Gastrointestinal regulation of food intake

Abstract

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.

Figure 1. Principal sites of synthesis of GI peptides implicated in the regulation of food intake.

Depicted are the main locations of production for each peptide, although many of these molecules are detectable in smaller quantities at other sites in the GI system. In addition, most of them are also synthesized within the brain, including CCK, APO AIV, GLP1, oxyntomodulin, PYY, enterostatin, ghrelin, gastrin-releasing peptide (GRP), neuromedin B (NMB), and possibly PP. GI peptides that regulate appetite and do not seem to be produced within the brain include leptin, insulin, glucagon, and amylin.

Figure 2. Topography of enteroendocrine cells and absorptive enterocytes on a villus within the small-intestinal wall.

Enteroendocrine cells sense nutritive and non-nutritive properties of luminal food and, in response, release satiation peptides from their basolateral aspect. These signals diffuse through the lamina propria to activate nearby vagal- and spinal-afferent fibers from neurons within the nodose and dorsal root ganglia, respectively, as well as myenteric neurons. Satiation peptides can also enter the bloodstream to act distantly as hormones. Gut-peptide release is regulated not only by luminal nutrients but also by somatic signals. The basolateral side of enteroendocrine cells bears receptors that respond to neurotransmitters, growth factors, and cytokines. Neurotransmitters mediate duodenal-ileal communication to regulate L cell secretion, and they enable central modulation of gut-peptide release. Whether vagal- or spinal-afferent nerves are directly activated by ingested nutrients is uncertain. Although vagal- and spinal-afferent fibers approach the abluminal aspect of enteroendocrine cells and enterocytes, they do not form synapse-like contacts with these epithelial cells, nor do they extend to the intestinal lumen. Some subepithelial nerve fibers might respond to luminal chemicals that diffuse across the epithelium, such as FAs, but this applies only to short-chain FAs, which do not efficiently elicit satiation (116). Other vagal-afferent fibers respond selectively to intestinal carbohydrates or fats. Although it is theoretically possible that these neurons sense nutrients in the extracellular space, it is more clearly established that signaling molecules released from enteroendocrine cells mediate macronutrient-specific neural activation.

Figure 3. Similarities in nutrient-sensing mechanisms used by taste-receptor cells of the tongue and enteroendocrine cells of the intestine (exemplified by an L cell).

Several types of enteroendocrine cell throughout the gut express components of nutrient-sensing and signal-transduction systems that were previously thought to be selective to taste-bud cells. These include apical G protein–coupled receptors for sweet and bitter chemicals; the unusual G protein isoforms Gα_gustducin, Gβ3, and Gγ13; phospholipase Cβ2; and the TRPM5 Ca2⁺-activated Na⁺/K⁺ channel. Additional contributions from plasma membrane delayed-rectifying K⁺ channels and voltage-gated Ca²⁺ channels that are important for taste sensation in the tongue have not yet been confirmed in enteroendocrine cells. In both cell types, the final common pathway for activation includes an increase in intracellular calcium concentration. This triggers basolateral exocytosis of neurotransmitters from lingual taste-receptor cells into synapses with nerve fibers that relay information to the hindbrain. In enteroendocrine cells, surges in intracellular calcium concentration trigger release from the basolateral membrane of signaling molecules, including satiation peptides, which diffuse across extracellular fluids to enter the circulation or to interact with nearby afferent nerve terminals from vagal, spinal, and myenteric neurons. IP3, inositol trisphosphate.

Figure 4. Central and peripheral sites at which the long-acting adiposity hormone leptin potentiates the actions of short-acting GI satiation factors.

Leptin-receptor signaling within the hypothalamus indirectly augments hindbrain neuronal responses to gut satiation signals, such as CCK, through hypothalamus-hindbrain projections involving oxytocin and other neuropeptides (10, 11). Central responses to CCK are also augmented by leptin acting directly on the hindbrain. In the periphery, leptin potentiates GI satiation signals both by enhancing gut-peptide secretion (for example, GLP1 release from distal-intestinal L cells) and by heightening vagal-afferent responsiveness to gut peptides (for example, to CCK from proximal-intestinal I cells). LepR, leptin receptor.