Hepatic portal vein deafferentation has no effect on the satiating effect of a high protein diet in rats

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Pre-absorptive signals specifically induced by protein ingestion

Ingestion of a high protein diet leads to an increase in gastric volume and a delay in gastric emptying (Bowen et al. 2006b; Faipoux et al. 2006). Gastric distension was demonstrated to participate in meal termination by activating vagal afferent fibres (Schwartz et al. 1991; Phillips and Powley 1996, 1998). Rats with a pyloric cuff terminate their food intake as soon as they reach a certain volume (10-12 ml), independent from the sort of nutrient. In rats that have no pyloric cuff, meal termination occurs after ingestion of an even smaller volume as nutrients can leak into the intestine and stimulate the release of CCK. CCK in turn slows down gastric emptying and maintains gastric distension for longer what leads to meal termination after a smaller meal size (Raybould 1991; Schwartz et al. 1991; Schwartz et al. 1993; Schwartz et al. 1997). However, some studies suggest that the caloric value of the ingested meal is the determining factor for gastric emptying rather than the nature of the nutrients (McHugh and Moran 1979; Maerz et al. 1994).
Electrophysiological studies demonstrated that protein is able to generate pre-absorptive signals in vagal afferents (L’Heureux-Bouron et al. 2004). Also gastric or intestinal distension was shown to stimulate certain afferent fibres. However, vagal response to duodenal infusion with amino acids or protein was delayed by 3 minutes, suggesting that Daily energy intakes (left panel) and body weight (right panel) of rats fed either a 14 g/100 g protein diet (P14), a 50 g/100 g protein diet (P50) or a 14 g/100 g protein diet pair-fed to the P50 group in energy (P14-pf) for 21 days. Values are means ± SEM, n=24. *P50 value is different from P14, P < 0.05. From d 1 to 21, the P14 rats consumed more energy than the P50 and the P14-pf rats. Additionally, during this period, the P50 rats consumed more protein energy than the rats from the other groups. There was no difference between the body weights of the P14-pf rats and P50 rats (Jean et al. 2001).

Scientific background 

these nutrients do not directly stimulate the intestinal sensory endings of vagus nerve. They are rather activated indirectly, for instance by the release of CCK. Moreover, parts of the hydrolysates might have been absorbed and lead to stimulation of hepatic afferent fibres.
Depression of food intake in response to a high protein diet can hence be explained by a larger gastric volume due to higher water intake as well as delay of gastric emptying and an amplification of vagal signalling in response to an increased release of CCK.

Post-absorptive peripheral signals

Additional to the pre-absorptive signals emerging during the passage of nutrients in the intestinal lumen, post-absorptive signals occur when nutrients or their metabolites enter the blood stream. Numerous metabolic events have also been hypothesised as signals in protein-induced satiety, including an increase in plasma amino-acid level, energy expenditure, thermogenesis and the production of glucose through gluconeogenesis.

Direct sensing of dietary protein

After the nutrient breakdown and absorption, the increase in circulating amino acids levels is detected by the brain and influence in this way satiety (Mellinkoff et al. 1956). Studies in rats have shown that replacing a normal protein diet with a high protein diet, animals immediately decrease their food intake (Figure 1.5). This depression in food intake has been demonstrated not to be due to a taste aversion to the protein diet, but indeed due to the protein content (Bensaid et al. 2002; Bensaid et al. 2003). Additionally a massive increase in the amino acid concentration could be detected in the first hours of a high protein diet which went back to baseline after adaptation to the new diet (Peters and Harper 1985, 1987). Together with the decrease in blood amino acid concentration, the protein induced satiety signalling becomes weaker (Long et al. 2000).
There is also some evidence that circulating leucine levels may influence food intake. An increase in dietary leucine (Ropelle et al. 2008) or the intra-cerebroventricular administration of either amino acids or only leucine reduced food intake and body weight (Cota et al. 2006; Morrison et al. 2007). These findings seem to be leucine-specific, as leucine alone exerts the same effect on food intake as a mixture of amino acids (Ropelle et al. 2008). Indeed, leucine is associated with mechanisms involving AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR), both of which are energy sensors active in the regulation of energy intake, at least in the arcuate nucleus (ARC) but probably also in other brain areas such as the paraventricular nucleus (PVN).
It was suggested that not only the amino acids themselves act on brain satiety centres, but they stimulate the synthesis of the neurotransmitter 5-HT which is derived from the amino acid tryptophan (Latham and Blundell 1979). Nowadays this hypothesis has been abandoned (Harper and Peters 1989; Stubbs 1999). Still, other amino acids such as tyrosine and histidine are precursors of the neurotransmitters noradrenalin and histamine, respectively which can then indirectly influence hunger and satiety (Mercer et al. 1990). However, Bassil failed to demonstrate any effect of a diet supplemented with 5 % of either histidine or tyrosine on the levels of food intake by Sprague-Dawley rats (Bassil et al. 2007).

