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Introduction Spaceflight is associated with numerous environmental changes including microgravity, extreme temperature fluctuation, intense UV radiation, and a nearly absolute vacuum. Space travelers experience anorexia and body weight loss in [...], Space travelers experience anorexia and body weight loss in a microgravity environment, and microgravity-like situations cause changes in hypothalamic activity. Hypothalamic melanocortins play a critical role in the regulation of metabolism. Therefore, we hypothesized that microgravity affects metabolism through alterations in specific hypothalamic signaling pathways, including melanocortin signaling. To address this hypothesis, the microgravity-like situation was produced by an antiorthostatic tail suspension in wild-type and agouti mice, and the effect of tail suspension on energy expenditure and hypothalamic gene expression was examined. Energy expenditure was measured using indirect calorimetry before and during the tail suspension protocol. Hypothalamic tissues were collected for gene expression analysis at the end of the 3 h tail suspension period. Tail suspension significantly increased oxygen consumption, carbon dioxide production, and heat production in wild-type mice. Tail suspension-induced increases in energy expenditure were not attenuated in agouti mice. Although tail suspension did not alter hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AGRP) mRNA levels, it significantly increased hypothalamic interleukin 6 (Il-6) mRNA levels. These data are consistent with the hypothesis that microgravity increases energy expenditure and suggest that these effects are mediated through hypothalamic signaling pathways that are independent of melanocortins, but possibly used by II-6. Key words: obesity, energy expenditure, hypothalamus, melanocortin, brown adipose tissue, microgravity, tail suspension, mouse. Les voyageurs spatiaux souffrent d'anorexie et subissent une perte de poids dans un environnement en microgravite, et les situations microgravitaires modifient l'activite hypothalamique. Les melanocortines hypothalamiques jouent un role essentiel dans la regulation du metabolisme. Ainsi, nous avons eemis l'hypothese que les situations microgravitaires influent sur le metabolisme en induisant des modifications dans des voies de signalisation hypothalamiques specifiques, y compris celle des melanocortines. Pour verifier cette hypothese, nous avons simule la situation microgravitaire par une suspension antiorthostatique chez des souris, et nous avons examine l'effet d'une suspension par la queue sur la depense energetique et l'expression genique hypothalamique chez des souris agouti de type sauvage. Nous avons mesure la depense energetique par calorimeetrie, avant et durant le protocole de suspension par la queue. A la fin de la peeriode de suspension de 3 h, nous avons preleve des tissus hypothalamiques pour analyser l'expression genique. La suspension par la queue a augmente significativement la consommation d'oxygene, la production de dioxyde de carbone et la production de chaleur chez les souris de type sauvage. Les augmentations de la depense energetique induites par la suspension caudale n'ont pas diminue chez les souris agouti. La suspension par la queue n'a pas modifie les taux d'ARNm de la proteine associeea l'agouti (AGRP) et de la proopiomelanocortin (POMC) dans l'hypothalamus, mais elle a augmente; de facon significative les taux d'ARNm de l'interleukine 6 (Il-6). Ces resultats confortent l'hypothese que la microgravite augmente la depense energetique et permettent de presumer que ces effets sont vehicules par des voies de signalisation hypothalamiques indeependantes des melanocortines, mais probablement utilisees par l'Il-6. Mots-cles: obesite, deepense energetique, hypothalamus, melanocortine, tissu adipeux brun, microgravite;, suspension par la queue, souris. [Traduit par la Redaction]

Large geographical variations exist in the incidence of clinical prostate cancer whereas the incidence microfocal disease is essentially constant worldwide. Dietary fat is implicated in this marked difference in the progression of latent cancers. A putative effector is the peroxisome proliferator-activated receptor gamma (PPAR[Gamma]), a nuclear transcription factor that is elevated in human prostate cancers. Activation of PPAR[Gamma] in late-stage human prostate cancer cell lines and tumor tissue leads to cell death; however, the role of PPAR[Gamma] in early progression of prostatic intraepithelial neoplasia (PIN) to invasive carcinoma is unknown and difficult to study in human subjects. To address early events in tumorigenesis, we have established a transgenic mouse model for prostate cancer (designated LPB-Tag) in which progression of PIN-like lesions can be assessed by histology and known biomarkers, including secreted proteins that reflect the differentiation state of the prostatic epithelium. As in human prostate tumors, PPAR[Gamma] expression in the LPB-Tag tumor model is highly elevated relative to normal prostate tissue. Both PPAR[Gamma]1 and [Gamma]2 isoforms are present; PPAR[Gamma]2 increases markedly with tumor progression, suggesting a mechanism for altered gene expression in the tumors. PPAR[Gamma] levels are enhanced after androgen ablation and suppressed by androgen replacement in both normal prostate and tumors. Oral administration of thiazolidinediaone to activate PPAR[Gamma] alters the isoform profile of PPAR[Gamma] and tumor growth and differentiation. These preliminary data suggest that progression of premalignant lesions to invasive cancer may be altered by interventions targeted to PPAR[Gamma]. Even modest changes in the rate of progression could result in substantial reductions in the incidence of clinically relevant prostate cancer.

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