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Individual amino acids - hungry brain and mobile gut - Zurich Open Repository and Archive


Jordi, Josua Hannes. Individual amino acids - hungry brain and mobile gut. 2013, University of Zurich, Faculty of Science.

Abstract

In every living organism amino acids are pivotally important multifunctional molecules. Single amino acids drive mayor intracellular signaling pathways controlling growth and proliferation, and enable neuronal communication in the synaptic cleft. Apart from signaling, their oxidative break down in the citric acid cycle provides energy and metabolic substrates for the cell. When several single amino acids are covalently linked and correctly folded, they form a functional protein. This certainly describes one of the most important processes in biology. All these vital functions depend on the availability of amino acids. Not surprisingly, amino acid pools are maintained within a physiological range by complex regulatory feedback mechanisms – a process termed homeostasis. A homeostatic challenge is to refill the amino acid pools without perturbing amino acid homeostasis, which might cause severe side effects. The temporal regulation of transport protein expression may solve this problem in single cell organisms, whereas eating behavior has to be balanced with the homeostatic needs and the specific available nutrient source in higher species. How this is achieved is currently under active research, but little is known in the context of individual amino acids. One reason might be that ingested proteins are broken down to twenty different individual amino acids leading to large complexity. Not only do they differ in their chemical structure, but some are also nutritionally essential. We hypothesize that, based on these structural differences; they may have distinct roles in the control of food intake and gastrointestinal function. We systematically assessed the impact of all 20 individual proteogenic amino acids on food intake and gastric function. These two functional readouts are particularly relevant in the short-term regulation of nutrient intake. Food intake determines the maximal achievable intake of nutrients, and gastric function i.e. gastric emptying and secretion dictates the concentration and the timing of nutrient release into the small intestine. Both have a direct impact on plasma nutrient concentration and the timing of nutrient appearance in plasma. Here, we show that short-term food intake was most potently reduced by oral L-arginine, L-lysine and L-glutamic acid compared to all other 17 proteogenic amino acids in the rat. As feeding behavior is controlled by neuronal circuits located in specific brain areas, we tested for neuronal activity using immunohistochemistry after L-arginine, L-lysine and L-glutamic acid application. An increased number of cFOS positive cells were detected in the blood-sensing area postrema and the nucleus of the solitary tract. To test whether circulating amino acids can directly signal to the brain to induce their anorectic effect, we administered L-arginine, L-lysine and L-glutamic acid intravenously. All three amino acids induced an anorectic response that was similar to the one induced after oral application. Surgical lesion of the area postrema abolished the anorectic responses of L-arginine and L-glutamic acid but not of L-lysine. The nucleus of the solitary tract is the main projection site of the vagus nerve which innervates the gastrointestinal tract. Surgical lesion of vagal afferents did not alter the anorectic effect of L-arginine and L-glutamic acid but of L-lysine. We presume that L-arginine and L-glutamic acid act in the area postrema to cause their anorectic response, while L-lysine stimulates hepatic vagal afferents projecting to the nucleus of the solitary tract. Interestingly, in the gastrointestinal tract all three amino acids induced gastric distension. L-arginine and L-lysine induced gastric secretion detected by changes in the alkaline tide. Gastric emptying, measured by stomach phenol red retention, was delayed after L-lysine and L-glutamic acid treatment. At the level of the small intestine, L-arginine and L-lysine accelerated phenol red dye passage into the cecum. The gastrointestinal effects of L-lysine were shown to be dose dependent in the rat and were analogously observed in healthy human subjects. The highest L-lysine dose caused self-limiting diarrhea in humans, but no other side effects were reported. The gastrointestinal effect induced by L-arginine and L-lysine was dissociated from their effect on food intake and induced conditioned taste aversion in the rat. Hence, L-arginine, L-lysine and L-glutamic acid had a remarkable specific impact on mechanism important for food processing in the gastrointestinal tract and on food intake in rats and humans. This may suggest that they act as direct sensory input to assess dietary protein content and quality in vivo. Here, we show that L-cysteine, L-lysine, L-arginine and L-tryptophan most potently delayed gastric emptying and that L-arginine and L-lysine most potently stimulated gastric secretion compared to all other proteogenic amino acids in the rat. The systematic assessment of these two key stomach functions was only feasible, because we established and validated a quantitative non-invasive high-throughput computed tomography based method. This novel method can measure simultaneously gastric emptying and secretion in rats in vivo. Future efforts aim to assess if gastric secretion and emptying induced by the candidate amino acids are conducted by a shared control mechanism, to identify its localization and potential effector molecules i.e. gastrointestinal hormones. In conclusion, we revealed remarkable amino acid specificity for two critical nutritional functions, namely food intake and gastric function. The main question arising from this work is the cellular mechanism enabling the remarkable amino acid specificity. This might give insights into how individual amino acids contribute to the control of protein intake, and how protein quality is assessed at a molecular level.

