manpei Suzuki Diabetes Foundation in Japan. G.P. was supported by grant 2019/20554-7 from The Sao Paulo Research Foundation, Sao Paulo Research Foundation. L.O.L. was supported by an American Diabetes Association post-doctoral fellowship (1-16-PDF-063) and by the Sao Paulo Research Foundation grants 2017/02684 and 2019/26008-4. We thank M. Lynes, F. Shamsi and Y. Zhang for providing general technical support and helpful advice. We thank S. Dong for helping with animal work and A. Clermont, A. Dean and M. Halpin of the Joslin Diabetes Research Center Animal Physiology core for assisting with the studies using the diurnal incubators. We thank H. Takahashi for providing helpful advice related to the clinical aspects of this work. We thank the laboratory of B. Hammock for providing the sEH antibody. All the schematics of the experimental design were created with BioRender.com.

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Authors and Affiliations

  1. Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Satoru Sugimoto, Tadataka Tsuji, Chih-Hao Wang, Tian Lian Huang, Joji Kusuyama, Sean D. Kodani, Justin Darcy, Gerson Profeta, Laurie J. Goodyear, Luiz Osório Leiria & Yu-Hua Tseng

  2. Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Hebe Agustina Mena, Brian E. Sansbury, Xuanzhi Yin & Matthew Spite

  3. Section of Immunobiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Shio Kobayashi & Thomas Serwold

  4. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Nayara Pereira & Luiz Osório Leiria

  5. Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Rudolph E. Tanzi & Can Zhang

  6. Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Efi Kokkotou

  7. Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA

    Aaron M. Cypess

  8. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

    Yu-Hua Tseng

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  1. Satoru Sugimoto
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Contributions

S.S., H.A.M., B.E.S., S.K., M.S. and Y.-H.T. developed the study concept and designed the experiments. S.S., H.A.M., B.E.S., S.K., T.T., C.H.W., X.Y., T.L.H., J.K., S.D.K., J.D., G.P., N.P., R.E.T., C.Z. and L.O.L. performed the research. E.K., L.J.G., T.S. and A.M.C. provided research advice. A.M.C. provided the human plasma samples. S.S., H.A.M., B.E.S., S.K., T.T., M.S. and Y.-H.T. contributed to data analysis. S.S., H.A.M., M.S. and Y.-H.T. wrote the paper. M.S. and Y.-H.T. directed the research. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Matthew Spite or Yu-Hua Tseng.

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Competing interests

M.S. and Y.-H.T. are inventors of a pending provisional patent application related to maresin 2 and metabolic therapeutics.

Peer review

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary handling editor: Isabella Samuelson, in collaboration with the Nature Metabolism team

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Extended data

Extended Data Fig. 1 Cold exposure reduces body weight, inflammation and insulin resistance in obese mice, related to Fig. 1.

(a) C57BL6/J male mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 14 weeks. The mice were then put in thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. Plasma levels of IFNγ, IL-6 and IL-1β at day 7 following TN or cold exposure (related to Fig. 1, n = 5 biologically independent animals per group, from 1 independent experiment). (b–e) C57BL6/J female mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 19 weeks. The mice were then put in thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. (b) Body weight on day 0 or day 7 following TN or cold exposure (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 6 for HF-TN, from 1 independent experiment). (c) Total caloric intake during the exposure period (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 6 for HF-TN, from 1 independent experiment). (d) Fasting blood glucose, plasma insulin and homeostatic model assessment of insulin resistance (HOMA-IR) (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 6 for HF-TN, from 1 independent experiment). (e) Plasma levels of TNF-α (n = 5 biologically independent animals per group, from 1 independent experiment, statistical significance was determined by two-tailed unpaired Student’s t-test). One-Way ANOVA followed by a Tukey’s post hoc test. Data are presented as mean ± SEM.

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Extended Data Fig. 2 Two days of cold exposure reduces insulin resistance and inflammation in DIO mice, related to Fig. 1.

