[Abstract unavailable

In adipose, muscle, liver and macrophages, signaling by the nuclear receptor PPARγ is a determinant of insulin sensitivity and this receptor mediates the insulin–sensitizing effects of thioazolidinediones (TZDs)1-4. Since PPARγ is also expressed in neurons5, we generated mice with neuron–specific Pparγ knockout (Pparγ BKO) to determine whether neuronal PPARγ signaling contributes to either weight gain or insulin resistance. During high fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparγ BKO mice, resulting in reduced weight gain. When treated with the TZD rosiglitazone, Pparγ BKO mice were resistant to rosiglitazone–induced hyperphagia and weight gain and, relative to rosiglitazone–treated controls, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the effect of rosiglitazone treatment to increase hepatic insulin sensitivity during HFD feeding was completely abolished in Pparγ BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPARγ signaling to limit thermogenesis and increase food intake. Neuronal PPARγ signaling is also required for the hepatic insulin sensitizing effects of TZDs.

Mutations in the bone morphogenetic protein 15 (BMP-15) gene cause female infertility in the monoovulatory human and sheep; however, in the polyovulatory mouse, loss-of-function of BMP-15 results only in reduced ovulation rate. To elucidate the cause of these species-specific differences, we investigated the functional role of BMP-15 in the mouse ovary. Here, we found that the functional mature form of BMP-15 is barely detectable in the mouse oocytes until just before ovulation, when it is markedly increased. Further, we found that BMP-15 induces cumulus expansion in mouse cumulus-oocyte complexes. The oocyte culture medium from immature mice primed with pregnant mare serum gonadotropin followed by human chorionic gonadotropin also stimulated cumulus expansion, and this activity was attenuated by BMP-15 antibody. Interestingly, the oocyte culture medium from mice treated with pregnant mare serum gonadotropin alone had no effect. Moreover, BMP-15 stimulated the expression of EGF-like growth factors in cumulus cells as well as a series of molecules downstream of EGF-like growth factor signaling, including cyclooxygenase 2, hyaluronan synthase 2, tumor necrosis factor-stimulated gene 6, and pentraxin 3, all of which are necessary for normal cumulus expansion. An antagonist of the EGF receptor completely abolished the effect of BMP-15 in inducing cumulus expansion. These results are consistent with the phenotype of BMP-15-null mice, which exhibit normal folliculogenesis but have defects in the ovulation process. The species-specific differences in the phenotypes caused by BMP-15 mutations may thus be attributed to the temporal variations in the production of the mature form of BMP-15.bone morphogenetic protein ͉ cumulus expansion enabling factor ͉ oocyte ͉ ovary ͉ ovulation ͉ folliculogenesis B one morphogenetic protein 15 (BMP-15) is an oocyte-specific growth factor that plays a crucial role in determining ovulation quota in mammals (1). Genetic studies have shown that mutations in the Bmp15 gene in ewes cause increased ovulation rates and fertility in heterozygotes, yet infertility in the homozygous carriers (2, 3). Studies by our laboratory have shown that these mutations are manifested through defects in the processing of the proproteins of the factors (4, 5). A recent study has shown that a mutation in the Bmp15 gene also causes infertility in humans (6), demonstrating a similar critical role of BMP-15 for fertility in women. Importantly, because this mutation occurs in the proregion of the BMP-15 protein, rather than in the functional mature region, the human BMP-15 mutation must be manifested by causing a defect in the posttranslational processing of the human BMP-15 proprotein, similar to the mutations in sheep (4, 5). However, in contrast to monoovulatory ewes and humans, BMP-15 does not seem to be necessary for folliculogenesis in the polyovulatory mouse (7). Specifically, BMP-15-null mice exhibit no obvious defects in folliculogenesis, completing all stages of follicle development and having multiple corp...

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