Abstract

In every living organism amino acids are pivotally important multifunctional molecules. Single amino acids drive mayor intracellular signaling pathways controlling growth and proliferation, and enable neuronal communication in the synaptic cleft. Apart from signaling, their oxidative break down in the citric acid cycle provides energy and metabolic substrates for the cell. When several single amino acids are covalently linked and correctly folded, they form a functional protein. This certainly describes one of the most important processes in biology. All these vital functions depend on the availability of amino acids. Not surprisingly, amino acid pools are maintained within a physiological range by complex regulatory feedback mechanisms – a process termed homeostasis. A homeostatic challenge is to refill the amino acid pools without perturbing amino acid homeostasis, which might cause severe side effects. The temporal regulation of transport protein expression may solve this problem in single cell organisms, whereas eating behavior has to be balanced with the homeostatic needs and the specific available nutrient source in higher species. How this is achieved is currently under active research, but little is known in the context of individual amino acids. One reason might be that ingested proteins are broken down to twenty different individual amino acids leading to large complexity. Not only do they differ in their chemical structure, but some are also nutritionally essential. We hypothesize that, based on these structural differences; they may have distinct roles in the control of food intake and gastrointestinal function. We systematically assessed the impact of all 20 individual proteogenic amino acids on food intake and gastric function. These two functional readouts are particularly relevant in the short-term regulation of nutrient intake. Food intake determines the maximal achievable intake of nutrients, and gastric function i.e. gastric emptying and secretion dictates the concentration and the timing of nutrient release into the small intestine. Both have a direct impact on plasma nutrient concentration and the timing of nutrient appearance in plasma. Here, we show that short-term food intake was most potently reduced by oral L-arginine, L-lysine and L-glutamic acid compared to all other 17 proteogenic amino acids in the rat. As feeding behavior is controlled by neuronal circuits located in specific brain areas, we tested for neuronal activity using immunohistochemistry after L-arginine, L-lysine and L-glutamic acid application. An increased number of cFOS positive cells were detected in the blood-sensing area postrema and the nucleus of the solitary tract. To test whether circulating amino acids can directly signal to the brain to induce their anorectic effect, we administered L-arginine, L-lysine and L-glutamic acid intravenously. All three amino acids induced an anorectic response that was similar to the one induced after oral application. Surgical lesion of the area postrema abolished the anorectic responses of L-arginine and L-glutamic acid but not of L-lysine. The nucleus of the solitary tract is the main projection site of the vagus nerve which innervates the gastrointestinal tract. Surgical lesion of vagal afferents did not alter the anorectic effect of L-arginine and L-glutamic acid but of L-lysine. We presume that L-arginine and L-glutamic acid act in the area postrema to cause their anorectic response, while L-lysine stimulates hepatic vagal afferents projecting to the nucleus of the solitary tract. Interestingly, in the gastrointestinal tract all three amino acids induced gastric distension. L-arginine and L-lysine induced gastric secretion detected by changes in the alkaline tide. Gastric emptying, measured by stomach phenol red retention, was delayed after L-lysine and L-glutamic acid treatment. At the level of the small intestine, L-arginine and L-lysine accelerated phenol red dye passage into the cecum. The gastrointestinal effects of L-lysine were shown to be dose dependent in the rat and were analogously observed in healthy human subjects. The highest L-lysine dose caused self-limiting diarrhea in humans, but no other side effects were reported. The gastrointestinal effect induced by L-arginine and L-lysine was dissociated from their effect on food intake and induced conditioned taste aversion in the rat. Hence, L-arginine, L-lysine and L-glutamic acid had a remarkable specific impact on mechanism important for food processing in the gastrointestinal tract and on food intake in rats and humans. This may suggest that they act as direct sensory input to assess dietary protein content and quality in vivo. Here, we show that L-cysteine, L-lysine, L-arginine and L-tryptophan most potently delayed gastric emptying and that L-arginine and L-lysine most potently stimulated gastric secretion compared to all other proteogenic amino acids in the rat. The systematic assessment of these two key stomach functions was only feasible, because we established and validated a quantitative non-invasive high-throughput computed tomography based method. This novel method can measure simultaneously gastric emptying and secretion in rats in vivo. Future efforts aim to assess if gastric secretion and emptying induced by the candidate amino acids are conducted by a shared control mechanism, to identify its localization and potential effector molecules i.e. gastrointestinal hormones. In conclusion, we revealed remarkable amino acid specificity for two critical nutritional functions, namely food intake and gastric function. The main question arising from this work is the cellular mechanism enabling the remarkable amino acid specificity. This might give insights into how individual amino acids contribute to the control of protein intake, and how protein quality is assessed at a molecular level.

Additional indexing

Other titles:Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich
Item Type:Dissertation
Referees:Verrey F, Lutz T A, Wagner C A, Tomé Daniel
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:07 Nov 2013 12:45
Last Modified:05 Apr 2016 17:07
Number of Pages:145

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