Summary Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this paper, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr−/− mice have reduced fat and preserve a healthier lipid profile. Old Ghsr−/− mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below detection in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues, but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline of thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin’s effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. GHS-R antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.

In the mouse, there is a large family of paralogous genes closely related to PRL. The objective of this report was to investigate the organization of the mouse PRL gene family locus. PRL family genes reside on chromosome 13 of the mouse genome. The PRL gene family members were localized to a series of overlapping bacterial artificial chromosome clones and arranged based on structural relationships. Additionally, several new members of the PRL gene family were identified. Placental lactogen I (PL-I) was found to be encoded by three closely related (>98% exon sequence identity) contiguous genes (termed: PL-Ialpha, PL-Ibeta, and PL-Igamma). Two previously unidentified mouse orthologs for members of the rat PRL family, PRL-like protein-I (PLP-I) and PLP-K were discovered, as were two new members of the PLP-C subfamily, PLP-Cgamma and PLP-Cdelta, and two new entirely unique members of the PRL family, PLP-N and PLP-O. Amino acid sequences predicted from the latter two genes most closely resembled proliferin-related protein. Each of the nine newly discovered genes is expressed in trophoblast cells of the mouse placenta in a gestationally specific pattern. In summary, elucidation of the mouse PRL gene family locus provides new insights into the expansion of the mouse PRL family and new tools for studying the genetics and biology of its members.

The TMPRSS2/ERG (T/E) fusion gene is present and thought to be an oncogenic driver of approximately half of all prostate cancers. Fusion of the androgen-regulated TMPRSS2 promoter to the ERG oncogene results in constitutive high level expression of ERG which promotes prostate cancer invasion and proliferation. Here, we report the characterization of multiple alternatively spliced T/E fusion gene isoforms which have differential effects on invasion and proliferation. We found that T/E fusion gene isoforms differentially increase NF-kBmediated transcription, which may explain in part the differences in biological activities of the T/E fusion isoforms. This increased activity is due to phosphorylation of NF-kB p65 on Ser536. Tissue microarray immunochemistry revealed that p65 phospho-Ser536 is present in the majority of prostate cancers where it is associated with ERG protein expression. The T/E fusion gene isoforms differentially increase expression of a number of NF-kB associated genes including PAR1, CCL2, FOS, TLR3, and TLR4 (Toll-like receptor). TLR4 activation is known to promote p65 Ser536 phosphorylation and knockdown of TLR4 with shRNA decreases Ser536 phosphorylation in T/E fusion gene expressing cells. TLR4 can be activated by proteins in the tumor microenvironment and lipopolysacharide from Gram (À) bacteria. Our findings suggest that bacterial infection of the prostate and/or endogenous microenvironment proteins may promote progression of high-grade prostatic intraepithelial neoplasia and/or prostate cancers that express the T/E fusion gene, where the NFkB pathway might be targeted as a rational therapeutic approach. Cancer Res; 71(4); 1325-33. Ó2010 AACR.