Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice.
Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. Rb(+/-) mice had body weight and adiposity indistinguishable from that of wild-type (Rb(+/+)) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, Rb(+/-) mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)gamma as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, Rb(+/-) mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPARalpha in liver and of PPARdelta in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances.
Laboratory of Molecular Biology, Nutrition, and Biotechnology, Universitat de les Illes Balears, Cra. Valldemossa Km 7.5, 07122 Palma de Mallorca, Spain.
Josep
J
Mercader
Joan
J
Ribot
Incoronata
I
Murano
Søren
S
Feddersen
Saverio
S
Cinti
Lise
L
Madsen
Karsten
K
Kristiansen
M Luisa
ML
Bonet
Andreu
A
Palou
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D007333:Insulin Resistance / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D001786:Blood Glucose; D004041:Dietary Fats; D016160:Retinoblastoma Protein