Satiety signalling (revision 6)

Satiety signalling comprises the peripheral signals and central circuits that end a meal and delay the next one. The literature distinguishes satiation — the process terminating an eating episode — from satiety, the inter-meal suppression of appetite; the distinction matters because different signals dominate each.^[1]

Peripheral signals include gastric distension relayed by vagal mechanoreceptors, nutrient-sensing hormones from the small intestine such as cholecystokinin, GLP-1, peptide YY and amylin, and longer-term adiposity signals such as leptin and insulin. These converge on the caudal brainstem and on hypothalamic circuits including the arcuate nucleus.^[1]

Pharmacological exploitation of this system is what GLP-1 receptor agonists do. They produce a sustained supraphysiological signal in a system evolved for episodic signalling, and the great majority of the weight loss they produce is attributable to reduced energy intake rather than to increased expenditure.^[2]

Gastric distension is the most immediate satiation signal, relayed by vagal afferents in the stomach wall. It is volume-dependent rather than calorie-dependent, which is why delayed gastric emptying produces satiation out of proportion to the nutrient consumed.^[1]

Intestinal hormones add nutrient specificity. Cholecystokinin is released from duodenal I cells in response to fat and protein and acts largely within a meal. GLP-1 and peptide YY are released from more distal L cells and act over a longer window. Amylin, co-secreted with insulin from the pancreas, acts at the area postrema.^[3]

Adiposity signals set the background against which meal-related signals are read. Leptin and insulin circulate in proportion to fat mass and modulate the sensitivity of the hypothalamic circuits to meal-related input rather than terminating meals themselves.^[4]