C57BL6/J male mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 14 weeks to create DIO mice. (a-f) The DIO mice were exposed to thermoneutral (30 °C, TN) or cold (5 °C) conditions for 2 days. (a) Body weight on day 0 or day 2 following TN or cold exposure (n = 5 biologically independent animals for NC-TN and NC-cold, n = 10 for HF-TN and HF-cold, from 2 independent experiments). (b) Total caloric intake during the exposure period (n = 5 biologically independent animals for NC-TN and NC-cold, n = 10 for HF-TN and HF-cold, from 2 independent experiments). (c) Tissue weights at the end of the exposure period (epiWAT, ingWAT, Liver, Muscle: n = 5 biologically independent animals for NC-TN and NC-cold, n = 10 for HF-TN and HF-cold, from 2 independent experiments; BAT: n = 5 per group, from 1 independent experiment). (d) Fasting blood glucose, plasma insulin and homeostatic model assessment of insulin resistance (HOMA-IR) (n = 5 biologically independent animals for NC-TN and NC-cold, n = 10 for HF-TN and HF-cold, from 2 independent experiments). (e) Plasma levels of TNF-α (n = 5 biologically independent animals per group, from 1 independent experiment). (f) Plasma leptin levels (n = 5 biologically independent animals per group, from 1 independent experiment). (g-k) The DIO mice fed a HF diet for 15 weeks were treated with CL316243 (1 mg/kg/day, daily, i.p) for 9 days. (g, h) Body weight on day 0 and day 9 (n = 5 biologically independent animals per group, from 1 independent experiment). (i) Total caloric intake between day 0 and day 9 (n = 5 biologically independent animals per group, from 1 independent experiment). (j) Glucose levels during IPGTT after 7 days of CL316243 treatment (n = 5 biologically independent animals per group, from 1 independent experiment, Two-Way ANOVA followed by a Tukey’s post hoc). (k) Plasma TNF-α levels in mice treated with CL316243 for 9 days (n = 5 biologically independent animals for Vehicle, n = 6 for CL316243, from 1 independent experiment). Two-tailed Unpaired Student’s t-tests were performed to compare only 2 groups and One-Way ANOVA followed by a Tukey’s post hoc test was performed to compare 4 groups. Data are presented as mean ± SEM.

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Extended Data Fig. 3 Cold does not resolve inflammation in white fat of DIO mice, related to Fig. 2.

C57BL6/J male mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 14 weeks. The mice were then put in thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. (a) Relative mRNA expression of proinflammatory and NLRP3 inflammasome-related genes in ingWAT (n = 5 biologically independent animals per group, from 1 independent experiment). (b) Representative image of F4/80 staining of epiWAT sections from each group (Scale bar=100 μm) (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 4 for HF-TN, from 1 independent experiment). (c) The number of crown-like structures in epiWAT was determined by counting F4/80 positive areas per mm2 (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 4 for HF-TN, from 1 independent experiment). (d) The percentage of CD11c+ cells or CD206+ cells within the CD45+ F4/80+ population from ingWAT of DIO mice (n = 4 biologically independent animals per group, from 1 independent experiment). (e, f) Gating strategy for identification of CD11c+ and CD206+ cells in the epiWAT, ingWAT and BAT (e) and in the liver (f). One-Way ANOVA followed by a Tukey’s post hoc test. Data are presented as mean ± SEM.

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Extended Data Fig. 4 Cold-induced resolution of inflammation precedes changes in lipid accumulation in the liver of DIO mice, related to Fig. 2.

(a-c) C57BL6/J male mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 14 weeks. The mice were then exposed to thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. (a) Relative mRNA expression of lipogenesis-related genes in the liver (n = 5 biologically independent animals per group, from 1 independent experiment). (b) Liver TG levels (n = 5 biologically independent animals per group, from 1 independent experiment). (c) Representative images of hematoxylin and eosin (H&E) staining of liver sections from NC-TN, HF-TN and HF-cold groups (Scale bar=100 μm). (d-g) C57BL6/J male mice were fed with normal chow (NC) or high-fat (HF) diet at room temperature for 14 weeks. The mice were then put in thermoneutral temperature (30 °C, TN) or cold (5 °C) for 2 days. (d) Relative mRNA expression of lipogenesis-related genes in the liver (n = 5 biologically independent animals for NC-TN and NC-cold and HF-cold, n = 4 for HF-TN, from 1 independent experiment). (e) Liver TG levels (n = 5 biologically independent animals per group, from 1 independent experiment). (f) Representative images of hematoxylin and eosin (H&E) staining of liver sections from HF-TN and HF-cold groups (Scale bar=100 μm). (g) Relative mRNA expression of proinflammatory, NLRP3 inflammasome-related- and fibrosis-related genes in the liver (n = 5 biologically independent animals for NC-TN, NC-cold and HF-cold, n = 4 for HF-TN, Casp1 NC-cold, Casp1 HF-cold, Il18 HF-cold, Tlr4 HF-cold, from 1 independent experiment). One-Way ANOVA followed by a Tukey’s post hoc test. Data are presented as mean ± SEM.

