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MEDICAL RESEARCH SOCIETY Communications for the Spring Meeting of the Medical Research Society on 5* February 2003 at the Royal College of Physicians, London MRS Communications: Wednesday 5* February 2003 Y1 - Y 6 M1 - M181 Spoken presentations Poster presentations Y1 Y2 Identification of mutations in the fumarate hydratase gene in the multiple cutaneous and uterine leiomyomatosis and renal carcinoma syndrome The gut hormone peptide W3.=(PYYss) regulates appetite in normal and overweight volunteers R. L. Batterham*, M. A. Cowley§, H. IIerzog 1, M. A. Cohen*, M. J. Low& M. A. Ghatei*, & S. R. Bloom* Dr N A Alam, D r I P M Tomlinson *Imperial College Faculty of Medicine at Hammersmith Campus, Du Cane Road, London, W12 ONN, UK. §The Vollurn Institute, Oregon Health and Sciences University, 3181 SW Sam Jackson P a r k Rd, Portland O R 97201,USA. Neurobiology Program, Garvan Institute of Medical Research, 384 Victoria Street Darlinghurst, NSW 2010, Sydney, Australia. Molecular and Population Genetics Laboratory, Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX Uterine fibroids, or leiomyomata, arc the most common turnours in women during the reproductive years and represent a significant health issue, yet little is known about their pathogenesis. We mapped a predisposition gene for multiple fibroids, cutaneous leiomyomata and renal carcinoma to chromosome lq42.3-q43 and refined the region of the gene by mapping critical recombinants and using FISH in patients with germline deletions. We identified heterozygous germline mutations in the fumarate hydratase (FH)gene, which codes for a component of the Kreb’s cycle, in 35 of 47 probands. Mutations resulted in truncated protein, aberrantly spliced transcripts, or substitutions or deletions of highly conserved amino acids. We carried out a functional assay of FH enzyme activity which showed reduced activity in lymphoblastoid cells from leiomyomatosis patients. We confirmed that FH acts as a tumour suppressor in familial leiomyomata, with loss of heterozygosity being the commonest ‘second hit’. Homozygous FH mutations have been reported in the autosomal recessive inborn error of metabolism, fumarase deficiency. We identified previously unreported leiomyomata in parents of FH deficiency patients. We collected detailed clinicopathological information on107 patients with multiple leiomyomatosis. FH mutations were found to be highly penetrant with affected females developing severely symptomatic fibroids requiring early hysterectomy. Fibroids were histologically indistinguishable from typical sporadic fibroids. Renal cell carcinoma and uterine leiomyosarcoma were uncommon associations. Evidence of FH dysfunction was found in almost all patients suggesting that this may be a genetically homogeneous condition. Thus, patients with skin leiomyomata should be screened for FH mutation and, if female, for uterine fibroids. Similarly, females presenting with fibroids, should be examined for skin leiomyomata. These results provide important clues about the pathogenesis of fibroids and renal cancers, and emphasise the role of housekeeping and mitochondria1 proteins in tumorigenesis. The hypothalamic arcuate nucleus is a key brain area regulating appetite. Activation of arcuate neuropeptide Y (NPY) neurons increases food intake, whereas activation of arcuate proopiomelanocortin (POMC) neurons decreases food intake. These two neuronal subsets act as sensors, responding to circulating hormones, such as leptin, that reflect body energy stores. However, the identity of peripheral factors signalling food ingestion to these feeding circuits remains largely unclear. The NPY Y2 receptor is an inhibitory auto-receptor highly expressed on arcuate NPY neurons. PeptideYY3.36 (PYY3.)6), a Y2 receptor agonist, is released from the gut postprandially in proportion to meal calorie content. Thus PYY,. 36 is a candidate hormone signalling food intake from the gut to the brain. We examined the effects of PYY3.36 on feeding behaviour in rodents. Peripheral administration of PYY3.36 mimicking postprandial levels inhibited food intake and repeated administration decreased body weight gain. Direct intra-arcuate PYY3.36 injection also reduced food intake. However, Y2 receptor knockout mice were resistant to the anorectic effect of PYY3.36 suggesting that PYY3.36 acts via the Y2 receptor. Peripheral PYY3.36 increased c-Fos expression in arcuate POMC neurons and electrophysiological studies revealed that PYY3. 36 inhibited NPY neurons and activated POMC. To study the physiological role of PYY3.36. in man we infused normal postprandial concentrations of PYY3.36 to 12 healthy normal weight volunteers. PYY3.36 infusion significantly decreased appetite and reduced food intake by 33.7 It 7.4% over 24 hours. To assess the potential role of PYY3.36 as an obesity treatment we infused 12 healthy overweight subjects with PYY3.36 Appetite and food intake were reduced in all 12 obese subjects (24 hr food intake; saline = 3341 f 401 kcal VS. PYY3.36= 2534 +I95 kcal, P<o.o1). These findings suggest that the gut hormone PYY3.36 acts via the Y2 receptor in the arcuate nucleus to regulate food intake in rodents and man. The responsiveness of obese subjects to the anorectic effects of PYY3.36 suggests that it may be a potential treatment for obesity. 1P