Altered growth in male peroxisome proliferator-activated receptor gamma (PPARgamma) heterozygous mice: involvement of PPARgamma in a negative feedback regulation of growth hormone action.
The peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPARgamma allele has been mutated reveals that male PPARgamma heterozygous (PPARgamma +/-) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARgamma- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARgamma +/- mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARgamma +/- mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARgamma +/- mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARgamma in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARgamma mutant mice.
Rieusset
Jennifer
J
Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Seydoux
Josiane
J
Anghel
Silvia I
SI
Escher
Pascal
P
Michalik
Liliane
L
Soon Tan
Nguan
N
Metzger
Daniel
D
Chambon
Pierre
P
Wahli
Walter
W
Desvergne
Béatrice
B
D000818:Animals; D001483:Base Sequence; D001823:Body Composition; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005246:Feedback; D006128:Growth / Q000235:genetics / Q000502:physiology; D013006:Growth Hormone / Q000502:physiology*; D006579:Heterozygote; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
D017931:DNA Primers; D007328:Insulin; D047495:PPAR gamma; D013006:Growth Hormone; D004247:DNA