Altered Growth in Male Peroxisome Proliferator-Activated Receptor γ (PPARγ) Heterozygous Mice: Involvement of PPARγ in a Negative Feedback Regulation of Growth Hormone Action

Abstract

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.

IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation

“…Indeed, we showed in PPAR␥ ϩ/Ϫ mice that IL-13 and PPAR␥ ligand treatment induced only half of the increase of MR expression and reduced yeasts colonization of the GI tract less efficiently. As demonstrated by PCR and Western blot, PPAR␥ ϩ/Ϫ mice express half the PPAR␥ mRNA and protein compared with homozygous PPAR␥ ϩ/ϩ mice (46). This heterozygous model has already been used to study the physiological effects of PPAR␥ deficiency in mice, and, for example, to reveal the role of PPAR␥ in the therapeutic effects of 5-aminosalicylic acid as an anti-inflammatory drug used in bowel disease treatment (47).…”

Fat poetry: a kingdom for PPARγ

“…Interestingly, a mild reduction in PPAR activity, as seen above with the 12A in humans, or with a partial antagonist in mice, promotes insulin sensitivity. In mice it also decreases fat depots, and brings the metabolic parameters to the levels seen in PPARg heterozygous mice [73,178,180]. These heterozygous mice are partially protected from high-fat diet or mono sodium glutamate-induced weight gain and insulin resistance.…”

“…In a model of generalized PPARg ablation where embryonic lethality is prevented by preserving PPARg expression in trophoblasts, severe lipodystrophy, insulin resistance and hypotension, probably due to increased vascular relaxation, were observed [177]. On the contrary, the PPARg+/-heterozygous animals are viable and do not present any major defects except mild growth retardation in males, possibly due to a deregulation of growth hormone signaling in the WAT [178]. The PPARg+/-mice have normal insulin sensitivity under a standard diet.…”

The Pro12Ala and C–681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren

“…However, detailed mechanistic studies regarding PPARγ and growth have not been performed. The role of PPARγ as a regulator of growth has been established recently in pparg+/− mice, in which lean mass growth was reduced, and IGF-1 production in white adipose tissue was attenuated [25]. However, this study did not examine the possibility of altered growth hormone signalling in muscle or bone.…”