Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity

Elisa Duregotti; Christina M. Reumiller; Ursula Mayr; Maria Hasman; Lukas E. Schmidt; Sean A. Burnap; Konstantinos Theofilatos; Javier Barallobre-Barreiro; Arne Beran; Maria Grandoch; Alessandro Viviano; Marjan Jahangiri; Manuel Mayr

doi:10.1038/s41467-022-34846-w

Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity

Elisa Duregotti, Christina M. Reumiller, Ursula Mayr, Maria Hasman, Lukas E. Schmidt, Sean A. Burnap, Konstantinos Theofilatos, Javier Barallobre-Barreiro, Arne Beran, Maria Grandoch, Alessandro Viviano, Marjan Jahangiri, Manuel Mayr^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese (ob/ob) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.

Original language	English
Article number	7269
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34846-w
Publication status	Published - Dec 2022

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Duregotti, E., Reumiller, C. M., Mayr, U., Hasman, M., Schmidt, L. E., Burnap, S. A., Theofilatos, K., Barallobre-Barreiro, J., Beran, A., Grandoch, M., Viviano, A., Jahangiri, M., & Mayr, M. (2022). Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity. Nature Communications, 13(1), [7269]. https://doi.org/10.1038/s41467-022-34846-w

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title = "Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity",

abstract = "While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese (ob/ob) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.",

author = "Elisa Duregotti and Reumiller, {Christina M.} and Ursula Mayr and Maria Hasman and Schmidt, {Lukas E.} and Burnap, {Sean A.} and Konstantinos Theofilatos and Javier Barallobre-Barreiro and Arne Beran and Maria Grandoch and Alessandro Viviano and Marjan Jahangiri and Manuel Mayr",

note = "Funding Information: We sincerely thank the Wohl Cellular Imaging Centre (King{\textquoteright}s College London) where the confocal microscopy images were acquired. We are also grateful to Dr. Matthew White for helping us setting up primary sympathetic neuronal cultures. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). M.M. received support from the BHF Centre for Vascular Regeneration with Edinburgh/Bristol (RM/17/3/33381). M.M. is also supported by the Leducq Foundation (“PlaqOmics”, 18CVD02) and VASCage-C (Research Centre on Vascular Ageing and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna with the grant number FSG 868624. This study was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Grant No. 236177352—SFB 1116, TPB10; GRK2576 vivid, P2 (M.G.). Funding Information: We sincerely thank the Wohl Cellular Imaging Centre (King{\textquoteright}s College London) where the confocal microscopy images were acquired. We are also grateful to Dr. Matthew White for helping us setting up primary sympathetic neuronal cultures. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). M.M. received support from the BHF Centre for Vascular Regeneration with Edinburgh/Bristol (RM/17/3/33381). M.M. is also supported by the Leducq Foundation (“PlaqOmics”, 18CVD02) and VASCage-C (Research Centre on Vascular Ageing and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna with the grant number FSG 868624. This study was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Grant No. 236177352—SFB 1116, TPB10; GRK2576 vivid, P2 (M.G.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-34846-w",

language = "English",

volume = "13",

journal = "Nature Communications",

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Duregotti, E, Reumiller, CM, Mayr, U, Hasman, M, Schmidt, LE, Burnap, SA, Theofilatos, K , Barallobre-Barreiro, J, Beran, A, Grandoch, M, Viviano, A, Jahangiri, M & Mayr, M 2022, 'Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity', Nature Communications, vol. 13, no. 1, 7269. https://doi.org/10.1038/s41467-022-34846-w

TY - JOUR

T1 - Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity

AU - Duregotti, Elisa

AU - Reumiller, Christina M.

AU - Mayr, Ursula

AU - Hasman, Maria

AU - Schmidt, Lukas E.

AU - Burnap, Sean A.

AU - Theofilatos, Konstantinos

AU - Barallobre-Barreiro, Javier

AU - Beran, Arne

AU - Grandoch, Maria

AU - Viviano, Alessandro

AU - Jahangiri, Marjan

AU - Mayr, Manuel

N1 - Funding Information: We sincerely thank the Wohl Cellular Imaging Centre (King’s College London) where the confocal microscopy images were acquired. We are also grateful to Dr. Matthew White for helping us setting up primary sympathetic neuronal cultures. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). M.M. received support from the BHF Centre for Vascular Regeneration with Edinburgh/Bristol (RM/17/3/33381). M.M. is also supported by the Leducq Foundation (“PlaqOmics”, 18CVD02) and VASCage-C (Research Centre on Vascular Ageing and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna with the grant number FSG 868624. This study was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Grant No. 236177352—SFB 1116, TPB10; GRK2576 vivid, P2 (M.G.). Funding Information: We sincerely thank the Wohl Cellular Imaging Centre (King’s College London) where the confocal microscopy images were acquired. We are also grateful to Dr. Matthew White for helping us setting up primary sympathetic neuronal cultures. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). M.M. received support from the BHF Centre for Vascular Regeneration with Edinburgh/Bristol (RM/17/3/33381). M.M. is also supported by the Leducq Foundation (“PlaqOmics”, 18CVD02) and VASCage-C (Research Centre on Vascular Ageing and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna with the grant number FSG 868624. This study was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Grant No. 236177352—SFB 1116, TPB10; GRK2576 vivid, P2 (M.G.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese (ob/ob) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.

AB - While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese (ob/ob) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.

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JO - Nature Communications

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ER -

Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity

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