Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

Jiandie Lin; Pei Hsuan Wu; Paul T. Tarr; Katrin S. Lindenberg; Julie St-Pierre; Chen Yu Zhang; Vamsi K. Mootha; Sibylle Jäger; Claudia R. Vianna; Richard M. Reznick; Libin Cui; Monia Manieri; Mi X. Donovan; Zhidan Wu; Marcus P. Cooper; Melina C. Fan; Lindsay M. Rohas; Ann Marie Zavacki; Saverio Cinti; Gerald I. Shulman; Bradford B. Lowell; Dimitri Krainc; Bruce M. Spiegelman

doi:10.1016/j.cell.2004.09.013

Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

Jiandie Lin, Pei Hsuan Wu, Paul T. Tarr, Katrin S. Lindenberg, Julie St-Pierre, Chen Yu Zhang, Vamsi K. Mootha, Sibylle Jäger, Claudia R. Vianna, Richard M. Reznick, Libin Cui, Monia Manieri, Mi X. Donovan, Zhidan Wu, Marcus P. Cooper, Melina C. Fan, Lindsay M. Rohas, Ann Marie Zavacki, Saverio Cinti, Gerald I. ShulmanBradford B. Lowell, Dimitri Krainc, Bruce M. Spiegelman^*

^*Corresponding author for this work

Neurology

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

1064 Scopus citations

Abstract

PGC-1α is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1α are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPβ is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1α null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1α in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Original language	English (US)
Pages (from-to)	121-135
Number of pages	15
Journal	Cell
Volume	119
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2004.09.013
State	Published - Oct 1 2004

Funding

We thank Drs. Eric Bachman and Pere Puigserver for comments and critiques on the manuscript. We also thank Dr. P. Reed Larsen for T3 antibody; Eric Smith for computer graphics support; and Jia Yu and Mingtao Lee for technical assistance in ES cell manipulations and CLAMS studies, respectively. This work is supported by grants from the N.I.H., DK54477 and DK61562 (B.M.S.), DK40936 (G.I.S.), NS002174 and NS045242 (D.K.) and DK065584 (J.L.), and QLK1-2001-00183 DLARFID (S.C.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2004.09.013

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Lin, J., Wu, P. H., Tarr, P. T., Lindenberg, K. S., St-Pierre, J., Zhang, C. Y., Mootha, V. K., Jäger, S., Vianna, C. R., Reznick, R. M., Cui, L., Manieri, M., Donovan, M. X., Wu, Z., Cooper, M. P., Fan, M. C., Rohas, L. M., Zavacki, A. M., Cinti, S., ... Spiegelman, B. M. (2004). Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell, 119(1), 121-135. https://doi.org/10.1016/j.cell.2004.09.013

@article{f167d9d1499c4f5e8a1fe427cce58237,

title = "Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice",

abstract = "PGC-1α is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1α are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPβ is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1α null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1α in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.",

author = "Jiandie Lin and Wu, {Pei Hsuan} and Tarr, {Paul T.} and Lindenberg, {Katrin S.} and Julie St-Pierre and Zhang, {Chen Yu} and Mootha, {Vamsi K.} and Sibylle J{\"a}ger and Vianna, {Claudia R.} and Reznick, {Richard M.} and Libin Cui and Monia Manieri and Donovan, {Mi X.} and Zhidan Wu and Cooper, {Marcus P.} and Fan, {Melina C.} and Rohas, {Lindsay M.} and Zavacki, {Ann Marie} and Saverio Cinti and Shulman, {Gerald I.} and Lowell, {Bradford B.} and Dimitri Krainc and Spiegelman, {Bruce M.}",

note = "Funding Information: We thank Drs. Eric Bachman and Pere Puigserver for comments and critiques on the manuscript. We also thank Dr. P. Reed Larsen for T3 antibody; Eric Smith for computer graphics support; and Jia Yu and Mingtao Lee for technical assistance in ES cell manipulations and CLAMS studies, respectively. This work is supported by grants from the N.I.H., DK54477 and DK61562 (B.M.S.), DK40936 (G.I.S.), NS002174 and NS045242 (D.K.) and DK065584 (J.L.), and QLK1-2001-00183 DLARFID (S.C.). ",

year = "2004",

month = oct,

day = "1",

doi = "10.1016/j.cell.2004.09.013",

language = "English (US)",

volume = "119",

pages = "121--135",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "1",

}

Lin, J, Wu, PH, Tarr, PT, Lindenberg, KS, St-Pierre, J, Zhang, CY, Mootha, VK, Jäger, S, Vianna, CR, Reznick, RM, Cui, L, Manieri, M, Donovan, MX, Wu, Z, Cooper, MP, Fan, MC, Rohas, LM, Zavacki, AM, Cinti, S, Shulman, GI, Lowell, BB, Krainc, D & Spiegelman, BM 2004, 'Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice', Cell, vol. 119, no. 1, pp. 121-135. https://doi.org/10.1016/j.cell.2004.09.013

TY - JOUR

T1 - Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

AU - Lin, Jiandie

AU - Wu, Pei Hsuan

AU - Tarr, Paul T.

AU - Lindenberg, Katrin S.

AU - St-Pierre, Julie

AU - Zhang, Chen Yu

AU - Mootha, Vamsi K.

AU - Jäger, Sibylle

AU - Vianna, Claudia R.

AU - Reznick, Richard M.

AU - Cui, Libin

AU - Manieri, Monia

AU - Donovan, Mi X.

AU - Wu, Zhidan

AU - Cooper, Marcus P.

AU - Fan, Melina C.

AU - Rohas, Lindsay M.

AU - Zavacki, Ann Marie

AU - Cinti, Saverio

AU - Shulman, Gerald I.

AU - Lowell, Bradford B.

AU - Krainc, Dimitri

AU - Spiegelman, Bruce M.

N1 - Funding Information: We thank Drs. Eric Bachman and Pere Puigserver for comments and critiques on the manuscript. We also thank Dr. P. Reed Larsen for T3 antibody; Eric Smith for computer graphics support; and Jia Yu and Mingtao Lee for technical assistance in ES cell manipulations and CLAMS studies, respectively. This work is supported by grants from the N.I.H., DK54477 and DK61562 (B.M.S.), DK40936 (G.I.S.), NS002174 and NS045242 (D.K.) and DK065584 (J.L.), and QLK1-2001-00183 DLARFID (S.C.).

PY - 2004/10/1

Y1 - 2004/10/1

N2 - PGC-1α is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1α are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPβ is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1α null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1α in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

AB - PGC-1α is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1α are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPβ is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1α null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1α in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

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DO - 10.1016/j.cell.2004.09.013

M3 - Article

C2 - 15454086

AN - SCOPUS:5344252327

SN - 0092-8674

VL - 119

SP - 121

EP - 135

JO - Cell

JF - Cell

IS - 1

ER -

Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

Abstract

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ASJC Scopus subject areas

UN SDGs

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