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Int J Mol Sci. 2018 Oct 1;19(10). pii: E3002. doi: 10.3390/ijms19103002.

aP2-Cre Mediated Ablation of GHS-R Attenuates Adiposity and Improves Insulin Sensitivity during Aging.

Author information

1
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. ligenl@umac.mo.
2
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China. ligenl@umac.mo.
3
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. jhleecw@gmail.com.
4
College of Pharmacy, Gachon University, Incheon 21936, Korea. jhleecw@gmail.com.
5
Institute of Critical Care Medicine, Heilongjiang Academy of Medical Science, Heilongjiang 150081, China. ruitaowang@126.com.
6
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China. wangru0612@163.com.
7
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. sheikh@bcm.edu.
8
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. qun.zang@utsouthwestern.edu.
9
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Yuxiang.Sun@tamu.edu.
10
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA. Yuxiang.Sun@tamu.edu.

Abstract

Ghrelin via its receptor, the growth hormone secretagogue receptor (GHS-R), increases food intake and adiposity. The tissue-specific functions of GHS-R in peripheral tissues are mostly unknown. We previously reported that while GHS-R expression is very low in white and brown fat of young mice, expression increases during aging. To investigate whether GHS-R has cell-autonomous effects in adipose tissues, we generated aP2-Cre-mediated GHS-R knockdown mice (aP2-Cre/Ghsrf/f). We studied young (5⁻6 months) and old (15⁻17 months) aP2-Cre/Ghsrf/f mice and their age-matched controls. Interestingly, young aP2-Cre/Ghsrf/f mice had normal body weight but reduced fat; old mice showed pronounced reductions of both body weight and body fat. Calorimetry analysis revealed that aP2-Cre/Ghsrf/f mice had normal food intake and locomotor activity at both young and old age; but intriguingly, while energy expenditure was normal at young age, it was significantly increased at old age. Both young and old aP2-Cre/Ghsrf/f mice exhibited improved insulin sensitivity and glucose tolerance. Importantly, old aP2-Cre/Ghsrf/f mice maintained higher core body temperature at 4 °C, and showed higher expression of the thermogenic uncoupling protein 1 (UCP1) gene. The ex vivo studies further demonstrated that GHS-R deficient white adipocytes from old mice exhibit increased glucose uptake and lipolysis, promoting lipid mobilization. Despite the fact that the in vivo phenotypes of aP2-Cre/Ghsrf/f mice may not be exclusively determined by GHS-R knockdown in adipose tissues, our data support that GHS-R has cell-autonomous effects in adipocytes. The anabolic effect of GHS-R in adipocytes is more pronounced in aging, which likely contributes to age-associated obesity and insulin resistance.

KEYWORDS:

GHS-R; UCP1; adipose tissues; ghrelin; thermogenesis; tissue-specific knockdown mice

PMID:
30275401
PMCID:
PMC6213105
DOI:
10.3390/ijms19103002
[Indexed for MEDLINE]
Free PMC Article

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