Glucose-mediated sensing of dietary protein

Blood glucose is not only detected by glucosensitive cells in the hypothalamus (Fioramonti et al. 2007) and the NTS (Ritter et al. 2000), but also at the level of the liver (Russek 1971). The longer a high blood glucose level can be maintained, the longer the sensation of satiety occurs (Holt et al. 1996).
As glucose is an important substrate for many body functions, especially performance of the brain, in a hypoglycaemic state the metabolism is forced to synthesise de novo glucose in order to maintain glucose homeostasis. This metabolic pathway is called gluconeogenesis and uses gluconeogenic amino acids such as alanine, glutamine, serine or glycine as precursor for glucose synthesis. During the postprandial state after ingestion of a high protein diet, due to the gluconeogenesis from dietary protein, the decrease in blood glucose concentration is more efficiently delayed (Blouet et al. 2006).

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Protein-induced thermogenesis can influence satiety

Increased energy expenditure was observed after a high protein load or meal and was proposed as another mechanism of protein satiety (Porrini et al. 1997; Westerterp-Plantenga et al. 1999). There was also a correlation noticed between increased energy expenditure and elevated satiety after a high protein meal (Crovetti et al. 1998; Westerterp-Plantenga et al. 1999; Lejeune et al. 2006). The satiating effect could be explained by the feeling of oxygen deprivation caused by elevated body temperature and greater use of oxygen in protein metabolism, used for absorption, storage and oxidation (Tappy 1996; Westerterp 2006). In contrast to lipids and carbohydrates, which can be stocked easily, proteins have to be metabolised prior to storage. Gluconeogenesis in the liver and building of muscle mass expend energy and in this way produce heat (Johnston et al. 2002; Westerterp-Plantenga et al. 2004). However, there is no consensus on this theory, as several studies failed to show a relation between the intake of a high protein diet, elevated body temperature or energy expenditure and satiety (Luscombe et al. 2003; Raben et al. 2003).

The role of hormones as peripheral adiposity signals

Other important factors among peripheral signals influencing satiety are hormones released from adipose tissue and the pancreas which are responsible for the control of energy homeostasis (Stanley et al. 2005). Most of them have an action site on both the level of the GI tract by activation of the vagus nerve and central on the hypothalamus and the dorsal vagal complex via the blood stream. Postprandial hormone profiles have been studied intensively in order to investigate in which way protein influences satiety (Al Awar et al. 2005; Bowen et al. 2006a; Bowen et al. 2006b).

Table of contents :

