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Umami-induced obesity and metabolic syndrome is mediated by nucleotide degradation and uric acid generation

Nature Metabolism volume 3, pages 1189–1201 (2021)Cite this article

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Abstract

Umami refers to the savoury taste that is mediated by monosodium glutamate (MSG) and enhanced by inosine monophosphate and other nucleotides. Umami foods have been suggested to increase the risk for obesity and metabolic syndrome but the mechanism is not understood. Here we show that MSG induces obesity, hypothalamic inflammation and central leptin resistance in male mice through the induction of AMP deaminase 2 and purine degradation. Mice lacking AMP deaminase 2 in both hepatocytes and neurons are protected from MSG-induced metabolic syndrome. This protection can be overcome by supplementation with inosine monophosphate, most probably owing to its degradation to uric acid as the effect can be blocked with allopurinol. Thus, umami foods induce obesity and metabolic syndrome by engaging the same purine nucleotide degradation pathway that is also activated by fructose and salt consumption. We suggest that the three tastes—sweet, salt and umami—developed to encourage food intake to facilitate energy storage and survival but drive obesity and diabetes in the setting of excess intake through similar mechanisms.

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Fig. 1: MSG stimulates intake by promoting nucleotide turnover and purine degradation into uric acid.
Fig. 2: Neuronal AMPD2 drives the intake of MSG and total calories.
Fig. 3: Hepatocyte-specific AMPD2 drives MSG-induced metabolic syndrome and intake.
Fig. 4: AMPD2 deletion ameliorates metabolic syndrome in MSG-receiving adult mice.
Fig. 5: IMP exacerbates MSG-mediated preference and food intake in WT and AMPD2 knockout mice.
Fig. 6: MSG + IMP combination induces metabolic syndrome in mice.
Fig. 7: MSG + IMP combination reduces leptin sensitivity in mice.
Fig. 8: Proposed mechanism for MSG-induced metabolic syndrome.

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Data availability

Requests for resources, newly generated mouse lines and reagents should be directed to and will be fulfilled by the lead contact, M.A.L. Figures 1–7 and Extended Data Figs. 1–6 represent in their majority the raw data from all individual points. The data that support the findings of this study are available from the corresponding author on reasonable request. This study did not generate unique datasets or code. Raw individual datasets for each study and figures will be available on reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank E. E. Smith for her contribution to this research and A. Quador and J. Arnold of the University of Colorado Denver Histology Shared Resource. This resource is supported in part by the Cancer Center Support Grant (no. P30CA046934). This work has been supported by NIH grant nos. 1R01DK121496-01A1 (to M.A.L. and R.J.J.) and 1R01DK108859 (to M.A.L.). A.A.H was supported by funding from the Colorado Nutrition Obesity Research Center (no. 25M9260) from parental grant P30DK048520.

Author information

Author notes

  1. These authors contributed equally: Ana Andres-Hernando, Christina Cicerchi.

Authors and Affiliations

  1. Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA

    Ana Andres-Hernando, Christina Cicerchi, Masanari Kuwabara, Richard J. Johnson & Miguel A. Lanaspa

  2. Division of Nephrology and Hypertension, Oregon Health Sciences University, Portland, OR, USA

    Ana Andres-Hernando & Miguel A. Lanaspa

  3. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

    David J. Orlicky

  4. Departamento de Fisiopatología Cardio-Renal, National Institute of Cardiology Ignacio Chavez, Tlalpan, México

    Laura Gabriela Sanchez-Lozada

  5. Department of Nephrology, Rakuwakai Otowa Hospital, Kyoto, Japan

    Takahiko Nakagawa

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Contributions

M.A.L. and R.J.J. designed the research. M.A.L., A.A-H., L.G.S-L., T.N. and R.J.J. analysed the data. A.A-H., C.C., D.J.O., M.K. and M.A.L. performed the research. A.A-H., M.A.L. and R.J.J. wrote the paper.

Corresponding author

Correspondence to Miguel A. Lanaspa.

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Competing interests

M.A.L. and R.J.J. are inventors in two patents (nos. 13/814,568 and 62/473,005) related to the blockade of fructokinase to treat metabolic syndrome. M.A.L. and R.J.J. are founders and members of Colorado Research Partners, a company dedicated to the generation of fructokinase inhibitors. The other authors declare no competing interests.

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Peer review information Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Christoph Schmitt was the primary handling editor.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 MSG is a more potent inducer of metabolic syndrome than fructose.

A) Mean daily water intake, B) daily food intake and C) total caloric intake in wild type mice on water control or exposed to the same amount of fructose or MSG (300 mM) for 15 weeks. D) Body weight gain in the same groups as in A). E) Representative H&E images of liver and F) epididymal adipose in the same groups as in A). Size bar: 20 µm G) Liver weight, H) intrahepatic triglycerides and I) plasma AST levels in the same groups as in A). J) Epididymal adipose weight and K) crown structure scoring as well as L) fasting plasma levels of insulin and M) leptin in the same groups as in A). Data in A-B and D-M represent individual points with mean ± SEM. Data in C represent mean ± SEM. One Way ANOVA. N = 6 mice per group.

Extended Data Fig. 2 Tamoxifen does not interfere in metabolic syndrome induced by MSG.

