p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α

Philip Hallenborg; Even Fjære; Bjørn Liaset; Rasmus Koefoed Petersen; Incoronata Murano; Si Brask Sonne; Mathias Falkerslev; Sally Winther; Benjamin Anderschou Holbech Jensen; Tao Ma; Jacob B. Hansen; Saverio Cinti; Blagoy Blagoev; Lise Madsen; Karsten Kristiansen

doi:10.1152/ajpendo.00119.2015

p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α

Philip Hallenborg, Even Fjære, Bjørn Liaset, Rasmus Koefoed Petersen, Incoronata Murano, Si Brask Sonne, Mathias Falkerslev, Sally Winther, Benjamin Anderschou Holbech Jensen, Tao Ma, Jacob B. Hansen, Saverio Cinti, Blagoy Blagoev, Lise Madsen, Karsten Kristiansen

Genome Research and Molecular Bio Medicine

19 Citations (Scopus)

Abstract

The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity.

Original language	English
Journal	American Journal of Physiology: Endocrinology and Metabolism
Volume	310
Issue number	2
Pages (from-to)	E116-128
Number of pages	13
ISSN	0193-1849
DOIs	https://doi.org/10.1152/ajpendo.00119.2015
Publication status	Published - 15 Jan 2016

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Hallenborg, P., Fjære, E., Liaset, B., Petersen, R. K., Murano, I., Sonne, S. B., Falkerslev, M., Winther, S., Jensen, B. A. H., Ma, T., Hansen, J. B., Cinti, S., Blagoev, B., Madsen, L., & Kristiansen, K. (2016). p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α. American Journal of Physiology: Endocrinology and Metabolism, 310(2), E116-128. https://doi.org/10.1152/ajpendo.00119.2015

Hallenborg, P, Fjære, E, Liaset, B, Petersen, RK, Murano, I, Sonne, SB, Falkerslev, M, Winther, S , Jensen, BAH, Ma, T, Hansen, JB, Cinti, S, Blagoev, B, Madsen, L & Kristiansen, K 2016, 'p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α', American Journal of Physiology: Endocrinology and Metabolism, vol. 310, no. 2, pp. E116-128. https://doi.org/10.1152/ajpendo.00119.2015

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title = "p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α",

abstract = "The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity.",

author = "Philip Hallenborg and Even Fj{\ae}re and Bj{\o}rn Liaset and Petersen, {Rasmus Koefoed} and Incoronata Murano and Sonne, {Si Brask} and Mathias Falkerslev and Sally Winther and Jensen, {Benjamin Anderschou Holbech} and Tao Ma and Hansen, {Jacob B.} and Saverio Cinti and Blagoy Blagoev and Lise Madsen and Karsten Kristiansen",

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language = "English",

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T1 - p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α

AU - Hallenborg, Philip

AU - Fjære, Even

AU - Liaset, Bjørn

AU - Petersen, Rasmus Koefoed

AU - Murano, Incoronata

AU - Sonne, Si Brask

AU - Falkerslev, Mathias

AU - Winther, Sally

AU - Jensen, Benjamin Anderschou Holbech

AU - Ma, Tao

AU - Hansen, Jacob B.

AU - Cinti, Saverio

AU - Blagoev, Blagoy

AU - Madsen, Lise

AU - Kristiansen, Karsten

PY - 2016/1/15

Y1 - 2016/1/15

N2 - The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity.

AB - The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity.

U2 - 10.1152/ajpendo.00119.2015

DO - 10.1152/ajpendo.00119.2015

M3 - Journal article

C2 - 26578713

SN - 0193-1849

VL - 310

SP - E116-128

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

IS - 2

ER -

p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α

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