UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity

Lise Madsen; Lone M Pedersen; Haldis Haukaas Lillefosse; Even Fjaere; Ingeborg Bronstad; Qin Hao; Rasmus Koefoed Petersen; Philip Hallenborg; Tao Ma; Rita De Matteis; Pedro Araujo; Josep Mercader; M Luisa Bonet; Jacob B Hansen; Barbara Cannon; Jan Nedergaard; Jun Wang; Saverio Cinti; Peter Voshol; Stein Ove Døskeland; Karsten Kristiansen

doi:10.1371/journal.pone.0011391

UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity

Lise Madsen, Lone M Pedersen, Haldis Haukaas Lillefosse, Even Fjaere, Ingeborg Bronstad, Qin Hao, Rasmus Koefoed Petersen, Philip Hallenborg, Tao Ma, Rita De Matteis, Pedro Araujo, Josep Mercader, M Luisa Bonet, Jacob B Hansen, Barbara Cannon, Jan Nedergaard, Jun Wang, Saverio Cinti, Peter Voshol, Stein Ove DøskelandKarsten Kristiansen

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Abstract

Background: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Methodology/Principal Findings: Here we report that cyclooxygenase (COX) activity and prostaglandin E₂ (PGE₂) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed b-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE₂ receptor antagonists implicated EP₄ as a main PGE₂ receptor, and injection of the stable PGE₂ analog (EP_3/4 agonist) 16,16 dm PGE₂ induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Conclusions/Significance: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.

Original language	English
Journal	PLoS ONE
Volume	5
Issue number	6
Pages (from-to)	1-13
Number of pages	111,391
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0011391
Publication status	Published - 30 Jan 2010

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Madsen, L., Pedersen, L. M., Lillefosse, H. H., Fjaere, E., Bronstad, I., Hao, Q., Petersen, R. K., Hallenborg, P., Ma, T., De Matteis, R., Araujo, P., Mercader, J., Bonet, M. L., Hansen, J. B., Cannon, B., Nedergaard, J., Wang, J., Cinti, S., Voshol, P., ... Kristiansen, K. (2010). UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS ONE, 5(6), 1-13. https://doi.org/10.1371/journal.pone.0011391

Madsen, L, Pedersen, LM, Lillefosse, HH, Fjaere, E, Bronstad, I, Hao, Q, Petersen, RK, Hallenborg, P, Ma, T, De Matteis, R, Araujo, P, Mercader, J, Bonet, ML, Hansen, JB, Cannon, B, Nedergaard, J, Wang, J, Cinti, S, Voshol, P, Døskeland, SO & Kristiansen, K 2010, 'UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity', PLoS ONE, vol. 5, no. 6, pp. 1-13. https://doi.org/10.1371/journal.pone.0011391

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title = "UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity",

abstract = "Background: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Methodology/Principal Findings: Here we report that cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed b-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE2 receptor antagonists implicated EP4 as a main PGE2 receptor, and injection of the stable PGE2 analog (EP3/4 agonist) 16,16 dm PGE2 induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Conclusions/Significance: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.",

author = "Lise Madsen and Pedersen, {Lone M} and Lillefosse, {Haldis Haukaas} and Even Fjaere and Ingeborg Bronstad and Qin Hao and Petersen, {Rasmus Koefoed} and Philip Hallenborg and Tao Ma and {De Matteis}, Rita and Pedro Araujo and Josep Mercader and Bonet, {M Luisa} and Hansen, {Jacob B} and Barbara Cannon and Jan Nedergaard and Jun Wang and Saverio Cinti and Peter Voshol and D{\o}skeland, {Stein Ove} and Karsten Kristiansen",

year = "2010",

month = jan,

day = "30",

doi = "10.1371/journal.pone.0011391",

language = "English",

volume = "5",

pages = "1--13",

journal = "PLoS Computational Biology",

issn = "1932-6203",

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T1 - UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity

AU - Madsen, Lise

AU - Pedersen, Lone M

AU - Lillefosse, Haldis Haukaas

AU - Fjaere, Even

AU - Bronstad, Ingeborg

AU - Hao, Qin

AU - Petersen, Rasmus Koefoed

AU - Hallenborg, Philip

AU - Ma, Tao

AU - De Matteis, Rita

AU - Araujo, Pedro

AU - Mercader, Josep

AU - Bonet, M Luisa

AU - Hansen, Jacob B

AU - Cannon, Barbara

AU - Nedergaard, Jan

AU - Wang, Jun

AU - Cinti, Saverio

AU - Voshol, Peter

AU - Døskeland, Stein Ove

AU - Kristiansen, Karsten

PY - 2010/1/30

Y1 - 2010/1/30

N2 - Background: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Methodology/Principal Findings: Here we report that cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed b-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE2 receptor antagonists implicated EP4 as a main PGE2 receptor, and injection of the stable PGE2 analog (EP3/4 agonist) 16,16 dm PGE2 induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Conclusions/Significance: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.

AB - Background: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Methodology/Principal Findings: Here we report that cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed b-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE2 receptor antagonists implicated EP4 as a main PGE2 receptor, and injection of the stable PGE2 analog (EP3/4 agonist) 16,16 dm PGE2 induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Conclusions/Significance: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.

U2 - 10.1371/journal.pone.0011391

DO - 10.1371/journal.pone.0011391

M3 - Journal article

C2 - 20613988

SN - 1932-6203

VL - 5

SP - 1

EP - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 6

ER -

UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity

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