Download The Gut Hormone Peptide YY3-36 (PYY3

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.
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