Dietary protein profoundly influences organismal traits ultimately affecting healthspan. While intracellular signalling downstream of altered amino acid supply is undoubtedly important, peptide hormones have emerged as critical factors determining systemic responses to variations in protein intake. Here the regulation and role of certain peptides hormones in such responses to altered dietary protein intake is reviewed.
Introduction of the major macronutrients, dietary protein is a powerful determinant of longevity, health span, and reproduction through both behavioural changes such as food intake as well as whole-body and cellular metabolism. This is likely fundamentally related to the fact that amino acids, the building blocks of protein, are an essential dietary component and that certain amino acids are critical for vital processes such as gut function, immune response and neurotransmitter synthesis. While there are clear intracellular signalling nodes such as mTORC1 and GCN2 as well as possible cell surface receptors for amino acids, it is becoming clear that hormones, in particular peptide hormones, are critical components relaying the systemic homeostatic responses to variations in dietary protein intake. Although amine (e.g., tryptophan derived serotonin) and steroid hormones are likely to be important as well, here we review the regulation and role of certain peptide hormones in the physiological responses to altered dietary protein. Rather than being exhaustive, this review is intended to be easily digestible, and summarises the major peptides hormones from the gut, pancreas, liver, and adipose tissue, and the information available about their responsiveness, and physiological role in variations, to dietary protein intake.
Gastrin is involved in the acute regulation of protein digestion. In addition to other stimuli, gastrin is mainly secreted from the G cells of the gastric antrum and duodenum via vagal stimulation as well as gastrin-releasing peptide, secondary to ingestion of peptides. Following secretion into the bloodstream, gastrin then travels to the gastric fundus and acts on parietal cells to secrete hydrochloric acid which alters gastric pH which cleaves pepsinogen into pepsin to aid in peptide chemical digestion.
Ghrelin is secreted by the stomach, mainly by the gastric fundus in response to lack of food. The levels of ghrelin typically rise shortly before and fall shortly after food consumption, and is thought to have a role in meal hunger and food intake initiation (i.e., feeding) via brain orexigenic circuits. Although this is the well-known role of ghrelin, the effects are pleiotropic including broader effects on mood, energy balance, as well as gastric-, cardiovascular-, and muscular-function. The meal response to suppress ghrelin depends on total caloric supply but does not seem to be selective for a particular macronutrient, although carbohydrate appears to be dominant.There is variable information on whether ghrelin is secreted in response to dietary protein alone. Nevertheless, a well-controlled study concluded that the satiating effects of increased dietary protein does not relate to alterations in ghrelin. Whether ghrelin is involved in protein-specific hunger, as well as whether ghrelin is involved in many of the effects of dietary protein on organismal function, remains to be formally investigated.
Secretin is the first discovered hormone by the seminal work of Bayliss and Starling. It is secreted by the S-cells of the duodenum in response to meal feeding and affects multiple tissues by acting on secretin receptors and increasing cell growth and proliferation. Secretin has a known role for affecting gastric acid secretion by the stomach and pancreatic secretory responses to meal feeding related acidification of the duodenum whereby it stimulates pancreatic fluid (ca. bicarbonate) release to neutralise the duodenal acid load from the stomach. It also has a role in satiety, and it may mediate satiety by affecting postprandial thermogenesis via brown fat action, at least in mice. In terms of macronutrient effects, there is not much known, but one study showed no effect of a protein rich meal on postprandial blood secretin levels. Whether secretin is involved in the acute and chronic effects of altered protein balance is yet to be systematically investigated.
Cholecystokinin (CCK) is secreted by the I-cells of the duodenal and jejunal mucosa in response to a meal and acts as a satiety hormone, mainly by affecting meal size and duration. It acts on CCK receptors within the stomach and duodenum, as well as vagal afferents within the gut to increasing firing to the hindbrain regions. CCK receptors are also expressed within the hindbrain and hypothalamus and thus CCK can signal in multiple ways to affect satiation. CCK is release in response to nutrients in the duodenal lumen, with fat and protein being more potent than carbohydrate. Dietary fibre can also affect CCK secretion. Concerning protein, digestion of protein is required for its effect on sustained CCK release but whether CCK has a role in the regulation of somatic responses to acute and chronic changes in dietary protein is unknown.
Glucagon-like peptide 1 (GLP1) is derives from the proglucagon gene, and is secreted mainly by the L-cells of the distal small intestine and colon in response to food intake. GLP1, mainly known for its incretin function where it enhances nutrient stimulation/inhibition of pancreatic hormone release, is also an anorexic hormone acting on the GLP1 receptor in multiple tissues including the gut, pancreas, brainstem, hypothalamus, and vagal-afferent nerves. In response to food intake, the response of secretion is rapid. This can occur via indirect neural mechanisms as well as direct effects on the intestinal L cells by nutrients. In terms of sensitivity to different macronutrients, GLP1 responses are highest after a protein rich meal when compared with fat or carbohydrate rich meals. Several lines of evidence suggest that certain amino acids such as glutamine and arginine appear to be important GLP1 secretagogues. Whether GLP1 affects the organismal responses to altered dietary protein is yet to be properly investigated.
Glucagon like peptide 2 (GLP2) also derives from the proglucagon gene, and is typically co-secreted with GLP1. GLP2 mainly has a known role in affecting intestinal mucosal epithelia proliferation/growth and is proposed to be a sensor for mucosal epithelium integrity to maintain nutrient absorption capacity. A recent study has shown that GLP2 also affects intestinal amino acid transport directly. Very little is known about how and which specific nutrients affect GLP2 secretion and whether GLP2 affects the systemic responses to changes in dietary protein.
Glucose-dependent insulinotropic polypeptide (a.k.a. gastric inhibitory polypeptide; GIP) is released from intestinal K-cells predominantly in the duodenum in response to the presence of nutrients in the intestinal lumen. GIP is mainly known to affect meal-induced glucose-stimulated pancreatic insulin secretion, GIP also affects postprandial adipose tissue lipid metabolism by adipose tissue action, but not gastric emptying. GIP levels are mainly affected by carbohydrate and fat, but not by protein.
Peptide tyrosine-tyrosine (PYY) is released from the intestinal L cells from the distal parts of the GI tract including the ileum and colon in response to meal feeding. PYY is involved in a wide range of postprandial functions, including the slowing of gastric emptying and digestive processes to improve nutrient absorption as well as affecting insulin secretion and glucose homeostasis. The postprandial PYY secretion is biphasic, with initial stimulation by neural pathways from the foregut followed by intestinal lumen nutrient stimulation. The rise and postprandial PYY levels are typically proportion to total food caloric intake but may also be affected by macronutrient content. There is a lack of consensus about which particular macronutrients play a dominant role in stimulating PYY secretion. However, a key study demonstrated that in humans, meals high in protein induced the greatest postprandial increase in PYY. In addition, PYY is required for the satiating and weight-reducing effects of a high-protein diet in mice probably via direct actions on the brain feeding circuits.
Fibroblast growth factor 19 (FGF19; FGF15 in rodents) is secreted from the enterocytes of the small intestine in response to meal feeding and coordinates postprandial nutrient homeostasis. The main ascribed role of FGF19 is in bile acid homeostasis whereby it responds to bile acids and affe
