Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress

Abstract

INTRODUCTIONIngestion of food is a necessary and pleasant occupation that allows humans and other species to maintain caloric homeostasis and a certain level of body weight. Ironically, in doing so, one's 'milieu interieur' is put at risk because meal-induced fuel excursions can have deleterious effects on metabolic (e.g. glycosylation causing loss of enzymatic efficacy) and cardiovascular (e.g. triglyceride accumulation, increased blood pressure, etc.) processes. 1,2 To reduce these perturbations to a minimum, evolution has provided many species (including humans and rodents) with a fine-tuned system enabling ingested nutrients to be anticipated, efficiently digested, and stored. 3 One of these mechanisms includes passage of nutrients through the digestive tract, triggering the release of a number of peptides from endocrine cells located in the wall of various parts of the gastrointestinal tract. These peptides serve important functions in facilitating the process of nutrient digestion/storage. Among these, the truncated (i.e. 7-36) amidated form of glucagon-like peptide-1 (GLP-1) has attracted considerable attention over the last several years. Firstly, because of its remarkable peripheral insulinotropic effects that could be useful for clinical purposes. Secondly, because more recent data suggest an important role of this peptide in the central nervous system (CNS) control of ingestive behavior. Although the present paper mainly focusses on the latter issue, a short review of peripheral GLP mechanisms is necessary for a better understanding of the processes that relate GLP-1 to food intake. GLP-1 FROM THE GASTROINTESTINAL TRACTGLP-1 is processed from proglucagon in mucosal L cells of the distal portion of the ileum and in the A cells of the pancreas. Ingested food, particularly when rich in carbohydrates, causes the level of circulating GLP-1 (mainly of ileal origin) to increase, and in turn, GLP-1 potently stimulates the secretion of insulin from pancreatic B cells via receptor-mediated processes (for reviews, see refs 4 and 5). In contrast, it reduces the secretion of glucagon, at least under ad libitum feeding conditions. 6 While GLP-1 may have some direct stimulatory effects on glucose clearance in peripheral tissue 7,8 (presumably via activation of specific GLP-1 receptors in liver, muscle, kidney Summary Glucagon-like peptide-1 (7-36) amide (GLP-1) is processed from proglucagon in the distal ileum as well as in the CNS. In the periphery, GLP-1 acts as an incretin factor and profoundly inhibits upper gastrointestinal motility ('ileal brake'), the latter presumably involving the CNS. Within the CNS, GLP-1 has a satiating effect, since administration of GLP-1 into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-1 antagonists have the opposite effect. In addition, activation of GLP-1 receptors in certain brain regions elicits strong taste aversions. Similarities between toxin-and GLP-1-induced neuronal activity in the CNS (brain stem) suggest a role f...

Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats

“…Consistent with this, behavioral and physiological responses to centrally administered GLP1 include pituitary stress hormone release, autonomic responses, hypophagia, and anxiety-like behavior (Maniscalco et al 2012; Kinzig et al 2003; Donahey et al 1998; Gulpinar et al 2000; Larsen et al 1997b; Mietlicki-Baase et al 2013; Moller et al 2002; Nakade et al 2006, 2007; Rinaman 1999a; Schick et al 2003; Seeley et al 2000; Thiele et al 1998; Turton et al 1996). A suggested role for central GLP1-R signaling pathways in body energy balance (Tang-Christensen et al 2001; Hayes 2012; Meeran et al 1999; vanDijk and Thiele 1999) also is supported by evidence in rats and mice implicating central GLP1 in temperature regulation (Rinaman and Comer 2000; O’Shea et al 1996) and glucose homeostasis (Sandoval et al 2008). GLP1-R agonists enhance both excitatory and inhibitory synaptic inputs to identified neurons through presynaptic stimulation of transmitter release from axon terminals (Wan et al 2007; Acuna-Goycolea and van den Pol 2004), and postsynaptic effects of GLP1 on neuronal activity also are reported (Acuna-Goycolea and van den Pol 2004; Riediger et al 2010; Hayes 2012).…”

Incretin hormones and the satiation signal

“…95, 96 As noted previously, GLP-1 may have direct effects in the CNS because it can reach the brainstem via the subfornical organ and AP, which lack a typical blood–brain barrier. 97 A direct central effect of GLP-1 is supported by results from a study which showed that only the effect of intraperitoneal, but not intravenous (intraportal), GLP-1 on eating required vagal afferent signaling.…”

Metabolic and Hormonal Alterations with Diacylglycerol and Low Glycemic Index Starch during Canine Weight Loss

“…For example, GLP-1 has an inhibitory effect on gastric emptying and therefore slows glucose absorption [26]. Moreover, GLP-1 reportedly has an effect on satiety and on reducing food intake [27–30]. Further study will be needed to understand the effect of weight loss on fasting incretin hormone concentrations.…”