Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss.
BACKGROUND
Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is known to increase food intake in lean humans and rodents. In addition, ghrelin levels are increased by fasting in lean rodents and are elevated before meals in humans, suggesting an important role for ghrelin in meal initiation. However, in obese human, circulating ghrelin levels were found to be significantly reduced as compared to lean individuals.


OBJECTIVE
To evaluate whether circulating ghrelin levels, as well as ghrelin sensitivity, are decreased in obese individuals in order to limit its effect on food intake.


METHODS
: Lean C57BL/6J mice fed a chow, a low- (LFD) or a high-fat diet (HFD) were used to determine ghrelin regulation and secretion as well as ghrelin sensitivity.


METHODS
Plasma ghrelin levels were measured in low- and high-fat fed mice. Ghrelin-induced food intake was measured in chow, low- and high-fat fed mice.


RESULTS
We measured ghrelin levels in lean and diet-induced obese mice, fed on an LFD or an HFD, respectively. We observed that not only ghrelin secretion was reduced in obese mice but its diurnal regulation was also lost. In addition, we failed to observe any change in ghrelin secretion upon fasting and refeeding. Moreover, we observed that the sensitivity to the orexigenic effects of exogenous ghrelin was reduced in obese mice when compared to lean mice fed a chow or a LFD. The insensitivity of obese mice to ghrelin was improved upon weigh loss.


CONCLUSIONS
: Altogether, these results indicate that ghrelin secretion and regulation is impaired in dietary-induced obesity in mice and suggest that ghrelin inhibition could prevent weight regain after weight loss.
Perreault
M
M
Metabolic Diseases Biology Department, Millennium Pharmaceuticals Inc., Cambridge, MA 02140, USA. mperreault@wyeth.com
Istrate
N
N
Wang
L
L
Nichols
A J
AJ
Tozzo
E
E
Stricker-Krongrad
A
A
D000818:Animals; D002940:Circadian Rhythm; D004041:Dietary Fats / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005215:Fasting / Q000097:blood; D054439:Ghrelin; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D036361:Peptide Hormones / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D015431:Weight Loss / Q000502:physiology
D004041:Dietary Fats; D054439:Ghrelin; D036361:Peptide Hormones