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.2007 Jan 23;104(4):1418-23.
doi: 10.1073/pnas.0607696104. Epub 2007 Jan 17.

Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis

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Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis

Josep A Villena et al. Proc Natl Acad Sci U S A..

Abstract

Survival of organisms requires the ability to adapt to changes in the environment. Adaptation of oxidative metabolism is essential for meeting increased energy demands in response to stressors, such as exposure to cold temperatures or increased physical activity. Adaptive changes in metabolism are often achieved at the level of gene expression, and nuclear receptors have prevalent roles in mediating such responses. Estrogen-related receptor alpha (ERRalpha) was the first orphan nuclear receptor to be identified, and yet its physiologic function remains unknown. Here, we show that mice lacking ERRalpha are unable to maintain body temperature when exposed to cold. Surprisingly, the inability to adapt to cold is not due to defects in the acute transcriptional induction of genes important for thermogenesis. Rather, we show that ERRalpha is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis. ERRalpha fulfills this role by acting directly at genes important for mitochondrial function, parallel to other factors controlling mitochondrial gene expression, such as NRF1 and NRF2/GABPA. Our findings demonstrate that ERRalpha is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Decreased expression of mitochondrial energy metabolism genes in BAT of ERRα KO, compared with WT mice. mRNA levels of genes encoding mitochondrial proteins important for OxPhos (A), TCA cycle (B), and fatty acid oxidation (C) in BAT were determined by real-time PCR. Similarly, mRNA levels of transcription factors NRF1, NRF2, and PPARα (D) and of coactivators PGC-1α and PGC-1β (E) were quantified. Data are expressed relative to levels of each gene in WT BAT (set as equal to 1) and are the mean ± SEM of 5–7 animals per group (10–11 animals for NRF1 and NRF2 quantitation). ∗,P < 0.05; ∗∗,P < 0.01.
Fig. 2.
Fig. 2.
In vivo binding of ERRα to regulatory sequences of mitochondrial genes in BAT. The presence of specific genomic regions in chromatin immunoprecipitated from BAT of WT mice by using antibodies against GFP (control, NS), ERRα, or Pol II was determined by real-time PCR. Numbers in parentheses indicate location of ERRE sequences relative to the transcription start site of each gene (seeSI Fig. 9 for sequences). TheEsrra distal region does not harbor ERREs and was used as a negative control. Data are expressed as percentage of genomic DNA in the immunoprecipitate relative to the input for the same sample and are the mean ± SEM of four mice, processed and assayed independently.
Fig. 3.
Fig. 3.
Decreased mitochondrial mass and increased lipid accumulation in BAT of ERRα KO mice. (A) Representative electron microscopy images of BAT of WT (Left) and ERRα KO (Right) mice; ∗, triglycerides; arrowheads point to mitochondria. (B) mtDNA content in BAT, determined by real-time PCR and expressed relative to content in WT mice. Data are the mean ± SEM of six animals in each group. (C) Mitochondrial protein mass in BAT of WT and ERRα KO, measured after purification of mitochondria. Data are expressed as micrograms of mitochondrial protein per milligram of BAT and are the mean ± SEM of four independent experiments with two WT and two ERRα KO mice per experiment. (D) Triglyceride content in BAT of WT and ERRα KO mice.
Fig. 4.
Fig. 4.
Impaired thermogenesis in ERRα KO mice upon acute exposure to 4°C. (A) Body temperature of WT and ERRα KO mice exposed for 6 h at 30°C (Left) or 4°C (Right). (B) UCP1, PGC-1α, and DIO2 mRNA levels in BAT of WT and ERRα KO mice after 6 h at 30°C or 4°C, determined by real-time PCR. Data are the mean ± SEM of 5–10 animals per group. ∗,P < 0.05; ∗∗,P < 0.01.
Fig. 5.
Fig. 5.
Impaired thermogenesis in ERRα KO mice during long-term exposure to 13°C. Body temperatures of five WT (Upper) and 5 ERRα KO (Lower) mice were monitored by telemetry for 5 days at 30°C, followed by 7 days at 13°C. Data shown are from one of two experiments.
Fig. 6.
Fig. 6.
Decreased respiratory capacity in brown adipocytes isolated from ERRα KO mice. Shown is the respiration of brown adipocytes isolated from WT and ERRα KO mice, measured with a Clark-type oxygen electrode in the absence (basal) or presence of 1 μM norepinephrine. Data are the mean ± SEM of three independent experiments, with three to six mice and three respiration measurements per experiment. ∗,P < 0.05.
Fig. 7.
Fig. 7.
Proposed role of ERRα in the BAT pathways required for adaptive thermogenesis.
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References

    1. Glass CK. J Clin Invest. 2006;116:556–560. - PMC - PubMed
    1. Giguère V, Yang N, Segui P, Evans RM. Nature. 1988;331:91–94. - PubMed
    1. Eudy JD, Yao S, Weston MD, Ma-Edmonds M, Talmadge CB, Cheng JJ, Kimberling WJ, Sumegi J. Genomics. 1998;50:382–384. - PubMed
    1. Giguère V. Trends Endocrinol Metab. 2002;13:220–225. - PubMed
    1. Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V. Mol Cell Biol. 2003;23:7947–7956. - PMC - PubMed

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