SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

Janna A. van Diepen; Joris H. Robben; Guido J. Hooiveld; Claudia Carmone; Mohammad Alsady; Lily Boutens; Melissa Bekkenkamp-Grovenstein; Anneke Hijmans; Udo F.H. Engelke; Ron A. Wevers; Mihai G. Netea; Cees J. Tack; Rinke Stienstra; Peter M.T. Deen

doi:10.1007/s00125-017-4261-z

SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

Janna A. van Diepen, Joris H. Robben, Guido J. Hooiveld, Claudia Carmone, Mohammad Alsady, Lily Boutens, Melissa Bekkenkamp-Grovenstein, Anneke Hijmans, Udo F.H. Engelke, Ron A. Wevers, Mihai G. Netea, Cees J. Tack, Rinke Stienstra, Peter M.T. Deen^*

^*Corresponding author for this work

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

42 Citations (Scopus)

Abstract

Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Methods: Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. Results: We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Conclusions/interpretation: Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. Data availability: The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.

Original language	English
Pages (from-to)	1304-1313
Journal	Diabetologia
Volume	60
Issue number	7
DOIs	https://doi.org/10.1007/s00125-017-4261-z
Publication status	Published - 2017

Keywords

Adipose tissue
Chemotaxis
Glucose
Inflammation
Macrophage
Obesity
Succinate
TCA cycle

Access to Document

10.1007/s00125-017-4261-zLicence: CC BY

Fingerprint Dive into the research topics of 'SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes'. Together they form a unique fingerprint.

SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.
van Diepen, J. A. (Creator), Hooiveld, G. (Creator), Stienstra, R. (Creator) & Deen, P. M. (Creator), Wageningen University, 7 Apr 2017
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104
Dataset

Cite this

van Diepen, J. A., Robben, J. H., Hooiveld, G. J., Carmone, C., Alsady, M., Boutens, L., Bekkenkamp-Grovenstein, M., Hijmans, A., Engelke, U. F. H., Wevers, R. A., Netea, M. G., Tack, C. J., Stienstra, R., & Deen, P. M. T. (2017). SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia, 60(7), 1304-1313. https://doi.org/10.1007/s00125-017-4261-z

van Diepen, Janna A. ; Robben, Joris H. ; Hooiveld, Guido J. ; Carmone, Claudia ; Alsady, Mohammad ; Boutens, Lily ; Bekkenkamp-Grovenstein, Melissa ; Hijmans, Anneke ; Engelke, Udo F.H. ; Wevers, Ron A. ; Netea, Mihai G. ; Tack, Cees J. ; Stienstra, Rinke ; Deen, Peter M.T. / SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. In: Diabetologia. 2017 ; Vol. 60, No. 7. pp. 1304-1313.

@article{bde21d3bc78c4416be53857955075caf,

title = "SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes",

abstract = "Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Methods: Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. Results: We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Conclusions/interpretation: Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. Data availability: The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.",

keywords = "Adipose tissue, Chemotaxis, Glucose, Inflammation, Macrophage, Obesity, Succinate, TCA cycle",

author = "{van Diepen}, {Janna A.} and Robben, {Joris H.} and Hooiveld, {Guido J.} and Claudia Carmone and Mohammad Alsady and Lily Boutens and Melissa Bekkenkamp-Grovenstein and Anneke Hijmans and Engelke, {Udo F.H.} and Wevers, {Ron A.} and Netea, {Mihai G.} and Tack, {Cees J.} and Rinke Stienstra and Deen, {Peter M.T.}",

year = "2017",

doi = "10.1007/s00125-017-4261-z",

language = "English",

volume = "60",

pages = "1304--1313",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "7",

}

van Diepen, JA, Robben, JH, Hooiveld, GJ, Carmone, C, Alsady, M, Boutens, L, Bekkenkamp-Grovenstein, M, Hijmans, A, Engelke, UFH, Wevers, RA, Netea, MG, Tack, CJ, Stienstra, R & Deen, PMT 2017, 'SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes', Diabetologia, vol. 60, no. 7, pp. 1304-1313. https://doi.org/10.1007/s00125-017-4261-z

SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. / van Diepen, Janna A.; Robben, Joris H.; Hooiveld, Guido J.; Carmone, Claudia; Alsady, Mohammad; Boutens, Lily; Bekkenkamp-Grovenstein, Melissa; Hijmans, Anneke; Engelke, Udo F.H.; Wevers, Ron A.; Netea, Mihai G.; Tack, Cees J.; Stienstra, Rinke; Deen, Peter M.T.

In: Diabetologia, Vol. 60, No. 7, 2017, p. 1304-1313.

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

TY - JOUR

T1 - SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

AU - van Diepen, Janna A.

AU - Robben, Joris H.

AU - Hooiveld, Guido J.

AU - Carmone, Claudia

AU - Alsady, Mohammad

AU - Boutens, Lily

AU - Bekkenkamp-Grovenstein, Melissa

AU - Hijmans, Anneke

AU - Engelke, Udo F.H.

AU - Wevers, Ron A.

AU - Netea, Mihai G.

AU - Tack, Cees J.

AU - Stienstra, Rinke

AU - Deen, Peter M.T.

PY - 2017

Y1 - 2017

N2 - Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Methods: Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. Results: We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Conclusions/interpretation: Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. Data availability: The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.

AB - Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Methods: Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. Results: We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Conclusions/interpretation: Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. Data availability: The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.

KW - Adipose tissue

KW - Chemotaxis

KW - Glucose

KW - Inflammation

KW - Macrophage

KW - Obesity

KW - Succinate

KW - TCA cycle

U2 - 10.1007/s00125-017-4261-z

DO - 10.1007/s00125-017-4261-z

M3 - Article

AN - SCOPUS:85017146846

VL - 60

SP - 1304

EP - 1313

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 7

ER -