2006 - (Nutritional protein and obesity.
The importance of glutamate in the regulation of appetite)
4. SGA-/IUGR-Workshop 24.-25.2.2006 Homburg/Saar
Risiken für das cardio-pulmo-reno-vasculäre System
bei Mangelgeborenen (Small for Gestational Age-Syndrom (SGA)
bzw. Intrauteriner Wachstumshemmung (IUGR)
Michael Hermanussen 1, JAF Tresguerres 2 .
1 Aschauhof, Germany, 2 Madrid, Spain.
World-wide obesity has risen to alarming levels. The average weight of German conscripts now increases by almost 400 g/year.
Similar data were obtained in Austria, Norway and the UK. The rising prevalence of obesity coincides with a rising popularity of protein-rich diets.
On average, Germans consume meat at 100 kg/year.
Children eat some threefold more protein than recommended; infants of 6 to 12 months receive daily up to 5 g/kg body weight of protein.
We hypothesised that it is not the protein, but the amino acid glutamate that determines the propensity of obesity.
The regulation of appetite relies on complex hypothalamic neurocircuitry of which the AN, and the hormone leptin play important roles.
AN neurones can be intoxicated by elevated serum levels of the amino acid glutamate (GLU).
Hyperglutamataemia can disrupt the hypothalamic signalling cascade of leptin action, causing voracity, obesity and hyperleptinaemia.
Hyperleptinaemia also exerts sympathetic effects including blood pressure elevation that are mediated via mechanisms different from the hypothalamic system, and other symptoms of the ‘metabolic syndrome’.
This may happen even before birth when in small-for-gestational-age foetuses with impaired umbilical plasma flow, foetal hyperglutamataemia induces AN damage followed by later impairment of feeding regulation, hyperleptinaemia and symptoms that characterise the ‘thrifty phenotype’.
The neurotoxic effects of GLU are mediated by the N-methyl-D-aspartate receptor (NMDA-R) .
But they can be prevented.
Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent non-competitive NMDA-R antagonist, antagonises GLU-gated Ca2+ ion channels, protects AN neurones, and thereby completely prevents the adverse effects of GLU in laboratory animals.
Also the non-competitive NMDA-R antagonist memantine displays neuroprotective properties.
In view of the hypothesis that human obesity results from chronic over-consumption of GLU, we performed a therapeutic trial in five obese, but otherwise healthy women.
Memantine treatment markedly decreased appetite within few hours and complete suppressed the binge-eating disorder within 24 hours. Body weight decreased by 7 to 15 kg within two months.
The findings strongly support the hypothesis that elevated levels of nutritional GLU play an important role in the pathomechanism of human obesity.
We suggest abandoning the flavouring agent monosodium glutamate and reconsidering the recommended daily allowances of protein and amino acids, and if necessary treating human obesity by protecting the hypothalamic signalling cascade of leptin action with low to moderate affinity, non-competitive NMDA-R antagonists that selectively block the GLU-gated Ca2+ ion channels.
update: 25.10.2005
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