Small-Molecule Ghrelin Receptor Antagonists Improve Glucose Tolerance, Suppress Appetite, and Promote Weight Loss

Esler, William P.; Rudolph, Joachim; Claus, Thomas H.; Tang, Weifeng; Barucci, Nicole; Brown, Su-Ellen; Bullock, William H.; Daly, Michelle; DeCarr, Lynn B.; Li, Yaxin; Milardo, Lucinda F.; Molstad, David H. H.; Zhu, Jian; Gardell, Stephen J.; Livingston, James N.; Sweet, Laurel J.

doi:10.1210/en.2007-0239

Cited by 212 publications

(169 citation statements)

References 52 publications

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“…The orexigenic and adipogenic effects of ghrelin can be suppressed by ghrelin antagonists (Asakawa et al 2003;Esler et al 2007;Salomé et al 2009a;Salomé et al 2009b). One week peripheral treatment of rats with the GHS-R1A antagonist, JMV2959, suppressed preference for palatable/rewarding food, and they did not gain as much weight as the vehicle-treated control rats .…”

Section: The Central Ghrelin Signalling System Is Required For Rewardmentioning

confidence: 99%

The role of the central ghrelin system in reward from food and chemical drugs

Dickson

Egecioglu

Landgren

et al. 2011

Molecular and Cellular Endocrinology

217

168

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Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergicdopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA

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Section: The Central Ghrelin Signalling System Is Required For Rewardmentioning

confidence: 99%

The role of the central ghrelin system in reward from food and chemical drugs

Dickson

Egecioglu

Landgren

et al. 2011

Molecular and Cellular Endocrinology

217

168

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“…A number of orally available GHS-R1a antagonists have also been developed, the most promising of which have been shown in rodents to cause reductions in food intake and body weight and to improve glucose tolerance [206,207]. However, a viable treatment for human obesity has yet to emerge from any of these strategies.…”

Section: Ghrelinmentioning

confidence: 99%

Obesity treatment: novel peripheral targets

Field¹,

Chaudhri²,

Bloom³

2009

Brit J Clinical Pharma

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Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short-and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

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“…This was shown to be the case, 16 and interestingly, in a recent study, it took 10 days for animals to compensate for the loss of ghrelin. 17 The magnitude of the reduction of food intake was substantial, being more than 25% over a few days, which reached a maximum of 50% before adaptation occurred. Although these data suggest that other orexigenic signals exist, it is not clear whether these are true hunger signals, and whether they are central or peripheral in origin.…”

mentioning

confidence: 96%

Peripheral satiety signals: view from the Chair

Sharkey

2009

Int J Obes

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The discovery and characterization of peripheral signals that regulate food intake and energy balance dates back over 50 years. Beginning with the 'glucostatic' and 'lipostatic' hypotheses, nutrients were considered strong candidates that could 'tell' the brain the state of satiety (glucose) or overall energy stores (fat), so that food intake and energy expenditure could be regulated to maintain energy balance. 1,2 Both of these hypotheses endure to this day. The lipostatic hypothesis remains as a central concept in our understanding of the regulation of energy balance. This is based on the key observations that (a) insulin is secreted from the pancreas in direct proportion to fat stores and provides a signal to the brain to initiate long-term changes in energy expenditure and food intake 3 and (b) the peptide hormone leptin is released from adipose tissue itself, and defects in either the production or the signalling of leptin lead to obesity. 4 The glucostatic hypothesis received validation with the discovery of glucose-sensitive neurons in the hypothalamic regions involved in the control of energy balance. 5,6 Over the years, other nutrient-based hypotheses were developed and the existing ones were modified, but none of these were completely capable of explaining the shortterm control of food intake or certain aspects of long-term energy balance. In the early 1970s, Gibbs et al. 7 found a gastrointestinal hormone, cholecystokinin (CCK), that produced satiety in rats. This discovery heralded the era of the 'gut hormones' as regulators of both food intake and energy balance. We now recognize more than 20 gut-derived peptides and lipid mediators are involved in aspects of energy homeostasis. [8][9][10] Many of these have now been tested or developed as potential therapeutic agents for the treatment of metabolic disorders or to aid in weight management. It seems unlikely that the full complement of peripheral energy balance signals have been discovered. As more are found, the opportunities for the development of novel therapeutics must be balanced with challenges of understanding their role in the physiology and pathophysiology of this complex regulatory system. Major challenges remain: How do the plethora of peripheral signals get integrated in the brain? Similarly, how does the brain actually receive these signals in the first place? In the three articles following this viewpoint, Timothy Moran, 11 Harvey Grill, 12 and Alastair Ferguson 13 and their colleagues begin to address these challenges by outlining where signals released from the gut and adipose tissues act to regulate energy balance.Peripheral signals arising from the gut are key elements in food intake regulation and energy balance, as discussed by Timothy Moran. 11 He illustrates how enteroendocrine peptides are released in sequence along the length of the gut and across the duration of a meal. These peptides regulate both the initiation of a meal and its termination. There are a multitude of anorexigenic peptide signals released from the gut. Moran ...

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Small-Molecule Ghrelin Receptor Antagonists Improve Glucose Tolerance, Suppress Appetite, and Promote Weight Loss

Cited by 212 publications

References 52 publications

The role of the central ghrelin system in reward from food and chemical drugs

The role of the central ghrelin system in reward from food and chemical drugs

Obesity treatment: novel peripheral targets

Peripheral satiety signals: view from the Chair

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