Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.
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.
Dali-Youcef
Nassim
N
Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Louis Pasteur, 1 Rue Laurent Fries, BP 10142, 67404 Illkirch, France.
Mataki
Chikage
C
Coste
Agnès
A
Messaddeq
Nadia
N
Giroud
Sylvain
S
Blanc
Stéphane
S
Koehl
Christian
C
Champy
Marie-France
MF
Chambon
Pierre
P
Fajas
Lluis
L
Metzger
Daniel
D
Schoonjans
Kristina
K
Auwerx
Johan
J
D002001:Adipose Tissue, Brown / Q000502:physiology* / Q000648:ultrastructure; D052436:Adipose Tissue, White / Q000502:physiology* / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D049109:Cell Proliferation; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D005347:Fibroblasts / Q000502:physiology; D015870:Gene Expression; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000517:prevention & control*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D004272:DNA, Mitochondrial; D004041:Dietary Fats; D016160:Retinoblastoma Protein