Distribution and ultrastructural localization of the glucagon-like peptide-1 receptor (GLP-1R) in the rat brain

AbstractGlucagon-like peptide-1 (GLP-1) inhibits food intake and regulates glucose homeostasis. These actions are at least partly mediated by central GLP-1 receptor (GLP-1R). Little information is available, however, about the subcellular localization and the distribution of the GLP-1R protein in the rat brain. To determine the localization of GLP-1R protein in the rat brain, immunocytochemistry was performed at light and electron microscopic levels. The highest density of GLP-1R-immunoreactivity was observed in the circumventricular organs and regions in the vicinity of these areas like in the arcuate nucleus (ARC) and in the nucleus tractus solitarii (NTS). In addition, GLP-1R-immunreactive (IR) neuronal profiles were also observed in a number of telencephalic, diencephalic and brainstem areas and also in the cerebellum. Ultrastructural examination of GLP-1R-immunoreactivity in energy homeostasis related regions showed that GLP-1R immunoreactivity is associated with the membrane of perikarya and dendrites but GLP-1R can also be observed inside and on the surface of axon varicosities and axon terminals. In conclusion, in this study we provide a detailed map of the GLP-1R-IR structures in the CNS. Furthermore, we demonstrate that in addition to the perikaryonal and dendritic distribution, GLP-1R is also present in axonal profiles suggesting a presynaptic action of GLP-1. The very high concentration of GLP-1R-profiles in the circumventricular organs and in the ARC and NTS suggests that peripheral GLP-1 may influence brain functions via these brain areas.

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

The Journal of Comparative Neurology ◽

10.1002/cne.23282 ◽

2013 ◽

Vol 521 (10) ◽

pp. 2235-2261 ◽

Cited By ~ 56

Author(s):

Guibao Gu ◽

Barbara Roland ◽

Kevin Tomaselli ◽

Carrie S. Dolman ◽

Carolyn Lowe ◽

...

Keyword(s):

Rat Brain ◽

Brain Distribution ◽

Functional Implication ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Structural Characterization by Affinity Cross-Linking of Glucagon-Like Peptide-1(7-36)Amide Receptor in Rat Brain

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1995.64010299.x ◽

2002 ◽

Vol 64 (1) ◽

pp. 299-306 ◽

Cited By ~ 31

Author(s):

José C. Calvo ◽

Bernardo Yusta ◽

Francisco Mora ◽

Enrique Blázquez

Keyword(s):

Rat Brain ◽

Structural Characterization ◽

Cross Linking ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Identification of Glucagon-Like Peptide-1(7–36) Amide in Rat Brain

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328902600214 ◽

1989 ◽

Vol 26 (2) ◽

pp. 169-171 ◽

Cited By ~ 14

Author(s):

S Yoshimoto ◽

M Hirota ◽

C Ohboshi ◽

K Shima

Keyword(s):

Rat Brain ◽

Anion Exchange ◽

Gel Filtration ◽

Anion Exchange Chromatography ◽

Exchange Chromatography ◽

Experimental Conditions ◽

Specific Radioimmunoassay ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Brain

Acid-urea extract of rat brain was examined by glucagon-like peptide-1 (GLP-1) specific radioimmunoassay. A single peak was observed which co-eluted with GLP-1(7–36)amide on gel filtration and anion exchange chromatography. In contrast, GLP-1(1–37) was not detected under our experimental conditions. The fact that GLP-1 (7–36)amide, but not GLP-1(1–37), was present in rat brain suggests that preproglucagon was processed in the brain in the same manner as in the intestine and not as in the pancreas.

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AMPK-dependent regulation of GLP1 expression in L-like cells

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0099 ◽

2016 ◽

Vol 57 (3) ◽

pp. 151-160 ◽

Cited By ~ 5

Author(s):

Sushi Jiang ◽

Hening Zhai ◽

Danjie Li ◽

Jiana Huang ◽

Heng Zhang ◽

...

Keyword(s):

Serum Starvation ◽

Energy Status ◽

Wild Type ◽

High Concentration ◽

Cellular Energy ◽

Compound C ◽

Ampk Phosphorylation ◽

Evolutionarily Conserved ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

This study examined whether AMPK, an evolutionarily conserved sensor of cellular energy status, determines the production of glucagon-like peptide-1 (GLP1). A negative relation existed between phosphorylation of AMPKα and the expression and secretion of GLP1 during changes in energy status in STC-1 cells, an L-like cell line. High concentration of glucose (25 mmol/L) decreased AMPKα phosphorylation, whereas it stimulated the expression and secretion of GLP1 relative to 5.6 mmol/L glucose. Serum starvation upregulated AMPKα phosphorylation, whereas it reduced GLP1 production significantly. Stimulation of AMPK phosphorylation by AICAR and overexpression of wild-type AMPKα1, constitutively active AMPKα1 plasmids, or AMPKα1 lentivirus particles suppressed proglucagon mRNA and protein contents in STC-1 cells. Inactivation of AMPK by Compound C, AMPKα1 siRNA or kinase-inactive AMPKα1 mutant increased the expression and secretion of GLP1. Our results suggest that AMPKα1 may link energy supply with the production of GLP1 in L-like cells.

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Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease

Physiological Reviews ◽

10.1152/physrev.00013.2014 ◽

2015 ◽

Vol 95 (2) ◽

pp. 513-548 ◽

Cited By ~ 180

Author(s):

Darleen A. Sandoval ◽

David A. D'Alessio

Keyword(s):

Glucose Homeostasis ◽

Energy Homeostasis ◽

Glucose Production ◽

Glucagon Secretion ◽

The Body ◽

Pharmacological Interaction ◽

Glucose Levels ◽

Health And Disease ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The preproglucagon gene ( Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.

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