The Anorectic Effect of GLP-1 in Rats Is Nutrient Dependent

Abstract

GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3rd cerebroventricularly (i3vt)-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1′s anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

Glucagon-Like Peptide 1 Interacts with Ghrelin and Leptin to Regulate Glucose Metabolism and Food Intake through Vagal Afferent Neuron Signaling ,

“…However, a thorough analysis of meal pattern has not been done and it is possible that GLP-1 can have effects on meal size and duration, consistent with other gut peptides, such as CCK. Consistent with other studies, we have recently demonstrated that peripheral, native GLP-1 requires either a postprandial state or an ongoing meal to induce satiation (59,(63)(64)(65). Prolonged fasting attenuates the satiating effects of GLP-1.…”

Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans

“…Also, infusion of GLP-1 was insufficient to significantly reduce food intake or modulate neural responses to visual food cues, whereas GLP-1 in combination with peptide YY(3–36) did suppress food intake and regional brain activation (De Silva et al, 2011). Moreover, w hen glucose utilization in the central nervous system is blocked, the anorectic effect of intraventricular GLP-1 is diminished (Sandoval et al, 2012). In sum, GLP-1 infusion or receptor stimulation appears to be sufficient to promote meal-related satiety in humans in a dose-dependent manner (Verdich et al, 2001).…”

Incretins and Amylin: Neuroendocrine Communication Between the Gut, Pancreas, and Brain in Control of Food Intake and Blood Glucose

“…shrew and ferret) will collectively deepen our understanding of the neurobiological mechanisms of emesis/nausea/malaise induced by GLP-1 and amylin-pharmacology. Indeed, in the case of GLP-1, we (84) and others (95; 166) have suggested that the field as a whole must utilize a multi-model approach to disentangle physiological (e.g. regulation of food intake and blood glucose) and pathophysiological (e.g.…”