Nondigestible oligosaccharides food intake and weight control a key role for gastrointestinal peptides

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7.5.1 Involvement in the regulation of food intake: from theory to experimental data

Endocrine L-cells are distributed all along the intestinal tract, but are mostly present in the caeco-colon, where fermentation of NDO occurs (Orskov et al. 1989). Endocrine cells present in the intestinal mucosa secrete peptides involved in the regulation of food intake, and/or pancreatic functions, the latter being called incretins [glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP)]. Among those peptides, GLP-1, peptide YY (PYY) and oxyntomodulin have recently been proposed as important modulators of appetite, through their peripheral effect (vagal nerve) and/or by acting directly on the arcuate nucleus (Druce et al. 2004; Wynne et al. 2005). GLP-1 is also involved in the regulation of pancreatic secretion of insulin, and in the differentiation and maturation of P-cells (Brubaker & Drucker 2004). Other gastro-intestinal peptides are implicated in the regulation of body weight and food intake such as ghrelin, a gastric orexigenic-derived hormone (Cowley et al. 2003).

Interestingly, we had previously observed that OFS feeding led to an increase in total cecal GLP-1 and jejunum GIP concentrations in rats (Kok et al. 1998a). Therefore, we postulated that the modulation of gut peptides could involve a key hormone mediating the effect of OFS - and other NDOs - on food intake, and glucose/lipid metabolism. The mechanism and relevance of endogenous modulation of the production of gut peptides by DF is poorly documented, but several experimental data suggest that those peptides could constitute a link between the outcome of fermentation in the lower part of the gut and systemic consequences of 'colonic food' intake.

Reduction of food/energy intake has been observed in several rat models (lean rats or mice, obese Zucker fa/fa rats, high-fat-diet-induced obese mice) in which inulin-type fructans fibres, extensively fermented in the caeco-colon, were added to the diet. The decrease in food/energy intake was not observed when fructans were substituted by non-fermentable DF (microcrystalline cellulose) (Daubioul et al. 2002).

What we knew at the beginning?

1 The peptides involved are produced in the gut (GIP, ghrelin), or in the lower part of the gut (PYY, GLP-1), where NDOs - including inulin-type fructans - are largely fermented.

2 The products of such a fermentation in the gut - namely SCFAs - are known to increase the expression of proglucagon mRNA (precursor of GLP-1) in the intestinal tissue (Cherbut et al. 1998; Tappenden et al. 1998; Drozdowski et al. 2002).

3 Some fermentable DFs are able to increase proglucagon mRNA expression when given in high doses in the diet of dogs or rats (Reimer & McBurney 1996; Massimino et al. 1998).

We report here experiments devoted to: (a) analysing the putative modulation of portal plasma GLP-1 and PYY and peripheral ghrelin concentrations in rats fed three types of fructans, differing in preferential site and extent of fermentation; and (b) identifying the major intestinal site of proglucagon mRNA expression and GLP-1 synthesis after feeding with fructans.

Are non-digestible oligosaccharides able to modulate gastro-intestinal peptides involved in appetite and body weight regulation? We first compared the influence of inulin-type fructans having different DPs - namely OFS, OFS-enriched inulin (Syn) and high-molecular-weight inulin (Inu) - on daily energy intake, and GLP-1 and PYY production. It is important to note that the differences among inulin-type fructans are not only the DP but also the preferential site of fermentation: OFS being fermented in the caecum and the proximal colon, Inu in the distal colon and Syn throughout the colon. The concentration of these peptides, and of the corresponding mRNA precursors, was measured in various segments of the intestinal tract in male Wistar rats that had been given fructans at a dose of 10% (w/w) for 3 weeks. All measurements were performed 8 h after removal of the diet.

We confirm that inulin-type fructans, when added in the diet, significantly reduce energy intake in rats. The short-chain inulin-type fructans (OFS/ Syn) significantly increase the concentration of GLP-1 in the proximal colon and, to a lesser extent, in the medial colon (OFS only) (Cani et al. 2004). The portal concentration of both GLP-1 and PYY peptides was increased after OFS treatment (Table 7.2). This is quite interesting since it means an increase flux of those peptides towards the hepato-portal system, where vagal 'sensors' act as a potential signal to the hypothalamic centres that control food intake (Schwartz et al. 2000; Holst & Deacon 2005; Wynne et al. 2005). The portal GLP-1 increase was correlated to the level of proglucagon mRNA in the proximal colon (R = 0.62, P < 0.001, Pearson's correlation) (Cani et al. 2004). Surprisingly, there was no modification of PYY protein or mRNA in the different intestinal segments, thus suggesting that the effect of OFS was linked to a specific effect on proglucagon gene expression in L-cells as previously suggested (Anini et al. 1999). Moreover, the co-localisation of PYY and GLP-1 has been reported for only 15% of the colonic L-cells (Aponte et al. 1988; Nilsson et al. 1991). Interestingly, even though there is no modification of peptides concentration per gram of caecal tissue, the enlargement of the organ was responsible for an increase in the total caecal pool of both GLP-1 and PYY.

