CoChat
Sign Up
Cited by 49

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor

Guo, Xuanming, Asthana, Pallavi, Gurung, Susma, Zhang, Shuo, Wong, Sheung Kin Ken, Fallah, Samane, Chow, Chi Fung Willis, Che, Sijia, Zhai, Lixiang, Wang, Zening, Ge, Xin, Jiang, Zhixin, Wu, Jiayan, Zhang, Yijing, Wu, Xiaoyu, Xu, Keyang, Lin, Cheng Yuan, Kwan, Hiu Yee, Lyu, Aiping, Zhou, Zhongjun, Bian, Zhao-Xiang, Wong, Hoi Leong Xavier·2022·Nature Communications
DOI 10.1038/s41467-022-31563-2PMC PMC9242991
Open this paper in CoChat — free account

Abstract

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-022-31563-2

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Hemizygous depletion of MT1-MMP promotes insulin sensitivity in aged mice. In all, 18-months-old WT and Mmp14+/− mice on a chow diet were compared: a body weight and composition (n = 6), b fasting plasma glucose (n = 6), c fasting plasma insulin (n = 6), d glucose-tolerance test (n = 6), e insulin-tolerance test (n = 6), f WT and Mmp14+/- mice fed chow diet at the age of 18 months were challenged with insulin. The expression of phosphorylated Akt (pAkt) in relative to the level of total Akt (tAkt) in the livers, white adipose tissues (WAT) and muscles was examined by western blotting and quantified. (n = 3) Representative western blots were shown in Supplementary Fig. S4D. Data are reported as average ± s.e.m.; two-sided unpaired t test (a–c) one-way ANOVA (f) or two-way ANOVA (d, e). Source data are provided as a Source Data file.
Fig. 1 Hemizygous depletion of MT1-MMP promotes insulin sensitivity in aged mice. In all, 18-months-old WT and Mmp14+/− mice on a chow diet were compared: a body weight and composition (n = 6), b fasting plasma glucose (n = 6), c fasting plasma insulin (n = 6), d glucose-tolerance test (n = 6), e insulin-tolerance test (n = 6), f WT and Mmp14+/- mice fed chow diet at the age of 18 months were challenged with insulin. The expression of phosphorylated Akt (pAkt) in relative to the level of total Akt (tAkt) in the livers, white adipose tissues (WAT) and muscles was examined by western blotting and quantified. (n = 3) Representative western blots were shown in Supplementary Fig. S4D. Data are reported as average ± s.e.m.; two-sided unpaired t test (a–c) one-way ANOVA (f) or two-way ANOVA (d, e). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 2 MT1-MMP ectopic expression in the liver induces insulin resistance. In all, 12-week-old male mice were injected intravenously with AAV and fed on a regular diet. a Western blotting analyses on the expression of MT1-MMP in the livers and other peripheral tissues including white adipose tissue (WAT), skeletal muscle and heart from mice receiving either AAV control, AAV-WT MT1, or AAV-MT1 EA (n = 4). b Plasma glucose level during the intraperitoneal glucose-tolerance tests (n = 6 for AAV control; n = 7 for AAV-WT MT1 & AAV-MT1 EA). c Plasma glucose level during the insulin-tolerance tests. (n = 6 for AAV control; n = 7 for AAV-WT MT1 & AAV-MT1 EA) (d–h) hyperinsulinemic/euglycemic clamp studies: plasma glucose level (d) and glucose infusion rate (GIR) during clamp studies (e), glucose disposal rate (GDR) (f), hepatic glucose production (HGP) (g), and suppression of HGP (h) in mice receiving either AAV control, AAV-WT MT1, or AAV-MT1 EA. (n = 4 for AAV control; n = 5 for AAV-WT MT1 & AAV-MT1 EA) Data are reported as average ± s.e.m.; one-way ANOVA (e–h) or two-way ANOVA (b–e). Source data are provided as a Source Data file.
Fig. 2 MT1-MMP ectopic expression in the liver induces insulin resistance. In all, 12-week-old male mice were injected intravenously with AAV and fed on a regular diet. a Western blotting analyses on the expression of MT1-MMP in the livers and other peripheral tissues including white adipose tissue (WAT), skeletal muscle and heart from mice receiving either AAV control, AAV-WT MT1, or AAV-MT1 EA (n = 4). b Plasma glucose level during the intraperitoneal glucose-tolerance tests (n = 6 for AAV control; n = 7 for AAV-WT MT1 & AAV-MT1 EA). c Plasma glucose level during the insulin-tolerance tests. (n = 6 for AAV control; n = 7 for AAV-WT MT1 & AAV-MT1 EA) (d–h) hyperinsulinemic/euglycemic clamp studies: plasma glucose level (d) and glucose infusion rate (GIR) during clamp studies (e), glucose disposal rate (GDR) (f), hepatic glucose production (HGP) (g), and suppression of HGP (h) in mice receiving either AAV control, AAV-WT MT1, or AAV-MT1 EA. (n = 4 for AAV control; n = 5 for AAV-WT MT1 & AAV-MT1 EA) Data are reported as average ± s.e.m.; one-way ANOVA (e–h) or two-way ANOVA (b–e). