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Animal Models

GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis

International Journal of Obesity volume 45, pages 1565–1575 (2021)Cite this article

Subjects

Abstract

Background/Objectives

Ghrelin is an orexigenic hormone that increases food intake, adiposity, and insulin resistance through its receptor Growth Hormone Secretagogue Receptor (GHS-R). We previously showed that ghrelin/GHS-R signaling has important roles in regulation of energy homeostasis, and global deletion of GHS-R reduces obesity and improves insulin sensitivity by increasing thermogenesis. However, it is unknown whether GHS-R regulates thermogenic activation in adipose tissues directly.

Methods

We generated a novel adipose tissue-specific GHS-R deletion mouse model and characterized the mice under regular diet (RD) and high-fat diet (HFD) feeding. Body composition was measured by Echo MRI. Metabolic profiling was determined by indirect calorimetry. Response to environmental stress was assessed using a TH-8 temperature monitoring system. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Tissue histology was analyzed by hematoxylin/eosin and immunofluorescent staining. Expression of genes involved in thermogenesis, angiogenesis and fibrosis in adipose tissues were analyzed by real-time PCR.

Results

Under RD feeding, adipose tissue-specific GHS-R deletion had little or no impact on metabolic parameters. However, under HFD feeding, adipose tissue-specific GHS-R deletion attenuated diet-induced obesity and insulin resistance, showing elevated physical activity and heat production. In addition, adipose tissue-specific GHS-R deletion increased expression of master adipose transcription regulator of peroxisome proliferator-activated receptor (PPAR) γ1 and adipokines of adiponectin and fibroblast growth factor (FGF) 21; and differentially modulated angiogenesis and fibrosis evident in both gene expression and histological analysis.

Conclusions

These results show that GHS-R has cell-autonomous effects in adipocytes, and suppression of GHS-R in adipose tissues protects against diet-induced obesity and insulin resistance by modulating adipose angiogenesis and fibrosis. These findings suggest adipose GHS-R may constitute a novel therapeutic target for treatment of obesity and metabolic syndrome.

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Fig. 1: Validation of Adipoq-Cre;Ghsrf/f mouse model and adipose tissue-specific GHS-R deletion reduced body weight and fat mass under HFD feeding.
Fig. 2: HFD-fed adipose tissue-specific GHS-R deletion improved insulin sensitivity.
Fig. 3: Adipose tissue-specific GHS-R deletion had no effect on thermogenesis.
Fig. 4: Adipose tissue-specific GHS-R deletion did not affect lipogenesis but increased transcription factor PPARγ1, and adipokines of FGF21 and adiponectin in epiWAT.
Fig. 5: Adipose tissue-specific GHS-R deletion modulated angiogenesis and fibrosis in epiWAT under HFD feeding.
Fig. 6: Schematic diagram of the proposed actions of GHS-R in adipose tissue under obesity.

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Acknowledgements

Metabolic analysis was performed in the Mouse Metabolic Research Unit at the USDA/ARS Children’s Nutrition Research Center (CNRC), Baylor College of Medicine. This study was supported by NIH 1R01DK118334 and AG064869, and BrightFocus A2019630S (YS). This work was also supported in part by the USDA National Institute of Food and Agriculture Hatch project 1010840 and Multistate Research NE1939 (YS), NIH P30 ES029067(PI: David Threadgill), and NIH DK109001 (KS).

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Author notes

  1. These authors contributed equally: Jong Han Lee, Chuo Fang

Authors and Affiliations

  1. USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Jong Han Lee & Yuxiang Sun

  2. Department of Marine Bio and Medical Sciences, Hanseo University, Seosan, Korea

    Jong Han Lee

  3. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA

    Chuo Fang

  4. Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA

    Xin Li & Kai Sun

  5. Department of Nutrition, Texas A&M University, College Station, TX, USA

    Chia Shan Wu, Ji Yeon Noh, Xiangcang Ye, Robert S. Chapkin & Yuxiang Sun

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Contributions

JHL, CF, XL, and JYN conducted research and analyzed data; JHL, CF, XY, and YS. wrote the paper. RSC, KS consulted the study. All authors read and approved the final paper.

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Correspondence to Yuxiang Sun.

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Lee, J.H., Fang, C., Li, X. et al. GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis. Int J Obes 45, 1565–1575 (2021). https://doi.org/10.1038/s41366-021-00820-7

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