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Extended Data Fig. 5 Identification and quantification of maresin pathway products in BAT and liver, related to Fig. 3.

(a, d) MRM peaks (top) and MS/MS spectra with diagnostic ions labeled (bottom) of authentic MaR2 standard (blue) and of MaR2 and a structural isomer (denoted isomer II, red) identified in a selected sample from BAT (a) and liver (d) of 14 weeks high-fat (HF)-fed mice exposed to cold (5 °C) or thermoneutral (30 °C, TN) conditions for 7 days. (b, c) Quantification of 14-HDHA, MaR2, and MaR2 isomer II in BAT of C57BL6/J mice fed a high-fat diet (HF; b; normalized to protein concentration; n = 5 biologically independent animals per group, from 1 independent experiment) or normal chow (NC; 14 weeks; c; n = 5 biologically independent animals for NC-TN and n = 4 for NC-cold, from 1 independent experiment) exposed to thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. ND: not detected. (e, f) Quantification of 14-HDHA, MaR2, and MaR2 isomer II in the liver of C57BL6/J mice fed HF (e; normalized to protein concentration; n = 5 biologically independent animals per group, except n = 4 for 14-HDHA HF-cold, from 1 independent experiment) or NC (f; n = 5 biologically independent animals per group, from 1 independent experiment) exposed to thermoneutral temperature (30 °C, TN) or cold (5 °C) for 7 days. (g) Quantification of 14-HDHA, MaR2, and MaR2 Isomer II (normalized to protein concentration) in the liver of HF-fed (15 weeks) male C57BL6/J mice treated with vehicle or CL316243 (1 mg/kg/day, daily i.p.) for 9 days (n = 5 biologically independent animals per group, from 1 independent experiment). Two-tailed Unpaired Student’s t-tests. Data are presented as mean ± SEM.

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Extended Data Fig. 6 Identification of maresin pathway products in ingWAT of obese mice exposed to cold and in plasma of mice with BAT removal, related to Fig. 4 and Fig. 5.

(a) Relative expression of Ucp1 mRNA in ingWAT of HF-fed (14 weeks) C57BL6/J mice exposed to TN or cold for 7 days (n = 5 biologically independent animals per group, from 1 independent experiment). (b, c) Quantification of 14-HDHA, MaR1, and MaR2 in ingWAT and normalized to tissue weight (n = 6 biologically independent animals for HF-TN, n = 5 for HF-cold, from 1 independent experiment; b) or protein concentration (n = 6 biologically independent animals for HF-TN, n = 5 for HF-cold, from 1 independent experiment; c). (d, e) MRM peaks (d) and MS/MS spectra with diagnostic ions labeled (e) of authentic MaR2 standard and of two MaR2 isomers (denoted isomer I and II) identified in a selected sample of plasma of HF-fed mice following BAT removal. ND: not detected. Two-tailed Unpaired Student’s t-tests. Data are presented as mean ± SEM.

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Extended Data Fig. 7 Identification of maresin pathway products in plasma of humans and expression of 12-LOX and sEH in human brown adipocytes, related to Fig. 6.

(a, b) MRM peaks (a) and MS/MS spectra with diagnostic ions labeled (b) of authentic 14-HDHA and MaR2 standards (top) and of 14-HDHA and MaR2 Isomer I identified in a selected sample of human plasma (bottom) following mirabegron administration. (c) Schematic of the treatment of human brown adipocytes with vehicle control or Forskolin (10μM), followed by the collection of the cells for qPCR (d) Relative mRNA expression of Alox12 and Ephx2 in human brown adipocytes treated with vehicle or Forskolin for indicated times (Alox12: n = 6 biologically independent cells for Vehicle, n = 4 biologically independent cells for 12 h, 18 h and 36 h, n = 3 biologically independent cells for 24 h, Ephx2: n = 6 biologically independent cells for Vehicle, n = 4 biologically independent cells for 12 h, 24 h and 36 h, n = 5 biologically independent cells for 18 h). One-Way ANOVA followed by a Tukey’s post hoc test. Data are presented as mean ± SEM.

