Role of Bioactive Peptide Sequences in the Potential Impact of Dairy Protein Intake on Metabolic Health

Abstract

For years, there has been an increasing move towards elucidating the complexities of how food can interplay with the signalling networks underlying energy homeostasis and glycaemic control. Dairy foods can be regarded as the greatest source of proteins and peptides with various health benefits and are a well-recognized source of bioactive compounds. A number of dairy protein-derived peptide sequences with the ability to modulate functions related to the control of food intake, body weight gain and glucose homeostasis have been isolated and characterized. Their being active in vivo may be questionable mainly due to expected low bioavailability after ingestion, and hence their real contribution to the metabolic impact of dairy protein intake needs to be discussed. Some reports suggest that the differential effects of dairy proteins-in particular whey proteins-on mechanisms underlying energy balance and glucose-homeostasis may be attributed to their unique amino acid composition and hence the release of free amino acid mixtures enriched in essential amino acids (i.e., branched-chain-amino acids) upon digestion. Actually, the research reports reviewed in this article suggest that, among a number of dairy protein-derived peptides isolated and characterized as bioactive compounds in vitro, some peptides can be active in vivo post-oral administration through a local action in the gut, or, alternatively, a systemic action on specific molecular targets after entering the systemic circulation. Moreover, these studies highlight the importance of the enteroendocrine system in the cross talk between food proteins and the neuroendocrine network regulating energy balance.

Keywords: DPP-IV activity; appetite and satiety; bioactive peptides; enteroendocrine hormones; food intake; food peptides; glucose homeostasis; identification and characterization; whey.

Figure 1

Schematic overview of some bioactive components that are released in the gastrointestinal tract upon intake and digestion of milk and dairy products, and their cellular and molecular targets at the level of the gut lumen and the gut wall. Digestion products of dairy proteins include free amino acids (not shown) and peptides. Some peptides act as signaling molecules and regulate the activity of enteroendocrine cells exposed to the gut lumen through binding to G-protein coupled receptors (GPR39, CaSR, GPRC6A, T1R1/T1R3 and T1R2/T1R3 heterodimers) and peptide transporters (PEPT1), at the level of their apical membrane. Some peptides act as inhibitors of dipeptidylpeptidase-IV (CD26/DPP-IV) activity and alpha-glucosidase activity, at the level of the brush border of enterocytes. On the other hand, the up-regulation of DPP-IV expression has been associated with the ingestion of the genetic A1-variant of beta-casein. Dairy proteins and their peptidic fragments (i.e., glycomacropeptide, GMP) are also believed to influence the composition of the gut microbiota. Some bioactive peptides can be transported across the intestinal epithelial barrier and into circulation. At the level of the basolateral pole of the enteroendocrine cells, the DPP-IV inhibitory peptides can reduce the degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), thus increasing their release into circulation. Bioactive peptides acting on endocrine cells not exposed to the gut lumen (ghrelin-secreting cells and somatostatin-secreting cells) have been also described. Finally, exosomes are a subpopulation of so called extracellular vesicles (EVs, submicron-sized lipid envelops). EVs are believed to mediate cellular signalling by carrying nucleic acids, proteins, lipids and cellular metabolites between cells and organs. Exosomes contain macromolecules like peptides, mRNA and microRNAs and can interact with human cells. Exosomes have been isolated from bovine milk and also from whey protein hydrolysates. Dietary exosomes may be considered a novel factor per se in the functional interaction between foods and biological systems. Bovine milk exosomes significantly alter the gut microbiome in non-bovine species. Although there is no evidence, yet of food-derived exosome absorption into circulation in vivo, it would be interesting to investigate a possible role of exosomes as a delivery system protecting bioactive peptides from degradation and facilitating their passage across the intestinal barrier and their delivery to tissue targets.

Figure 2

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), so called incretin hormones, are secreted by distinct enteroendocrine cells, K cells in the proximal bowel and l cells in the ileum and colon, respectively, in response to food digestion products. The aminopeptidase dipeptidylpeptidase-IV (DPP-IV) rapidly deactivates GLP-1 and GIP by removing their N-terminal dipeptides. GIP and GLP-1 share some amino acids in their sequences. They activates two distinct G-protein coupled receptors (GPCRs), which both activate adenylyl cyclase (AC), thus increasing cyclic adenosinmonophosphate (cAMP) levels in target cells. GIP and GLP-1 are well-known glucose-dependent insulinotropic peptides. They also promote satiety and reduce appetite and contribute to regulate gastric emptying and acid secretion. The enzymatic digestion of dietary proteins cause the release of free amino acids and peptides that can stimulate GLP-1 secretion by activating nutrient-sensing receptors expressed by l cells [12]. Peptidic inhibitors of the α-glucosidase activity may also have an impact on GLP-1 secretion after a meal. Indeed, the enzyme inhibition delays the monosaccharide absorption, with the outcome of an increase in free sugar levels in the lower intestine, which in turn may enhance the release of GLP-1 from l cells Finally, evidence has been accumulated that the enzymatic digestion of dietary proteins can produce peptidic DPP-IV inhibitors that have the potential to slow-down incretin cleavage, thus enhancing the biological activities of both GLP-1 and GIP. Moreover, there is increasing interest in a possible effects of food derived compounds on DPP-IV expression in the gut [53].