Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure

被引:89
作者
Dali-Youcef, Nassim
Mataki, Chikage
Coste, Agnes
Messaddeq, Nadia
Giroud, Sylvain
Blanc, Stephane
Koehl, Christian
Champy, Marie-France
Chambon, Pierre
Fajas, Lluis
Metzger, Daniel
Schoonjans, Kristina
Auwerx, Johan
机构
[1] Univ Strasbourg 1, CNRS, Inst Natl St & Rech Med, Inst Genet & Biol Mol & Cellulaire Strasbourg, F-67404 Illkirch Graffenstaden, France
[2] Hop Univ Strasbourg, Lab Biochim Gen & Specialisee, F-67098 Strasbourg, France
[3] CNRS, UMR 7178, Dept Ecol Physiol & Ethol, Inst Pluridisciplinaire Hubert Curien, F-67087 Strasbourg 02, France
[4] Univ Strasbourg, F-67087 Strasbourg 02, France
[5] Inst Clin Souris, F-67404 Illkirch Graffenstaden, France
[6] Ctr Reg Lutte Contre Canc Val Aurelle, Metab & Canc Lab, F-34298 Montpellier 05, France
关键词
brown adipose tissue; mitochondria; pocket proteins; obesity;
D O I
10.1073/pnas.0611568104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro. We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure. This protection against weight gain was caused by the activation of mitochondrial activity in white and brown fat as evidenced by histologic, electron microscopic, and gene expression studies. Moreover, pRb(-/-) mouse embryonic fibroblasts displayed higher proliferation and apoptosis rates than pRb(+/+) mouse embryonic fibroblasts, which could contribute to the altered white adipose tissue morphology. Taken together, our data support a direct role of pRb in adipocyte cell fate determination in vivo and suggest that pRb could serve as a potential therapeutic target to trigger mitochondrial activation in white adipose tissue and brown adipose tissue, favoring an increase in energy expenditure and subsequent weight loss.
引用
收藏
页码:10703 / 10708
页数:6
相关论文
共 36 条
[11]   Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation [J].
Hansen, JB ;
Jorgensen, C ;
Petersen, RK ;
Hallenborg, P ;
De Matteis, R ;
Boye, HA ;
Petrovic, N ;
Enerbäck, S ;
Nedergaard, J ;
Cinti, S ;
te Rielet, H ;
Kristiansen, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (12) :4112-4117
[13]   The block of adipocyte differentiation by a C-terminally truncated, but not by full-length, simian virus 40 large tumor antigen is dependent on an intact retinoblastoma susceptibility protein family binding domain [J].
Higgins, C ;
Chatterjee, S ;
Cherington, V .
JOURNAL OF VIROLOGY, 1996, 70 (02) :745-752
[14]   Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor α mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes [J].
Imai, T ;
Jiang, M ;
Chambon, P ;
Metzger, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (01) :224-228
[15]   EFFECTS OF AN RB MUTATION IN THE MOUSE [J].
JACKS, T ;
FAZELI, A ;
SCHMITT, EM ;
BRONSON, RT ;
GOODELL, MA ;
WEINBERG, RA .
NATURE, 1992, 359 (6393) :295-300
[16]   EFFICIENT GENE ACTIVATION IN MAMMALIAN-CELLS BY USING RECOMBINANT ADENOVIRUS EXPRESSING SITE-SPECIFIC CRE RECOMBINASE [J].
KANEGAE, Y ;
LEE, G ;
SATO, Y ;
TANAKA, M ;
NAKAI, M ;
SAKAKI, T ;
SUGANO, S ;
SAITO, I .
NUCLEIC ACIDS RESEARCH, 1995, 23 (19) :3816-3821
[17]   Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α [J].
Lagouge, Marie ;
Argmann, Carmen ;
Gerhart-Hines, Zachary ;
Meziane, Hamid ;
Lerin, Carles ;
Daussin, Frederic ;
Messadeq, Nadia ;
Milne, Jill ;
Lambert, Philip ;
Elliott, Peter ;
Geny, Bernard ;
Laakso, Markku ;
Puigserver, Pere ;
Auwerx, Johan .
CELL, 2006, 127 (06) :1109-1122
[18]   MICE DEFICIENT FOR RB ARE NONVIABLE AND SHOW DEFECTS IN NEUROGENESIS AND HEMATOPOIESIS [J].
LEE, EYHP ;
CHANG, CY ;
HU, NP ;
WANG, YCJ ;
LAI, CC ;
HERRUP, K ;
LEE, WH ;
BRADLEY, A .
NATURE, 1992, 359 (6393) :288-294
[19]   Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells [J].
Lefebvre, AM ;
Paulweber, B ;
Fajas, L ;
Woods, J ;
McCrary, C ;
Colombel, JF ;
Najib, J ;
Fruchart, JC ;
Datz, C ;
Vidal, H ;
Desreumaux, P ;
Auwerx, J .
JOURNAL OF ENDOCRINOLOGY, 1999, 162 (03) :331-340
[20]   Nuclear receptor corepressor RIP140 regulates fat accumulation [J].
Leonardsson, G ;
Steel, JH ;
Christian, M ;
Pocock, V ;
Milligan, S ;
Bell, J ;
So, PW ;
Medina-Gomez, G ;
Vidal-Puig, A ;
White, R ;
Parker, MG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (22) :8437-8442