Integration of satiety signals by the central nervous system

Abstract

Individual meals are products of a complex interaction of signals related to both short-term and long-term availability of energy stores. In addition to maintaining the metabolic demands of the individual in the short term, levels of energy intake must also maintain and defend body weight over longer periods. To accomplish this, satiety pathways are regulated by a sophisticated network of endocrine and neuroendocrine pathways. Higher brain centers modulate meal size through descending inputs to caudal brainstem regions responsible for the motor pattern generators associated with ingestion. Gastric and intestinal signals interact with central nervous system pathways to terminate food intake. These inputs can be modified as a function of internal metabolic signals, external environmental influences, and learning to regulate meal size.

Figure 1. Nutrient-sensing in intestinal I-cells

Luminal nutrients activate specialized receptors coupled to Gq proteins. The activation of PLC, and downstream effector pathways triggers membrane depolarization and the release of CCK which activates CCK1 receptors expressed on vagal afferent fibers. Following uptake into epithelial cells monoglycerides (MG) and free fatty acids (FA) can either diffuse across the cell and exit into circulation from the basolateral membrane, or be re-synthesized into triglycerides (TG) by the 2-monoglyceride (2MG) or α-glycerol-3 phosphate (G3P) pathways. The re-synthesized TG’s are assembled into chylomicrons before undergoing exocytosis by the golgi apparatus. Once in circulation, a portion of the Apo A-IV dissociates from the chylomicron and acts on CCK1 receptors via an unknown mechanism.

Figure 2. Nutrient-sensing in intestinal L-cells

G-protein coupled receptors and their effector pathways that have been identified as potential nutrient sensors on intestinal L-cells. Activation of these receptors triggers elevations in intracellular Ca²⁺ stores and the Ca²⁺ sensitive transient receptor potential channel M5 (TRPM5)[136, 137]. The resulting depolarization triggers the release of GLP-1 and the subsequent activation of GLP-1 receptors expressed on vagal afferent fibers.

Figure 3. Central nervous system integration of satiety signals

Examples of peripherally derived signals that act on central nervous system pathways to affect food intake. Nutrient-sensing is distributed across multiple regions of the central nervous system. Circuits in the hypothalamus (hypo) and brainstem interact with higher centers to initiate and terminate meals.