TY - JOUR
T1 - Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function
AU - Gantner, Marin L.
AU - Hazen, Bethany C.
AU - Eury, Elodie
AU - Brown, Erin L.
AU - Kralli, Anastasia
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant R01DK095686 (to A.K.), the Ruth L. Kirschstein National Research Service Award 5F31AG033487 (to M.L.G.), and the Shared Instrumentation Grant 1S10D16357.
Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/12
Y1 - 2016/12
N2 - Brown adipose tissue (BAT) thermogenesis relies on a high abundance of mitochondria and the unique expression of the mitochondrial Uncoupling Protein 1 (UCP1), which uncouples substrate oxidation from ATP synthesis. Adrenergic stimulation of brown adipocytes activates UCP1-mediated thermogenesis; it also induces the expression of Ucp1 and other genes important for thermogenesis, thereby endowing adipocytes with higher oxidative and uncoupling capacities. Adipocyte mitochondrial biogenesis and oxidative capacity are controlled by multiple transcription factors, including the estrogen-related receptor (ERR)β. Whole-body ERRβ knockout mice show decreased BAT mitochondrial content and oxidative function but normal induction of Ucp1 in response to cold. In addition to ERRβ, brown adipocytes express ERRα and ERR, 2 nuclear receptors that are highly similar to ERRβ and whose function in adipocytes is largely unknown. To gain insights into the roles of all 3 ERRs, we assessed mitochondrial function and adrenergic responses in primary brown adipocytes lacking combinations of ERRs. We show that adipocytes lacking just ERRβ, the most abundant ERR, show only mild mitochondrial defects. Adipocytes lacking ERRα and ERR also show just mild defects. In contrast, adipocytes lacking all 3 ERRs have severe reductions in mitochondrial content and oxidative capacity. Moreover, adipocytes lacking all 3 ERRs have defects in the transcriptionalandmetabolic response to adrenergic stimulation, suggesting a wider role of ERRs in BAT function than previously appreciated. Our study shows that ERRs have a great capacity to compensate for each other in protecting mitochondrial function and the metabolic response to adrenergic signaling, processes vital to BAT function.
AB - Brown adipose tissue (BAT) thermogenesis relies on a high abundance of mitochondria and the unique expression of the mitochondrial Uncoupling Protein 1 (UCP1), which uncouples substrate oxidation from ATP synthesis. Adrenergic stimulation of brown adipocytes activates UCP1-mediated thermogenesis; it also induces the expression of Ucp1 and other genes important for thermogenesis, thereby endowing adipocytes with higher oxidative and uncoupling capacities. Adipocyte mitochondrial biogenesis and oxidative capacity are controlled by multiple transcription factors, including the estrogen-related receptor (ERR)β. Whole-body ERRβ knockout mice show decreased BAT mitochondrial content and oxidative function but normal induction of Ucp1 in response to cold. In addition to ERRβ, brown adipocytes express ERRα and ERR, 2 nuclear receptors that are highly similar to ERRβ and whose function in adipocytes is largely unknown. To gain insights into the roles of all 3 ERRs, we assessed mitochondrial function and adrenergic responses in primary brown adipocytes lacking combinations of ERRs. We show that adipocytes lacking just ERRβ, the most abundant ERR, show only mild mitochondrial defects. Adipocytes lacking ERRα and ERR also show just mild defects. In contrast, adipocytes lacking all 3 ERRs have severe reductions in mitochondrial content and oxidative capacity. Moreover, adipocytes lacking all 3 ERRs have defects in the transcriptionalandmetabolic response to adrenergic stimulation, suggesting a wider role of ERRs in BAT function than previously appreciated. Our study shows that ERRs have a great capacity to compensate for each other in protecting mitochondrial function and the metabolic response to adrenergic signaling, processes vital to BAT function.
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U2 - 10.1210/en.2016-1767
DO - 10.1210/en.2016-1767
M3 - Article
C2 - 27763777
AN - SCOPUS:85002244016
SN - 0013-7227
VL - 157
SP - 4770
EP - 4781
JO - Endocrinology
JF - Endocrinology
IS - 12
ER -