Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (<i>Macaca mulatta</i>) Brain

Heppner, Kristy M.; Kirigiti, Melissa A.; Secher, Anna; Paulsen, Sarah Juel; Buckingham, Rikley; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels; Grove, Kevin L.

doi:10.1210/en.2014-1675

Cited by 148 publications

(148 citation statements)

References 86 publications

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“…Electrophysiological recordings in acute slices from rat hippocampus demonstrated that application of GLP-1 and Ex4 increased the amplitude and frequency of postsynaptic inhibitory currents in hippocampal CA3 pyramidal neurons (49). Additionally, a new transgenic mouse model expressing Cre-recombinase under the promoter for GLP-1R (79) demonstrated that GLP-1Rs are functional in a subset of hippocampal pyramidal cells (11), in support of the in situ hybridization data from the rat (65) and nonhuman primate (35).…”

Section: Hippocampusmentioning

confidence: 61%

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

Trapp

Cork

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short-and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. appetite; brain stem; glucagon-like peptide-1; hippocampus; neuroanatomy FOR TWO DECADES, IT HAS BEEN known that glucagon-like peptide (GLP-1) reduces food intake by acting within the central nervous system (95). That first study showed through the use of the GLP-1 receptor antagonist exendin-9 (Ex9) that endogenous GLP-1 has the ability to suppress food intake and that this effect is dependent on the feeding state of the animal. While unequivocally showing that GLP-1 has a physiological role in brain, the source of centrally acting GLP-1 remains less clear. Does postprandially released GLP-1 from the enteroendocrine L-cells reach the central nervous system (CNS) from the circulation, despite its short half-life in the blood, or does the small number of preproglucagon (PPG) neurons in the lower brain stem (37,58,65) provide sufficient GLP-1 for the plethora of brain regions that express its receptor? Although this question remains largely unanswered, it is clear that central GLP-1 is integral to many more processes linked to energy homeostasis than simply food intake. This review provides a detailed account of the different actions of GLP-1 in the brain, with a particular emphasis on the potential role of the PPG...

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Section: Hippocampusmentioning

confidence: 61%

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

Trapp

Cork

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…For example, GLP-1 receptors (GLP-1Rs) are located on vagal afferents that innervate the gut in close proximity to L-cells (Richards et al 2014), indicating a possible paracrine gut-brain axis for mediating its glycaemic effects. However, GLP-1Rs are also located on neurons innervating the portal vein (Vahl et al 2007), on β cells of the pancreas , and in the central 230:3 nervous system (Shimizu et al 1987, Heppner et al 2015, all possible targets for GLP-1 action (described in more detail below). Nonetheless, most studies demonstrate that vagal neural transmission is necessary for nutrientinduced gut feedback as anaesthetics, neurotoxins or vagotomy abolishes nutrient-induced reductions in food intake (Schwartz 2011), and in the case of lipid-induced CCK release, the lowering of hepatic glucose production (Wang et al 2008a).…”

Section: Gut Peptide Signalling In Regulating Glucose Metabolismmentioning

confidence: 99%

Targeting the gastrointestinal tract to treat type 2 diabetes

Bauer

Duca

2016

Journal of Endocrinology

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The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

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“…This is a very important aspect of central food evaluation, as the taste of palatable food can induce an immediate reward that can be a powerful drive for food consumption, therefore leading to an increase in energy intake. Interestingly, GLP1 receptors have not only been found in the CNS (Shugrue et al 1996, Heppner et al 2014, but also in the mammalian taste buds (Shin et al 2008), and GLP1 signalling was shown to mediate sweet taste perception (Shin et al 2008). Therefore, we hypothesise that GLP1 and GLP1RA treatment may affect the central processing and reward value of palatable food and that this may be an important mechanism by which GLP1 contributes to the central regulation of feeding in humans.…”

Section: Introductionmentioning

confidence: 96%

Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption

Kulve

Veltman

Bloemendaal

et al. 2016

Journal of Endocrinology

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Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using functional MRI, we determined the effects of endogenous GLP1 and treatment with the GLP1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP1 receptor antagonist exendin 9 -39 (blocking actions of endogenous GLP1) and during placebo infusion. Study 2 was a randomised, cross-over intervention study carried out in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10 days and 12 weeks. Compared with lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P = 0.04). In lean individuals, blockade of endogenous GLP1 effects inhibited activation in bilateral insula (P ≤ 0.03). Treatment in T2DM with liraglutide, vs insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P ≤ 0.03); however, these effects ceased to be significant after 12 weeks. Our findings in healthy lean individuals indicate that endogenous GLP1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed. 1-12Effect of GLP1 on CNS response to palatable food j s ten kulve and others

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Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (Macaca mulatta) Brain

Cited by 148 publications

References 86 publications

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

Targeting the gastrointestinal tract to treat type 2 diabetes

Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption

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