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

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.

• Authors: Jong Han Lee, Chuo Fang, Xin Li, Chia Shan Wu, Ji Yeon Noh, Xiangcang Ye, Robert S Chapkin, Kai Sun, Yuxiang Sun
• Journal: International journal of obesity (2005) (Int J Obes (Lond)) Vol. 45 Issue 7 Pg. 1565-1575 (07 2021) ISSN: 1476-5497 [Electronic] England
• PMID: 33903722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adiponectin
• Receptors, Ghrelin

Topics

• Adipocytes (cytology, metabolism)
• Adiponectin (metabolism)
• Adipose Tissue (blood supply, metabolism)
• Animals
• Diet, High-Fat
• Fibrosis (metabolism)
• Insulin Resistance (genetics)
• Male
• Mice
• Obesity (metabolism)
• Receptors, Ghrelin (genetics, metabolism)
• Thermogenesis (genetics)