1 Scientific background
1.1 Appetite, satiety and the control of food intake
1.2 Peripheral signals involved in protein induced satiety
1.2.1 Sensory information from lingual detection
1.2.2 Pre-absorptive signals generated in the gastrointestinal tract
1.2.2.1 The stomach is sensitive to gastric distension
1.2.2.2 The vagus nerve builds the gut-brain axis
1.2.2.3 Chemoreceptors sense nutrients in the intestine and activate the vagus nerve
1.2.2.4 Peptide hormones act as humoral peripheral signals
1.2.3 Pre-absorptive signals specifically induced by protein ingestion
1.2.4 Post-absorptive peripheral signals
1.2.4.1 Direct sensing of dietary protein
1.2.4.2 Glucose-mediated sensing of dietary protein
1.2.4.3 Protein-induced thermogenesis can influence satiety
1.2.4.4 The role of hormones as peripheral adiposity signals
1.3 Central signalling of dietary protein
1.3.1 Short-term regulation of food intake: the dorsal vagal complex controls meal size
1.3.1.1 The blood-brain barrier
1.3.1.2 The area postrema mainly responding to humoral signals
1.3.1.3 The NTS receives signals from vagal afferents and the blood stream
1.3.2 Long-term regulation of energy balance: the hypothalamic area is responsible for maintaining body weight through meal initiation
1.3.2.1 The arcuate nucleus
1.3.2.2 The paraventricular nucleus
1.3.2.3 The ventromedial hypothalamus
1.3.2.4 Central neurotransmitters involved in hypothalamic projections
1.3.3 Integration of short-term satiation signals and long-term hunger signals in the DVC and the hypothalamus
1.4 Effect of a diet high in protein on body composition
1.5 Summary and objective of this thesis
2 Hepatic portal vein deafferentation has no effect on the satiating effect of a high protein diet in rats
2.1 Introduction
2.1.1 High protein diet altering food intake
2.1.2 Capsaicin for selective deafferentation
2.1.3 Aims of the study
2.2 Materials and Methods
2.2.1 Materials
2.2.2 Animals
2.2.3 Surgical procedures for selective hepatic vein deafferentation using capsaicin
2.2.4 Histological verification of selective deafferentation
2.2.4.1 Sampling of portal veins
2.2.4.2 Immunohistochemical analysis of CGRP reactivity
2.2.5 Diets and feeding procedures
2.2.6 Statistical analysis
2.3 Results
2.3.1 Hepatic portal vein deafferentation
2.3.2 Daily energy intake and body weight
2.4 Discussion
2.4.1 Deafferentation of the portal vein by a capsaicin solution
2.4.2 The effect of hepatic portal vein deafferentation on food intake suppression induced by a high protein diet
2.5 Conclusion and perspectives
2.6 Article: Protein, amino acids, vagus nerve signaling, and the brain. D Tomé, J Schwarz, N Darcel, G Fromentin
3 Central cartography of macronutrients’ internal sensibility
3.1 Integration of signals from intestinal nutrient sensing in the dorsal vagal complex
3.2 Article: Three-dimensional Macronutrient-associated Fos Expression Patterns in the Mouse Brainstem J Schwarz, J Burguet, O Rampin, G Fromentin, P Andrey, D Tomé, Y Maurin, N Darcel.
3.3 Additional methods: Calculation of density curves
3.4 Discussion, conclusion and perspectives
4 Modulation of body composition and the effect of gut peptides by a high protein diet
4.1 Introduction
4.1.1 Aims of studies
4.2 Material and Methods
4.2.1 Materials
4.2.2 Animals
4.2.3 Effect of a HP diet on body weight and food intake
4.2.4 Effect of a HP diet on body adipose tissue composition
4.2.4.1 Whole body MRI
4.2.4.2 1H MRS of the whole body, liver and muscle
4.2.5 Manganese Enhanced MRI of the appetite centres in the brain to measure alteration of the effect of oxyntomodulin by a high protein diet
4.2.5.1 Image analysis
4.2.6 Statistical analysis
4.3 Results
4.3.1 Effect of a HP diet on body weight and food intake
4.3.2 Effect of a HP diet on body composition
4.3.3 Alteration of the effect of oxyntomodulin by a high protein diet
4.4 Discussion
4.4.1 Effect of a HP diet on body weight and food intake
4.4.2 Effect of a HP diet on body composition
4.4.3 Alteration of the effect of oxyntomodulin by a high protein diet
4.5 Conclusion and perspectives
5 General conclusion and perspectives
6 Annex
6.1 Composition of the experimental diets1
6.2 Used R codes
6.2.1 Chapter 2
6.2.2 Chapter 3
6.2.3 Chapter 4
6.3 Principle of the magnetic resonance technique
6.3.1 1H MR Spectroscopy
6.3.2 Brain activity measured by Manganese enhanced MRI (MEMRI)
7 References

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