Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J Mice

Even Fjære; Ulrike Liisberg Aune; Kristin Røen; Alison Haller Keenan; Tao Ma; Kamil Borkowski; David Møbjerg Boslev Kristensen; Guy Wayne Novotny; Thomas Mandrup-Poulsen; Brian D. Hudson; Graeme Milligan; Yannan Xi; John W. Newman; Fawaz G. Haj; Bjørn Liaset; Karsten Kristiansen; Lise Madsen

doi:10.1074/jbc.M113.525220

Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C₅₇BL/6J Mice

Even Fjære, Ulrike Liisberg Aune, Kristin Røen, Alison Haller Keenan, Tao Ma, Kamil Borkowski, David Møbjerg Boslev Kristensen, Guy Wayne Novotny, Thomas Mandrup-Poulsen, Brian D. Hudson, Graeme Milligan, Yannan Xi, John W. Newman, Fawaz G. Haj, Bjørn Liaset, Karsten Kristiansen, Lise Madsen

30 Citationer (Scopus)

Abstract

Chronic low grade inflammation is closely linked to obesityassociated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (γINDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HSαINDOfed mice remained insulin-sensitive. However, mice fed HF/HSαINDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS⁺ INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.

Originalsprog	Engelsk
Tidsskrift	The Journal of Biological Chemistry
Vol/bind	289
Udgave nummer	23
Sider (fra-til)	16032-16045
Antal sider	14
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.M113.525220
Status	Udgivet - 6 jun. 2014

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10.1074/jbc.M113.525220

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Fjære, E., Aune, U. L., Røen, K., Keenan, A. H., Ma, T., Borkowski, K., Kristensen, D. M. B., Novotny, G. W., Mandrup-Poulsen, T., Hudson, B. D., Milligan, G., Xi, Y., Newman, J. W., Haj, F. G., Liaset, B., Kristiansen, K., & Madsen, L. (2014). Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C₅₇BL/6J Mice. The Journal of Biological Chemistry, 289(23), 16032-16045. https://doi.org/10.1074/jbc.M113.525220

Fjære, E, Aune, UL, Røen, K, Keenan, AH, Ma, T, Borkowski, K, Kristensen, DMB, Novotny, GW, Mandrup-Poulsen, T, Hudson, BD, Milligan, G, Xi, Y, Newman, JW, Haj, FG, Liaset, B, Kristiansen, K & Madsen, L 2014, 'Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C₅₇BL/6J Mice', The Journal of Biological Chemistry, bind 289, nr. 23, s. 16032-16045. https://doi.org/10.1074/jbc.M113.525220

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title = "Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J Mice",

abstract = "Chronic low grade inflammation is closely linked to obesityassociated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (γINDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HSαINDOfed mice remained insulin-sensitive. However, mice fed HF/HSαINDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+ INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.",

author = "Even Fj{\ae}re and Aune, {Ulrike Liisberg} and Kristin R{\o}en and Keenan, {Alison Haller} and Tao Ma and Kamil Borkowski and Kristensen, {David M{\o}bjerg Boslev} and Novotny, {Guy Wayne} and Thomas Mandrup-Poulsen and Hudson, {Brian D.} and Graeme Milligan and Yannan Xi and Newman, {John W.} and Haj, {Fawaz G.} and Bj{\o}rn Liaset and Karsten Kristiansen and Lise Madsen",

note = "{\textcopyright} 2014 by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2014",

month = jun,

day = "6",

doi = "10.1074/jbc.M113.525220",

language = "English",

volume = "289",

pages = "16032--16045",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "23",

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TY - JOUR

T1 - Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J Mice

AU - Fjære, Even

AU - Aune, Ulrike Liisberg

AU - Røen, Kristin

AU - Keenan, Alison Haller

AU - Ma, Tao

AU - Borkowski, Kamil

AU - Kristensen, David Møbjerg Boslev

AU - Novotny, Guy Wayne

AU - Mandrup-Poulsen, Thomas

AU - Hudson, Brian D.

AU - Milligan, Graeme

AU - Xi, Yannan

AU - Newman, John W.

AU - Haj, Fawaz G.

AU - Liaset, Bjørn

AU - Kristiansen, Karsten

AU - Madsen, Lise

PY - 2014/6/6

Y1 - 2014/6/6

N2 - Chronic low grade inflammation is closely linked to obesityassociated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (γINDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HSαINDOfed mice remained insulin-sensitive. However, mice fed HF/HSαINDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+ INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.

AB - Chronic low grade inflammation is closely linked to obesityassociated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (γINDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HSαINDOfed mice remained insulin-sensitive. However, mice fed HF/HSαINDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+ INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.

U2 - 10.1074/jbc.M113.525220

DO - 10.1074/jbc.M113.525220

M3 - Journal article

C2 - 24742673

SN - 0021-9258

VL - 289

SP - 16032

EP - 16045

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 23

ER -