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Title: Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

item MA, XIAOJUN - Children'S Nutrition Research Center (CNRC)
item LIN, LIGEN - Children'S Nutrition Research Center (CNRC)
item QIN, GUIJUN - Zhengzhou University
item LU, XINPING - National Institutes Of Health (NIH)
item FIOROTTO, MARTA - Arkansas Children'S Nutrition Research Center (ACNC)
item DIXIT, VISHWA - Louisiana State University
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: PLoS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/14/2010
Publication Date: 1/26/2011
Citation: Ma, X., Lin, L., Qin, G., Lu, X., Fiorotto, M.L., Dixit, V.D., Sun, Y. 2011. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging. PLoS One. 6(1),e16391:1-10.

Interpretive Summary: Ghrelin is a hormone produced by the stomach that increases growth hormone, stimulates appetite, and causes fat deposition. In this study we compared the metabolism of normal mice to mice that either do not make or do not respond to ghrelin. We found no differences among mice when they were young adults. As they aged, however, we observed that the mice who do not respond to ghrelin did not get as fat as the other mice (i.e., the normal mice and the mice that do not make ghrelin) even though they ate the same amount of food and were all equally active. This response occurred because the ghrelin nonresponders maintained higher metabolic rates. They were able to do this because their brown fat which, unlike white fat, burns energy and generates heat had become more active. This is the first direct evidence that ghrelin can regulate energy expenditure, and provides a potential target for preventing excessive fat deposition with aging.

Technical Abstract: Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Ghrl"(-/-) mice have impaired thermoregulatory responses to cold and fasting stresses, while "Ghsr"(-/-) mice are adaptive. To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3–4 months) and older (10–12 months) "Ghrl"(-/-) and "Ghsr"(-/-) mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older "Ghsr"(-/-) mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in "Ghrl"(-/-) mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of "Ghsr"(-/-) mice, but not in "Ghrl"(-/-) mice. In conclusion, our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as yet-unidentified new ligand of GHS-R.