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 3 MT1-MMP suppresses insulin signaling in vitro. a, b Western blotting analyses on the expression of phosphorylated Akt (pAkt) in serum-starved wild-type and Mmp14−/− primary hepatocytes upon the stimulation of insulin (a). Total Akt serves as a loading control. Quantification of pAkt expression in relative to tAkt expression was shown in (b) (n = 3). c, d HEK293T cells were transfected with either WT or E/A catalytic mutant MT1-MMP (MT1 E240A). The total cell lysates were subjected to western blotting analyses using antibodies indicated. Quantification of pAkt expression in relative to tAkt expression in 293T cells was shown in (d) (n = 3). Data are reported as average ± s.e.m.; one-way ANOVA (b, d). Source data are provided as a Source Data file.
Fig. 3 MT1-MMP suppresses insulin signaling in vitro. a, b Western blotting analyses on the expression of phosphorylated Akt (pAkt) in serum-starved wild-type and Mmp14−/− primary hepatocytes upon the stimulation of insulin (a). Total Akt serves as a loading control. Quantification of pAkt expression in relative to tAkt expression was shown in (b) (n = 3). c, d HEK293T cells were transfected with either WT or E/A catalytic mutant MT1-MMP (MT1 E240A). The total cell lysates were subjected to western blotting analyses using antibodies indicated. Quantification of pAkt expression in relative to tAkt expression in 293T cells was shown in (d) (n = 3). Data are reported as average ± s.e.m.; one-way ANOVA (b, d). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 MT1-MMP directly cleaves insulin receptor to suppress insulin signaling. a Western blotting analyses on the expression of insulin receptor (IR) in the livers, white adipose tissues (WAT) and skeletal muscles from p15 wild-type (WT), Mmp14+/−, and Mmp14−/− mice (n = 4). b The protein expression of IR protein in primary wild-type and Mmp14−/− hepatocytes as well as Mmp14−/− hepatocytes reconstituted with either wild-type MT1-MMP (WT MT1) or catalytic inactive MT1-MMP (MT1 E280A) (n = 3). c HEK293T cells were transfected with either WT or E/A catalytic mutant MT1-MMP (MT1 E280A). The expression of full-length IR and sIR was detected in total cell lysate and conditioned media respectively by western blotting (n = 3). d The level of soluble insulin receptor (sIR) was measured in the plasma from p15 wild type (WT), Mmp14+/− and Mmp14−/− mice. (n = 8 for WT & Mmp14+/− mice; n = 6 for Mmp14−/− mice); one-way ANOVA (e) sIR amount was measured in the conditioned media from the wild-type (WT) and Mmp14−/− liver explants (n = 5); two-sided unpaired t test. f rIR was incubated with the recombinant catalytic domain of MT1-MMP (rMT1). The protein mixture was subjected to western blotting analyses using specific antibodies indicated (n = 3). g Co-immunoprecipitation experiments demonstrated the endogenous interaction between MT1-MMP and IR. IR and MT1-MMP immunoprecipitations (IP) were generated from liver lysates from wild-type mice and examined by western blotting analyses using indicated antibodies. IgG immunoprecipitation served as controls. Input loading showed the expression of the protein of interest in the cell lysate without the addition of an antibody (n = 3). Data are reported as average ± s.e.m. Source data are provided as a Source Data file.
Fig. 4 MT1-MMP directly cleaves insulin receptor to suppress insulin signaling. a Western blotting analyses on the expression of insulin receptor (IR) in the livers, white adipose tissues (WAT) and skeletal muscles from p15 wild-type (WT), Mmp14+/−, and Mmp14−/− mice (n = 4). b The protein expression of IR protein in primary wild-type and Mmp14−/− hepatocytes as well as Mmp14−/− hepatocytes reconstituted with either wild-type MT1-MMP (WT MT1) or catalytic inactive MT1-MMP (MT1 E280A) (n = 3). c HEK293T cells were transfected with either WT or E/A catalytic mutant MT1-MMP (MT1 E280A). The expression of full-length IR and sIR was detected in total cell lysate and conditioned media respectively by western blotting (n = 3). d The level of soluble insulin receptor (sIR) was measured in the plasma from p15 wild type (WT), Mmp14+/− and Mmp14−/− mice. (n = 8 for WT & Mmp14+/− mice; n = 6 for Mmp14−/− mice); one-way ANOVA (e) sIR amount was measured in the conditioned media from the wild-type (WT) and Mmp14−/− liver explants (n = 5); two-sided unpaired t test. f rIR was incubated with the recombinant catalytic domain of MT1-MMP (rMT1). The protein mixture was subjected to western blotting analyses using specific antibodies indicated (n = 3). g Co-immunoprecipitation experiments demonstrated the endogenous interaction between MT1-MMP and IR. IR and MT1-MMP immunoprecipitations (IP) were generated from liver lysates from wild-type mice and examined by western blotting analyses using indicated antibodies. IgG immunoprecipitation served as controls. Input loading showed the expression of the protein of interest in the cell lysate without the addition of an antibody (n = 3). Data are reported as average ± s.e.m. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 Pharmacological inhibition of MT1-MMP improves insulin sensitivity in aged mice. Male mice at 4- and 18 months old on chow diet received treatment (twice a week) with either 3A2 antibody or control IgG for 4 weeks. a, b Western blotting (a) and qPCR analyses (c) on the expression of IR in the livers. The relative expression of IR protein level in relative to β-actin levels was quantified in (b) (n = 4). d The level of sIR was measured in the plasma (n = 5). e–g Fasting plasma glucose (n = 5). e Fasting plasma insulin (n = 5). f Glucose-tolerance test (n = 5) (g) in mice. Data are reported as average ± s.e.m.; two-sided unpaired t test (e–f) or one-way ANOVA (b–d, g). Source data are provided as a Source Data file.
Fig. 5 Pharmacological inhibition of MT1-MMP improves insulin sensitivity in aged mice. Male mice at 4- and 18 months old on chow diet received treatment (twice a week) with either 3A2 antibody or control IgG for 4 weeks. a, b Western blotting (a) and qPCR analyses (c) on the expression of IR in the livers. The relative expression of IR protein level in relative to β-actin levels was quantified in (b) (n = 4). d The level of sIR was measured in the plasma (n = 5). e–g Fasting plasma glucose (n = 5). e Fasting plasma insulin (n = 5). f Glucose-tolerance test (n = 5) (g) in mice. Data are reported as average ± s.e.m.; two-sided unpaired t test (e–f) or one-way ANOVA (b–d, g). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 Elevated level of the soluble insulin receptor in aged primates. a, b, d, e ELISA assay reveals that there is a significant upregulation of both plasma MMP14 and soluble insulin receptor (sIR) in the plasma of healthily aged cynomolgus macaques (a, b) and human subjects (d, e) (n = 5 for non-human primates; 21 young and 23 elderly human subjects; two-sided t test). c, f There is also a positive correlation between plasma MT1-MMP and soluble insulin receptor in the plasma from aged and young non-human primates (c) and humans (f). (non-human primates: P = 0.012, R = 0.751, n = 10; human: P < 0.001, R = 0.742, n = 44; two-sided Spearman’s correlation). Data are reported as average ± s.e.m. Source data are provided as a Source Data file.
Fig. 6 Elevated level of the soluble insulin receptor in aged primates. a, b, d, e ELISA assay reveals that there is a significant upregulation of both plasma MMP14 and soluble insulin receptor (sIR) in the plasma of healthily aged cynomolgus macaques (a, b) and human subjects (d, e) (n = 5 for non-human primates; 21 young and 23 elderly human subjects; two-sided t test). c, f There is also a positive correlation between plasma MT1-MMP and soluble insulin receptor in the plasma from aged and young non-human primates (c) and humans (f). (non-human primates: P = 0.012, R = 0.751, n = 10; human: P < 0.001, R = 0.742, n = 44; two-sided Spearman’s correlation). Data are reported as average ± s.e.m. Source data are provided as a Source Data file.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 3 references

