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Inge Seim, Amy A Lubik, Melanie L Lehman, Nadine Tomlinson, Eliza J Whiteside, Adrian C Herington, Colleen C Nelson, and Lisa K Chopin

Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.

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S-M Luoh, F Di Marco, N Levin, M Armanini, M-H Xie, C Nelson, G L Bennett, M Williams, S A Spencer, A Gurney, and F J de Sauvage


Leptin, the product of the ob gene, is a hormone secreted by fat cells which is primarily involved in the regulation of body weight. We have generated a leptin immunoadhesin (leptin-IgG) which was more potent than leptin alone at reducing body weight and food intake when injected into ob/ob mice. This molecule was used to identify high affinity binding sites on human embryonic 293 kidney cells and subsequently to isolate a cDNA encoding the leptin receptor from this cell line by expression cloning. This receptor corresponds to the short form of the recently isolated leptin receptor. Analysis of the expression pattern of the two forms of receptor by Northern blot, in situ hybridization and quantitative PCR showed that the receptor is expressed in most tissues but that the long form is prevalent in the hypothalamus.