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Research Project: Developmental Determinants of Obesity in Infants and Children

Location: Children's Nutrition Research Center

Title: Ghrelin receptor regulates adipose tissue inflammation in aging

Author
item Lin, Ligen - Children's Nutrition Research Center (CNRC)
item Lee, Jong Han - Children's Nutrition Research Center (CNRC)
item Buras, Eric - University Of Michigan
item Yu, Kaijiang - Harbin Medical University
item Wang, Ruitao - Harbin Medical University
item Smith, C. Wayne - Children's Nutrition Research Center (CNRC)
item Wu, Huaizhu - Baylor College Of Medicine
item Sheikh-hamad, David - Baylor College Of Medicine
item Sun, Yuxiang - Children's Nutrition Research Center (CNRC)

Submitted to: Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2016
Publication Date: 1/30/2016
Citation: Lin, L., Lee, J., Buras, E.D., Yu, K., Wang, R., Smith, C., Wu, H., Sheikh-Hamad, D., Sun, Y. 2016. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging. 8(1):178-191.

Interpretive Summary: Aging is commonly associated with low-grade adipose inflammation, which is linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive characteristics. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that old Ghsr(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. Our studies suggest that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

Technical Abstract: Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.