Expression of the leptin receptor in rat and human nodose ganglion neurones

Burdyga, Galina; Spiller, David G.; Morris, Richard; Lal, Simon; Thompson, David G.; Saeed, Shakeel R; Dimaline, R.; Varró, Andrea; Dockray, Graham J.

doi:10.1016/s0306-4522(01)00474-2

Cited by 119 publications

(75 citation statements)

References 29 publications

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“…Leptin is produced in the mucosa of the stomach and rapidly mobilized by feeding and high doses of exogenous cholecystokinin (Bado et al, 1998), and it appears to activate vagal afferents (Wang et al, 1997), shown to express the long form of leptin receptor (Buyse et al, 2001;Burdyga et al, 2002). Small doses of leptin infused into the celiac artery significantly decreased sucrose intake and this effect was not observed in rats with subdiaphragmatic vagotomy or perivagal capsaicin-treatment aimed to selectively ablate vagal afferent fibers.…”

Section: Stomach: Stretch Tension Leptin and Ghrelinmentioning

confidence: 99%

The vagus nerve, food intake and obesity

Berthoud

2008

Regulatory Peptides

259

199

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Food interacts with sensors all along the alimentary canal to provide the brain with information regarding its composition, energy content, and beneficial effect. Vagal afferents innervating the gastrointestinal tract, pancreas, and liver provide a rapid and discrete account of digestible food in the alimentary canal, as well as circulating and stored fuels, while vagal efferents together with the sympathetic nervous system and hormonal mechanisms codetermine the rate of nutrient absorption, partitioning, storage, and mobilization. Although vagal sensory mechanisms play a crucial role in the neural mechanism of satiation, there is little evidence suggesting a significant role in long-term energy homeostasis. However, increasing recognition of vagal involvement in the putative mechanisms making bariatric surgeries the most effective treatment for obesity should greatly stimulate future research to uncover the many details regarding the specific transduction mechanisms in the periphery and the inter-and intra-neuronal signaling cascades disseminating vagal information across the neuraxis.

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Section: Stomach: Stretch Tension Leptin and Ghrelinmentioning

confidence: 99%

The vagus nerve, food intake and obesity

Berthoud

2008

Regulatory Peptides

259

199

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“…The cannabinoid CB1 receptor is another highly constitutively active receptor that stimulates food intake. The CB1 receptor is expressed, for example, in vagal afferent neurons, where its expression is also highly up-regulated during fasting, and the expression returns rapidly to normal when the animals are fed again (51).…”

Section: Figmentioning

confidence: 99%

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Holst

Holliday

Bach

et al. 2004

Journal of Biological Chemistry

308

305

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Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G q , phospholipase C pathway was ϳ50% of their maximal capacity as determined through inositol phosphate accumulation. These two receptors also showed very high constitutive activity in activation of cAMP response element-driven transcription. GPR39 displayed a clear but lower degree of constitutive activity through the inositol phosphate and cAMP response element pathways. In contrast, GPR39 signaled with the highest constitutive activity in respect of activation of serum response element-dependent transcription, in part, possibly, through G 12/13 and Rho kinase. Antibody feeding experiments demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically be tuned up and down depending on the size and hydrophobicity of the side chain in position VI:16 in the context of an aromatic residue at VII:09 and a large hydrophobic residue at VII:06. It is concluded that the three ghrelin-like receptors display an unusually high degree of constitutive activity, the structural basis for which is determined by an aromatic cluster on the inner face of the extracellular ends of TMs VI and VII.

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“…The metabolic effects of leptin are generally attributed to activation of receptors in the hypothalamus [15]. However, reports indicate that leptin receptor mRNA is present on vagal afferent neurons [16]. Interestingly, the long form of the leptin receptor has been found to be coexpressed with the CCK 1 receptor in a subset of vagal afferents [16].…”

Section: Introductionmentioning

confidence: 99%

“…However, reports indicate that leptin receptor mRNA is present on vagal afferent neurons [16]. Interestingly, the long form of the leptin receptor has been found to be coexpressed with the CCK 1 receptor in a subset of vagal afferents [16]. Thus, CCK-and leptin-derived peptides could have additive therapeutic promise for obesity/diabetes.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

2013

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Aims/hypothesis Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. Methods The actions and overall therapeutic use of (pGluGln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice. Results (pGlu-Gln)-CCK-8 had prominent (p<0.01 to p< 0.001), acute feeding-suppressive effects, which were significantly augmented (p<0.05 to p<0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p<0.05 to p<0.001), energy intake (p<0.01), circulating triacylglycerol (p<0.01), nonfasting glucose (p<0.05 to p<0.001) and triacylglycerol deposition in liver and adipose tissue (p<0.001). All treatment regimens improved glucose tolerance (p<0.05 to p<0.001) and insulin sensitivity (p<0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p<0.001) energy expenditure. Conclusions/interpretationThese studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

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Expression of the leptin receptor in rat and human nodose ganglion neurones

Cited by 119 publications

References 29 publications

The vagus nerve, food intake and obesity

The vagus nerve, food intake and obesity

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

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