Glucagon‐like peptide‐1 in the rat brain: Distribution of expression and functional implication

Abstract

Glucagon-like-peptide 1 (GLP-1) is expressed not only in gut endocrine cells, but also in cells in the caudal brainstem and taste buds. To better understand the functions of central GLP-1, GLP-1 expression was immunohistochemically profiled in normal rat brain and its distribution correlated with FOS induction following systemic administration of a GLP-1 receptor agonist, exendin-4. In the present study, only a small number of GLP-1-immunoreactive cell bodies were observed in the nucleus of the solitary tract (NTS). However, these neurons send abundant projections to other regions of the brain, in particular the forebrain, including the paraventricular and dorsomedial nuclei of the hypothalamus, the central nucleus of the amygdala, the oval nucleus of the bed nuclei of the stria terminalis, and the paraventricular nucleus of the thalamus. Intraperitoneal administration of exendin-4 resulted in extensive FOS expression in areas of the forebrain and the hindbrain. In the forebrain, FOS expression was largely confined to regions where a high density of GLP-1-immunoreactive terminals was also localized. The majority of GLP-1-immunoreactive cells in the NTS were not FOS-positive. FOS-positive cells appeared to represent a different population from those expressing GLP-1. Thus, GLP-1-containing neurons in the brainstem may not be involved in receiving and relaying to other regions of the brain the physiological signals of prandial GLP-1 secreted by intestinal L-cells. Projections of GLP-1-containing neurons to the distinctive structures in the forebrain imply that central GLP-1 may play an important role in the behavioral and metabolic integration of autonomic control and arousal in the rat.

Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

“…By changing the potency, our results present a novel way to regulate GLP-1 receptor signaling without altering the extracellular level of GLP-1 peptide. GLP1Rs in the brain stem are considered activated by the centrally derived GLP-1, which is transmitted through neural fibers in most of brain areas (11,12,40). However, neurons expressing GLP-1Rs in notable areas, such as caudal hippocampus and the dopaminergic neurons in the substantia nigra, have no apparent innervations from GLP-1-producing neurons (1,3,14).…”

“…We probed the potential conformation of GLP-1(7-36) amide based on its susceptibility to trypsin digestion. The two trypsin cleavage products of GLP-1 amide are an inactive GLP-1 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and a partially active GLP-1(7-34) (Fig. 8A) (32).…”

“…Circulating GLP-1 has a short plasma half-life of only a few min due to renal clearance after rapid enzymatic inactivation by a plasma enzyme, dipeptidyl peptidase 4 (10). Other cells outside of the gut shown to produce GLP-1 include pancreatic ␣ cells and neurons in the localized area of the brain stem (4,(11)(12)(13)(14), but our knowledge of the physiological regulation of GLP-1 secretion by these cells is limited.…”

“…These neurons send abundant projections to other regions of the brain, including the forebrain, hypothalamus, amygdala, stria terminalis, and thalamus, where GLP-1Rs are expressed; this neuronal circuit of GLP-1 signaling is considered relevant to satiety and energy homeostasis (2,11). GLP-1R is also expressed in neurons in the hippocampus (1) and dopaminergic neurons in substantia nigra (3), where no known GLP-1-secreting neuron innervation is found (3,14).…”

Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

“…GLP-1R is present in many different tissues and is involved in diverse physiological functions (1). It is often the case that local concentrations of GLP-1, rather than systemic levels, regulate tissue-specific GLP-1R activation (11). Therefore, constitutive activation of GLP-1R could result in various off-target effects; chronically high plasma GLP-1 levels can also lead to loss of spatial or tissue-specific control of GLP-1R activation.…”