Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue

被引：166

作者：

Kiefer, Florian W. ^{[1
]}

Vernochet, Cecile ^{[2
]}

O'Brien, Patrick ^{[1
]}

Spoerl, Steffen ^{[1
]}

Brown, Jonathan D. ^{[1
]}

Nallamshetty, Shriram ^{[1
]}

Zeyda, Maximilian ^{[3
,4
]}

Stulnig, Thomas M. ^{[3
,4
]}

Cohen, David E. ^{[5
]}

Kahn, C. Ronald ^{[2
]}

Plutzky, Jorge ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA

[3] Christian Doppler Lab Cardiometab Immunotherapy, Vienna, Austria

[4] Med Univ Vienna, Dept Med, Clin Div Endocrinol & Metab, Vienna, Austria

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02115 USA

来源：

NATURE MEDICINE | 2012年 / 18卷 / 06期

基金：

美国国家卫生研究院; 奥地利科学基金会;

关键词：

RETINOIC ACID; BROWN FAT; RECEPTOR ANTAGONISTS; OBESITY; MICE; ADIPOGENESIS; METABOLISM; RECRUITMENT; HOMEOSTASIS; ADIPOCYTES;

D O I：

10.1038/nm.2757

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1 alpha and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.

引用

页码：918 / +

页数：10

共 48 条

[1] RAR and RXR modulation in cancer and metabolic disease [J].

Altucci, Lucia ;

Leibowitz, Mark D. ;

Ogilvie, Kathleen M. ;

de Lera, Angel R. ;

Gronemeyer, Hinrich .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (10) :793-810

[2] A NOVEL REGULATORY PATHWAY OF BROWN FAT THERMOGENESIS - RETINOIC ACID IS A TRANSCRIPTIONAL ACTIVATOR OF THE MITOCHONDRIAL UNCOUPLING PROTEIN GENE [J].

ALVAREZ, R ;

DEANDRES, J ;

YUBERO, P ;

VINAS, O ;

MAMPEL, T ;

IGLESIAS, P ;

GIRALT, M ;

VILLARROYA, F .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (10) :5666-5673

[3] 2'-O-(2-methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells [J].

Baker, BF ;

Lot, SS ;

Condon, TP ;

ChengFlournoy, S ;

Lesnik, EA ;

Sasmor, HM ;

Bennett, CF .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (18) :11994-12000

[4] Epidemiology, trends, and morbidities of obesity and the metabolic syndrome [J].

Bray, GA ;

Bellanger, T .

ENDOCRINE, 2006, 29 (01) :109-117

[5] VLDL Hydrolysis by Hepatic Lipase Regulates PPARδ Transcriptional Responses [J].

Brown, Jonathan D. ;

Oligino, Eric ;

Rader, Daniel J. ;

Saghatelian, Alan ;

Plutzky, Jorge .

PLOS ONE, 2011, 6 (07)

[6] Brown adipose tissue: Function and physiological significance [J].

Cannon, B ;

Nedergaard, J .

PHYSIOLOGICAL REVIEWS, 2004, 84 (01) :277-359

[7] Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells [J].

Chute, John P. ;

Muramoto, Garrett G. ;

Whitesides, John ;

Colvin, Michael ;

Safi, Rachid ;

Chao, Nelson J. ;

McDonnell, Donald P. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (31) :11707-11712

[8] Between brown and white: Novel aspects of adipocyte differentiation [J].

Cinti, Saverio .

ANNALS OF MEDICINE, 2011, 43 (02) :104-115

[9] Progress in antisense technology [J].

Crooke, ST .

ANNUAL REVIEW OF MEDICINE, 2004, 55 :61-95

[10] Brown fat as a therapy for obesity and diabetes [J].

Cypess, Aaron M. ;

Kahn, C. Ronald .

CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY, 2010, 17 (02) :143-149

← 1 2 3 4 5 →