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Extended Data Fig. 8 MaR2 resolves inflammation systemically and in the liver of DIO mice, related to Fig. 8.

(a) Schematic of the experimental design of MaR2 treatment. C57BL6/J male mice were fed with a high-fat (HF) diet at room temperature for 14 weeks. Then the mice were administered vehicle or MaR2 (5 μg/kg/day; daily i.p.) for 28 days. (b) Body weight at day 0 and day 28 post-treatment (n = 5 biologically independent animals per group, from 1 independent experiment). (c) Plasma TNF-α levels post-treatment (n = 5 biologically independent animals per group, from 1 independent experiment). (d) Relative mRNA expression of proinflammatory, NLRP3-inflammasome-related- and fibrosis-related genes in the liver post-treatment (n = 5 biologically independent animals per group, from 1 independent experiment). (e) Schematic of the experimental design of MaR2 treatment. C57BL6/J male mice were fed with a high-fat (HF) diet at room temperature for 16 weeks. Then, the mice were administered vehicle or MaR2 (10 μg/kg/day; daily i.p.) for 26 days. (f) Body weight at day 0 and day 25 post-treatment, and the body weight change from baseline (n = 6 biologically independent animals per group, from 1 independent experiment). (g) Total caloric intake (n = 6 biologically independent animals per group, from 1 independent experiment). (h, i) Liver weight and TG levels in liver (n = 6 biologically independent animals per group, from 1 independent experiment). (j) Relative mRNA expression of lipogenesis-related genes in liver (n = 6 biologically independent animals per group, from 1 independent experiment). (k) Representative liver H&E staining from each group (Scale bar=100 μm). (l) Plasma levels of ALT in mice treated with vehicle or MaR2 (n = 6 biologically independent animals per group, from 1 independent experiment). (m, n) Relative mRNA expression of inflammation and NLRP3-inflammasome-related genes in the BAT (n = 6 biologically independent animals per group, from 1 independent experiment, m) and epiWAT (n = 5 for Vehicle, except Casp1 n = 4, n = 6 for MaR2, from 1 independent experiment, n) of mice treated with vehicle or MaR2. Two-tailed Unpaired Student’s t-tests. Data are presented as mean ± SEM.

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Extended Data Fig. 9 Absorption kinetics of d5-MaR2 and regulation of liver monocytes/macrophages by MaR2, related to Fig. 8.

(a) Recovery of d5-MaR2 spiked into murine plasma and subjected to solid phase extraction and LC-MS/MS analysis, with mean d5-MaR2 recovered indicated along with the calculated coefficient of variation (CV) from 4 individual replicates. (b) Schematic of the administration of d5-MaR2 to male mice fed a high-fat diet for 15 weeks, followed by collection of blood at the indicated time points. The red circle indicates the position of the deuterium (D) atoms at the omega end of MaR2. (c) Quantification of d5-MaR2 in plasma after intraperitoneal administration to obese mice, as determined by LC-MS/MS (n = 3 biologically independent animals per group, from 1 independent experiment, Kruskal-Wallis test, followed by Dunn’s multiple comparisons post-tests). (d) Flow cytometry gating strategy of monocyte and macrophage populations in the liver. Representative dot plots showing Single cells, Live cells and CD45 + cells (related to Fig. 8e). (e, f) Quantification of monocyte (e) and macrophage (f) populations in the liver of mice treated with vehicle or MaR2 (10 μg/kg/day; daily i.p.) for 5 days (related to Fig. 8; n = 5 biologically independent animals per group, from 1 independent experiment) (g) Primary rat Kupffer cells were incubated with vehicle or MaR2 (50 nM) for 18 hours, then RNA was harvested for qPCR to measure relative mRNA expression of proinflammatory, NLRP3-inflammasome-related- and fibrosis-related genes (n = 3 technical replicates per group). Two-tailed Unpaired Student’s t-tests, except c. Data are presented as mean ± SEM.

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Sugimoto, S., Mena, H.A., Sansbury, B.E. et al. Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation. Nat Metab 4, 775–790 (2022). https://doi.org/10.1038/s42255-022-00590-0

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