A) Representative western blot in liver for AMPD2 (top) and actin loading control (bottom) in tamoxifen-resistant AMPD2Fl/FL mice and tamoxifen-inducible AMPD2 knockout mice (AMPD2Fl/FLxCre-UBC) at days 0, 5 and 12 after tamoxifen treatment. B) Seven hour food intake in AMPD2Fl/FL (black) and AMPD2Fl/FLxCre-UBC (red) mice before (weeks 0 to week 7) and after (week 7 to week 15) tamoxifen (TMX) treatment C) MSG solution drinking in the same groups as in B) D) Body weight gain in in the same groups as in B) E) Fat/fat free mass ratio in in the same groups as in B) F) Fasting plasma insulin in AMPD2Fl/FL (black) and AMPD2Fl/FLxCre-UBC (red) mice at baseline (week 0), before TMX treatment (week 7) and after TMX treatment (week 15). G) Fasting plasma leptin levels in the same groups as in G). H) Leptin sensitivity in AMPD2Fl/FL mice at baseline (week 0), and after TMX treatment (weeks 9 and 15). I) Leptin sensitivity in AMPD2Fl/FLxCre-UBC mice at baseline (week 0), before TMX treatment (weeks 9 and 15). Data in F-G represent individual points with mean ± SEM. Data in B-E represent mean ± SEM. Data in H-I represent the mean. One Way ANOVA (F-G) and 2-tail t-test (A-E and H-I). N = 6 mice per group.

Source data

Extended Data Fig. 3 Leptin sensitivity in wild type mice exposed to MSG + IMP for 30 weeks.

A) Seven hour food intake after leptin injection in mice on water control, or exposed to IMP (300 μM), MSG (30 mM) or a MSG + IMP combination for 30 weeks and injected with leptin. B) Hypothalamic uric acid and C) TBAR levels in mice on water control, or exposed to IMP (300 μM), MSG (30 mM) or a MSG + IMP combination for 15 weeks. D) Hypothalamic mRNA levels of the leptin receptor (lepr), and cytokines il6 and tnfa. Data in B-D represent individual points with mean ± SEM. Data in A represent the meanOne Way ANOVA (B-D) and 2-tail t-test (A). N = 6 mice per group.

Extended Data Fig. 4 Downstream products of IMP exacerbate MSG-induced metabolic syndrome.

A) Body weight gain and B) cumulative total caloric intake in wild type mice on water control, or exposed to IMP, inosine, hypoxanthine, uric acid or allantoin (300 μM) for 30 weeks. C) Body weight gain and D) total caloric intake in wild type mice on water control, or exposed to MSG (30 mM) alone or in combination with IMP, inosine, hypoxanthine, uric acid or allantoin (300 μM) for 30 weeks. E) Epididymal adipose weight, F) liver weight, G) representative H&E images of liver, H) intrahepatic triglycerides and I) plasma AST, J) insulin and K) leptin levels in wild type mice of the same groups as in C). Size bar: 20 µm. Data in E-F, H-K represent individual points with mean ± SEM. Data in B and D represent mean ± SEM. Data in A and C represent the meanOne Way ANOVA. N = 6 mice per group.

Extended Data Fig. 5 Allopurinol ameliorates metabolic syndrome induced by MSG + IMP.

A) Plasma and B) intrahepatic uric acid levels in wild type mice on water control, allopurinol (AP, 1.1 mM), MSG (30 mM) alone, or in combination with IMP (300 μM) or IMP + allopurinol (AP, 1.1 mM) for 30 weeks. C) Cumulative total caloric intake and D) body weight gain in the same mice as in A). E) Epididymal adipose weight, F) liver weight, G) representative H&E images of liver, H) intrahepatic triglycerides and I) plasma AST, J) insulin and K) leptin levels in wild type mice of the same groups as in A). Size bar: 20 µm. Data in A-B and D-K represent individual points with mean ± SEM. Data in C represent mean ± SEMOne Way ANOVA (A-C, F, H-J and N-O) and 2-tail t-test (D-E, G, K-M and P-Q). N = 6 mice per group.

Extended Data Fig. 6 MSG and IMP activate astrocytes and microglia in the hypothalamus.

A) Representative western blot and B) densitometry for GFAP (astrocyte marker), Iba1 (microglia marker) and actin loading control in hypothalamus of wild type mice exposed to water, IMP, MSG (30 mM) or MSG + IMP. Data in B-C represent individual points with mean ± SEM. One Way ANOVA. N = 6 mice per group.

Source data

Supplementary information

Reporting Summary

42255_2021_454_MOESM2_ESM.pdf

Supplementary Table 1 General parameters in water control mice or mice exposed to MSG alone or in combination with purines.

Source data

Source Data Fig. 1

Unprocessed western blot for Fig. 1.

Source Data Fig. 2

Unprocessed western blot for Fig. 2.

Source Data Fig. 3

Unprocessed western blot for Fig. 3.

Source Data Fig. 4

Unprocessed western blot for Fig. 4.

Source Data Fig. 5

Unprocessed western blot for Fig. 5.

Source Data Fig. 7

Unprocessed western blot for Fig. 7.

Source Data Extended Data Fig. 2

Unprocessed western blot for Extended Data Fig. 2.

Source Data Extended Data Fig. 6

Unprocessed western blot for Extended Data Fig. 6.

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Andres-Hernando, A., Cicerchi, C., Kuwabara, M. et al. Umami-induced obesity and metabolic syndrome is mediated by nucleotide degradation and uric acid generation. Nat Metab 3, 1189–1201 (2021). https://doi.org/10.1038/s42255-021-00454-z

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