Research works printed but not linked: 17

  1. Frojdo, S., Vidal, H. & Pirola, L. Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Biochim Biophys. Acta 1792, 83–92 (2009). · DOI
  2. Olefsky, J. M., Kolterman, O. G. & Scarlett, J. A. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am. J. Physiol. 243, E15–E30 (1982).
  3. Meakin, P. J. et al. The beta secretase BACE1 regulates the expression of insulin receptor in the liver. Nat. Commun. 9, 1306 (2018). · DOI · Paper page
  4. Maesako, M. et al. Effect of glycogen synthase kinase 3 beta-mediated presenilin 1 phosphorylation on amyloid beta production is negatively regulated by insulin receptor cleavage. Neuroscience 177, 298–307 (2011). · DOI
  5. Yuasa, T. et al. Sequential cleavage of insulin receptor by calpain 2 and gamma-secretase impairs insulin signalling. Diabetologia 59, 2711–2721 (2016). · DOI
  6. Soluble Insulin Receptor Study, G. Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes 56, 2028–2035 (2007). · DOI
  7. Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999). · DOI · Paper page
  8. Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000). · DOI · Paper page
  9. Gutierrez-Fernandez, A. et al. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid. EMBO J. 34, 1875–1888 (2015). · DOI · Paper page
  10. Mori, H. et al. New insight into the role of MMP14 in metabolic balance. PeerJ 4, e2142 (2016). · DOI
  11. Frankwich, K. et al. Proof of concept: matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. J. Inflamm. (Lond.) 9, 35 (2012). · DOI
  12. Chow, C.F.W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). · DOI · Paper page
  13. Nam, D. H., Rodriguez, C., Remacle, A. G., Strongin, A. Y. & Ge, X. Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries. Proc. Natl Acad. Sci. USA 113, 14970–14975 (2016). · DOI
  14. Remacle, A. G. et al. Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis. Oncotarget 8, 2781–2799 (2017). · DOI
  15. Li, X. et al. Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity. Mol. Cell. Biol. 40, https://doi.org/10.1128/MCB.00564-19 (2020). · DOI
  16. Hui, X. et al. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue. EMBO Rep. 18, 645–657 (2017). · DOI
  17. Wong, H. L. et al. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Nat. Commun. 7, 10824 (2016). · DOI

Cited by

Sorted by citations

Metadata

Authors
Guo, X., Asthana, P., Gurung, S., Zhang, S., Wong, S. K. K., Fallah, S., Chow, C. F. W., Che, S., Zhai, L., Wang, Z., Ge, X., Jiang, Z., Wu, J., Zhang, Y., Wu, X., Xu, K., Lin, C. Y., Kwan, H. Y., Lyu, A., Zhou, Z., Bian, Z.-X., & Wong, H. L. X.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-06-29
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-31563-2
PMC
PMC9242991
Cited by
49
References
3
Language
en
Licence
Funders
  • Research Grants Council, University Grants Committee (12101019, 12102020)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (06170056, 08793626)
  • National Natural Science Foundation of China (81802838)
  • Natural Science Foundation of Guangdong Province (2021A1515011128, 2019A1515011851)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review