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Title: The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

Author
item LIN, LIGIN - Children'S Nutrition Research Center (CNRC)
item LEE, JONG HAN - Children'S Nutrition Research Center (CNRC)
item BONGMBA, ODELIA - Children'S Nutrition Research Center (CNRC)
item MA, XIAOJUN - Zhengzhou University
item ZHU, XIONGWEI - Case Western Reserve University (CWRU)
item SHEIKH-HAMAD, DAVID - Case Western Reserve University (CWRU)
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/12/2014
Publication Date: 12/15/2014
Citation: Lin, L., Lee, J., Bongmba, O., Ma, X., Zhu, X., Sheikh-Hamad, D., Sun, Y. 2014. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment. Aging. 6:(12):1019-1032.

Interpretive Summary: Aging is associated with increased obesity. It is known that increased energy storing in white fat and/or decreased energy burning in brown fat can lead to obesity. Ghrelin is the only known hormone in the circulation which promotes obesity. In this study, we have shown that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) results in reduced fat and preserves a healthy metabolic profile. Old Ghsr-deleted mice have similar food intake and physical activity, but have increased energy expenditure. Our data further revealed that GHS-R modulates the function of brown fat. The brown fat of old Ghsr-deleted mice produces more heat, thus consuming fat. Hence, GHS-R plays an important role in energy metabolism during aging. GHS-R blockers may be a new means of combating obesity by fat burning.

Technical Abstract: Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis.