Ghrelin increases food intake in obese as well as lean subjects

Druce, Maralyn; Wren, Alison; Park, A J; Milton, Joanne; Patterson, Michael; Frost, Gary; Ghatei, Mohammad A.; Small, Caroline J.; Bloom, Stephen R.

doi:10.1038/sj.ijo.0803001

Cited by 344 publications

(271 citation statements)

References 39 publications

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“…6,[9][10][11] Earlier studies suggest that the adipose tissue also constitutes an important target for the adipogenic actions of ghrelin in rodents. 19,21 This study has explored whether acylated and desacyl ghrelin directly act on visceral adipose tissue for regulating adipocyte metabolism in humans.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8] Administration of exogenous ghrelin reportedly enhances appetite and increases food intake through the activation of hypothalamic neuropeptide Y/agouti-related peptide neurones expressing GHS-R type 1a. 6,[8][9][10][11] Both activities, GH-release and food intake stimulation, require n-octanoyl modification of ghrelin. 1 In addition, ghrelin controls glucose homeostasis by regulating insulin secretion and sensitivity in pancreatic b-cells 12 and by stimulating glucose output by primary hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

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Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

et al. 2009

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Objectives: The orexigenic hormone ghrelin circulates mainly in two forms, acylated and desacyl ghrelin. We evaluated the impact of obesity and obesity-associated type 2 diabetes (T2D) on ghrelin forms and the potential role of acylated and desacyl ghrelin in the control of adipogenesis in humans. Methods: Plasma concentrations of the different ghrelin forms were measured in 80 subjects. The expression of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) was analyzed in omental adipose tissue using western blot and immunohistochemistry, and the effect of acylated ghrelin and desacyl ghrelin (0.1-1000 pmol l À1 ) on adipogenesis was determined in vitro in omental adipocytes. Results: Circulating concentrations of acylated ghrelin were increased, whereas desacyl ghrelin levels were decreased, in obesity and obesity-associated T2D. Body mass index, waist circumference, insulin and HOMA (homeostasis model assessment) index were positively correlated with acylated ghrelin levels. Obese individuals showed a lower protein expression of GHS-R in omental adipose tissue. In differentiating omental adipocytes, incubation with both acylated and desacyl ghrelin significantly increased PPARg (peroxisome proliferator-activated receptor g) and SREBP1 (sterol-regulatory element binding protein-1) mRNA levels, as well as several fat storage-related proteins, including acetyl-CoA carboxylase, fatty acid synthase, lipoprotein lipase and perilipin. Consequently, both the ghrelin forms stimulated intracytoplasmatic lipid accumulation. Conclusions: Both acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Given the lipogenic effect of acylated ghrelin on visceral adipocytes, the herein-reported elevation of its circulating concentrations in obese individuals may play a role in excessive fat accumulation in obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

et al. 2009

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“…14,16 However, peripheral administration of exogenous ghrelin prior to a buffet-style meal has been shown to increase subsequent caloric intake in humans. 19 Furthermore, peripherally administered ghrelin affects meal size in rodents as well, depending on the experimental circumstances. 20,21 This effect on meal size may be explained by the finding that pretreatment with ghrelin was able to completely abolish the effect of CCK on food intake, an effect that seems to be due to ghrelin preventing the activation of vagal nerves by subsequent CCK administration.…”

Section: Introductionmentioning

confidence: 99%

The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature

et al. 2011

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Objective: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. Methods and results: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. Conclusion: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

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“…This modification is critical for ghrelin's active transport across the blood-brain barrier (54) and potent GHSR1a activity (55). Whereas infusion of acylated ghrelin acutely stimulates food intake and subjective hunger (17,56) and chronic administration causes weight gain (6), administration of the hydrolytic degradation product des-acyl ghrelin either does not stimulate appetite or does so less effectively than acylated ghrelin (57). Here, administration of a catalytic antibody that can both bind and degrade ghrelin to its des-acyl form maintained a relatively increased metabolic rate in fasting mice suppressed refeeding after food deprivation.…”

Section: Resultsmentioning

confidence: 99%

Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice

Mayorov

Amara

Chang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is a chronic, costly, and globally prevalent condition, with excess caloric intake a suspected etiologic factor. Nonsurgical treatments are modestly efficacious, and weight loss maintenance is hampered by anti-famine homeostatic mechanisms. Ghrelin, a gastric hormone linked to meal initiation, energy expenditure, and fuel partitioning, is hypothesized to facilitate weight gain and impede weight loss. Unique among known animal peptides, the serine-3 residue of ghrelin is posttranslationally acylated with an n-octanoic acid, a modification important for the peptide's active blood-brain transport and growth hormone secretagogue receptor-1 agonist activity. Pharmacological degradation of ghrelin would be hypothesized to reduce ghrelin's biological effects. To study endogenous ghrelin's role in appetite and energy expenditure, we generated antibodies that hydrolyze the octanoyl moiety of ghrelin to form des-acyl ghrelin. The most proficient antibody catalyst, GHR-11E11, was found to display a second-order rate constant of 18 M ؊ 1⅐s ؊1 for the hydrolysis of ghrelin to des-acyl ghrelin. I.v. administration of GHR-11E11 (50 mg/kg) maintained a greater metabolic rate in fasting C57BL/6J mice as compared with mice receiving a control antibody and suppressed 6-h refeeding after 24 h of food deprivation. Indirect respiratory measures of metabolism after refeeding and relative fuel substrate utilization were unaffected. The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl ghrelin does not potently share these functions. Catalytic anti-ghrelin antibodies might thereby adjunctively aid consolidation of caloric restrictioninduced weight loss and might also be therapeutically relevant to Prader-Willi syndrome, characterized after infancy by hyperghrelinemia, hyperphagia, and obesity.hormone inactivation ͉ obesity ͉ neuropeptides A pproximately 1 billion people worldwide are overweight or obese (body mass index ϭ 25-29.9 or Ͼ30 kg/m 2 , respectively) (1), conditions associated with significant morbidity and mortality and for which new treatments are needed (2). Among recently characterized molecules implicated in energy homeostasis, ghrelin was identified in 1999 during a search for the endogenous ligand for the GH secretagogue receptor (GHSR) (ghrelin receptor), previously localized to peripheral tissues and to several CNS sites, including the arcuate nucleus and ventromedial hypothalamic nucleus (3). Human ghrelin is a 28-amino acid acylated peptide (GSS(n-octanoyl)FLSPEHQRVQQRKESKKPPAKLQPR) released mainly from endocrine cells of the stomach and upper gastrointestinal tract but also expressed in testes, kidney, pituitary, pancreas, lymphocytes, and brain (3-7). Several findings establish gastric ghrelin as an indicator of energy insufficiency and anabolic modulator of energy homeostasis (3). Ghrelin secretion is thought to stimulate food intake, slow metabolic rate, and spare lipid oxidation via central (8) and, possi...

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Ghrelin increases food intake in obese as well as lean subjects

Cited by 344 publications

References 39 publications

Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature

Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice

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