Regulation of adipogenesis by natural and synthetic REV-ERB ligands

Naresh Kumar, Laura A. Solt, Yongjun Wang, Pamela M. Rogers, Gargi Bhattacharyya, Theodore M. Kamenecka, Keith R. Stayrook, Christine Crumbley, Z. Elizabeth Floyd, Jeffrey M. Gimble, Patrick R. Griffin, Thomas P. Burris

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbα expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-γ agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases.

Original languageEnglish (US)
Pages (from-to)3015-3025
Number of pages11
JournalEndocrinology
Volume151
Issue number7
DOIs
StatePublished - Jul 1 2010

Fingerprint

Adipogenesis
Heme
Ligands
rosiglitazone
Aminolevulinic Acid
3T3-L1 Cells
Adipocytes
Co-Repressor Proteins
Metabolic Diseases
Porphyrins
Cytoplasmic and Nuclear Receptors
Gene Expression
Enzymes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Kumar, N., Solt, L. A., Wang, Y., Rogers, P. M., Bhattacharyya, G., Kamenecka, T. M., ... Burris, T. P. (2010). Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology, 151(7), 3015-3025. https://doi.org/10.1210/en.2009-0800

Regulation of adipogenesis by natural and synthetic REV-ERB ligands. / Kumar, Naresh; Solt, Laura A.; Wang, Yongjun; Rogers, Pamela M.; Bhattacharyya, Gargi; Kamenecka, Theodore M.; Stayrook, Keith R.; Crumbley, Christine; Floyd, Z. Elizabeth; Gimble, Jeffrey M.; Griffin, Patrick R.; Burris, Thomas P.

In: Endocrinology, Vol. 151, No. 7, 01.07.2010, p. 3015-3025.

Research output: Contribution to journalArticle

Kumar, N, Solt, LA, Wang, Y, Rogers, PM, Bhattacharyya, G, Kamenecka, TM, Stayrook, KR, Crumbley, C, Floyd, ZE, Gimble, JM, Griffin, PR & Burris, TP 2010, 'Regulation of adipogenesis by natural and synthetic REV-ERB ligands', Endocrinology, vol. 151, no. 7, pp. 3015-3025. https://doi.org/10.1210/en.2009-0800
Kumar N, Solt LA, Wang Y, Rogers PM, Bhattacharyya G, Kamenecka TM et al. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology. 2010 Jul 1;151(7):3015-3025. https://doi.org/10.1210/en.2009-0800
Kumar, Naresh ; Solt, Laura A. ; Wang, Yongjun ; Rogers, Pamela M. ; Bhattacharyya, Gargi ; Kamenecka, Theodore M. ; Stayrook, Keith R. ; Crumbley, Christine ; Floyd, Z. Elizabeth ; Gimble, Jeffrey M. ; Griffin, Patrick R. ; Burris, Thomas P. / Regulation of adipogenesis by natural and synthetic REV-ERB ligands. In: Endocrinology. 2010 ; Vol. 151, No. 7. pp. 3015-3025.
@article{8ad24d05f6cd475ab88826265acac740,
title = "Regulation of adipogenesis by natural and synthetic REV-ERB ligands",
abstract = "The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbα expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-γ agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases.",
author = "Naresh Kumar and Solt, {Laura A.} and Yongjun Wang and Rogers, {Pamela M.} and Gargi Bhattacharyya and Kamenecka, {Theodore M.} and Stayrook, {Keith R.} and Christine Crumbley and Floyd, {Z. Elizabeth} and Gimble, {Jeffrey M.} and Griffin, {Patrick R.} and Burris, {Thomas P.}",
year = "2010",
month = "7",
day = "1",
doi = "10.1210/en.2009-0800",
language = "English (US)",
volume = "151",
pages = "3015--3025",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "7",

}

TY - JOUR

T1 - Regulation of adipogenesis by natural and synthetic REV-ERB ligands

AU - Kumar, Naresh

AU - Solt, Laura A.

AU - Wang, Yongjun

AU - Rogers, Pamela M.

AU - Bhattacharyya, Gargi

AU - Kamenecka, Theodore M.

AU - Stayrook, Keith R.

AU - Crumbley, Christine

AU - Floyd, Z. Elizabeth

AU - Gimble, Jeffrey M.

AU - Griffin, Patrick R.

AU - Burris, Thomas P.

PY - 2010/7/1

Y1 - 2010/7/1

N2 - The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbα expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-γ agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases.

AB - The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbα expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-γ agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases.

UR - http://www.scopus.com/inward/record.url?scp=77954577358&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954577358&partnerID=8YFLogxK

U2 - 10.1210/en.2009-0800

DO - 10.1210/en.2009-0800

M3 - Article

C2 - 20427485

AN - SCOPUS:77954577358

VL - 151

SP - 3015

EP - 3025

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 7

ER -