Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well.RESEARCH DESIGN AND METHODS—We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons.RESULTS—We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide tyrosine.CONCLUSIONS—These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production.The importance of gastrointestinal hormones signaling gut absorption of carbohydrates and downstream processes involved in glucose disposal has received increasing attention. Prominent among these is glucagon-like peptide-1 (GLP-1), which is produced by L-cells of the ileum and is secreted during meal ingestion. GLP-1 augments nutrient-induced insulin release (1,2), inhibits glucagon release (3), slows gastric emptying (4), and has islet-independent effects to reduce hepatic glucose production (5–8). Studies in animals and humans have demonstrated that GLP-1 signaling is necessary for normal glucose tolerance (9). Moreover, two newly approved therapies for type 2 diabetic patients act through GLP-1 signaling to improve glucose homeostasis.Most of the evidence demonstrating a role for GLP-1 in glucose homeostasis has focused on actions within the pancreatic islet. However, GLP-1 is also synthesized in a discrete population of neurons in the hindbrain (10–12), and GLP-1 receptors are highly expressed in various regions of the hypothalamus (13) including the arcuate nucleus (ARC) and the paraventricular nucleus (PVN) (14), two areas where immunoreactive GLP-1 fibers terminate (11). Central nervous system (CNS) GLP-1 receptors have been linked to the control of food intake, endocrine and behavioral responses to stress, and visceral illness (15–17). Although there is evidence that circulating GLP-1 agonists can activate CNS neurons (18) and that GLP-1 may cross the blood-brain barrier (19), central and peripheral GLP-1 signaling systems are generally held to be separate.Compelling recent evidence links a number of CNS systems to the regulation of peripheral glucose levels. While hypothalamic areas such as the PVN and the dorsal medial and the ventromedial hypothalamus may play a role in glucose homeostasis during stress (20–22), there is strong evidence that the ARC plays a key role in maintaining normal glucose levels in response to anorectic peptides or nutrients by regulation of glucose production (23–26). Given this emerging evidence for CNS involvement in the regulation of peripheral metabolism and the broad role that peripheral GLP-1 signaling plays in regulating glucose homeostasis, we hypothesized that CNS GLP-1 receptors would have multiple coordinated effects to improve glucose tolerance. Specifically, we focused on the ARC because GLP-1 receptors are found in this region, and previous studies have shown that neurons in this area regulate glucose production. Thus, a second hypothesis was that ARC GLP-1 receptors regulate glucose output. Finally, using dual in situ hybridization histochemistry, we evaluated ARC GLP-1 receptor expression on orexigenic neuropeptide tyrosine (NPY) and anorexigenic proopiomelanocortin (POMC) neurons.