Table 7.2 Portal vein plasma GLP-1 (7-36) amide and PYY (3-36) amide, and cava vein plasma acylated ghrelin concentrations of rats fed a control diet (CT) or a diet supplemented with OFS, OFS-enriched inulin (Syn) or high-molecular-weight inulin (Inu). Values are means ± s.E.M., n = 6 per group. Statistical analysis has been performed through one-way ANOVA followed by Tukey's test separately for each peptide. Mean values with unlike superscript letters are significantly different, P < 0.05 (Adapted from Cani et al., 2004, and Delzenne et al., 2005)

Table 7.2 Portal vein plasma GLP-1 (7-36) amide and PYY (3-36) amide, and cava vein plasma acylated ghrelin concentrations of rats fed a control diet (CT) or a diet supplemented with OFS, OFS-enriched inulin (Syn) or high-molecular-weight inulin (Inu). Values are means ± s.E.M., n = 6 per group. Statistical analysis has been performed through one-way ANOVA followed by Tukey's test separately for each peptide. Mean values with unlike superscript letters are significantly different, P < 0.05 (Adapted from Cani et al., 2004, and Delzenne et al., 2005)

Portal vein

Cava vein, acylated ghrelin

GLP 1(7-36) amide

PYY(3-36) amide





7.8 ± 0.7a

9.9 ± 1.9a

131.7 ± 7.4a


11.4 ± 1.2b

19.7 ± 2.4b

91 ± 7.2b


10.5 ± 1.7b

12.9 ± 2.6a

87.2 ± 12.6b


8.4 ± 1.3a

11.2 ± 3.2a

102.6 ± 12ab

We have shown that the plasma GLP-1 increase in the portal vein was positively correlated to an increase in the number of cells producing GLP-1 in the proximal colon (P. D. Cani, submitted to Br J. Nutr 2006, personal communication). An increase in intestinal proglucagon mRNA concentration has already been shown in rodents or dogs who received fermentable DF (Reimer et al. 1997; Massimino et al. 1998; Nian et al. 2002). In mice, this was accompanied by a higher GLP-1 incremental area under the curve after a glucose load (Nian et al. 2002). None of these studies reported an effect on food intake, body weight gain or insulin sensitivity.

A recent study has suggested that plasma GLP-1 might also influence the production of ghrelin (Lippl et al. 2004). Ghrelin stimulates feeding behaviour, lowers energy expenditure and drives body weight increase due to a change in fuel partitioning. Acylated ghrelin concentration increases during food deprivation and rapidly falls during meals (Kojima et al. 1999; Tschop et al. 2000). Ghrelin could constitute a potential relay of the effects of OFS on satiety because plasma GLP-1 and ghrelin concentrations are inversely correlated after glucose ingestion, and GLP-1 reduces ghrelin secretion (Djurhuus et al. 2002; Lippl et al. 2004). As shown in Table 7.2, the plasma acylated ghrelin level is almost 30% lower in rats fed short-chain fructans. This suggests that a lower ghrelin production can also contribute to a decrease in appetite during fasting, linked to the presence of NDO in the diet.

In conclusion, we may assess that short-chain fructans, which are fermented in the caecum and the proximal colon, are effective NDOs able to increase proglucagon mRNA and portal and intestinal GLP-1 concentrations, and to decrease peripheral plasma acylated ghrelin, at least in animal models. Due to the results of these experiments, we have chosen to investigate further the effects of OFS, as DF, on the modulatation of gut peptides.

7.5.2 Putative modulation of gastro-intestinal peptides by non-digestible oligosaccharides in a high-fat-diet induced hyperphagia model in rats

The role of dietary fat as a key nutrient influencing the energy balance has been a topic of interest for researchers and for those concerned with public health in general. Many epidemiological studies, and experimental data obtained in animals, have characterised the response to high-fat feeding in humans and rodents (Bray & Popkin 1998, 1999; West & York 1998). A high-fat diet produces a consistent and significant increase in body fat content, which is dependent on both the amount of fat in the diet and the duration of feeding. Hyperphagia might be one important mechanism by which high-fat diets promote obesity, since fat is less satiating than carbohydrate (Ramirez & Friedman 1990; Lucas et al. 1998; Lucas & Sclafani 1999); it has thus been suggested that fat may lead to passive diet overcon-sumption (Blundell et al. 1996; Blundell & Macdiarmid 1997a,b). The model of high-fat-diet induced hyperphagia is known to be associated with an inhibition of ghrelin. Since ghrelin is inhibited, it is unable to counteract hyperphagia (Lee et al. 2002). The reduction in plasma ghrelin levels with the high-fat diet is in accordance with results reported in an article that shows decreased circulating ghrelin levels in obese humans (Tschop et al. 2001). The authors of the human study suggest that the reduced plasma ghrelin levels reflect an adaptation to the excessive caloric intake in obese subjects.

Only a small amount of data is available concerning the potential modulation of high-fat-diet induced hyperphagia by DFs or NDOs (Sullivan et al. 1978; Ramirez & Friedman 1990). The presence of OFS in a high-fat diet as compared with a high-fat diet alone increases proglucagon mRNA in the proximal colon, with consequences on GLP-1 concentrations. This model has no effect, however, on PYY and ghrelin levels (Cani et al. 2005b). OFS also reduces dipeptidyl peptidase IV (DPPIV) activity by about 30%. Thus, a lower DPPIV activity due to OFS may contribute, together with the higher intestinal production, to the promotion of GLP-1 production and of its biological activity in the portal vein. In fact, we know neither the origin of soluble portal DPPIV nor by which mechanisms OFS reduces DPPIV activity (Cani et al. 2005b). Thus, because of the protective effect of OFS against high-fat-diet induced body weight gain, hyperphagia and fat mass development, despite the lack of effect of OFS on PYY and ghrelin levels, we postulate that the modulation of GLP-1 synthesis and secretion could be linked to the beneficial effects of OFS.

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