Brainstem sensing of meal-related signals in energy homeostasis

The dorsovagal complex comprises: (1) a chemosensory structure, the area postrema (AP), (2) a center for integrating distension, mechanosensory and other inputs from the viscera, the nucleus of the tractus solitarius (NTS), and (3) a center to integrate motor and secretory drive to the viscera, the dorsal motor nucleus of the vagus (DMX). There is recent evidence for considerable autonomy of dorsovagal reflexes traversing this loop in ingestive control, especially in meal-termination/anorexic responses, and in other controls on nutrient flux. The characteristics of this system, including (1) activation of several parallel effector pathways, and (2) glucose-sensitivity (hypoglycemic override) have profound therapeutic implications for anti-diabetic and anti-obesity drug development. Agents acting via the brain structures similar to those activated by amylin promise efficacy via multiple effectors, but, via glucose-dependence of effects, without increased risk of hypoglycemia. Several peptides, including those secreted in response to meals, are sensed at area postrema, and because they degrade to innocuous metabolites (amino acids) are thereby candidates as safe and effective drugs. Recently developed GLP-1 agonists and amylin agonists are examples of the therapeutic potential of such agents for metabolic diseases. Others in development include PYY agonists and MC4 agonists. Especially promising may be combinations of peptides and/or their analogs. Certain pairs of peptides, including those acting via the dorsovagal complex, exhibit surprising synergies (eg amylin + CCK (Bhavsar et al., 1998), amylin + leptin (Roth et al., 2008), CCK + glucagon + bombesin (Hinton et al., 1986), PYY and GLP-1 (Paulik et al., 2011)). Peptide combinations may thus attain transformational efficacy without invoking burdensome toxic risk. This article is part of a Special Issue entitled 'Central Control of Food Intake'.