2024-01-16 テキサス A&M大学
◆研究では、GHSRのマクロファージ内での活性が肥満条件下で急増し、マクロファージ内のGHSR欠如が食事誘発性の全身炎症とインスリン抵抗性を減少させることが実証されました。これにより、GHSRの免疫調節機能が明らかになり、マクロファージGHSRの阻害が肥満、糖尿病、炎症の免疫療法として有望である可能性が示唆されました。
<関連情報>
- https://agrilifetoday.tamu.edu/2024/01/16/texas-am-agrilife-research-study-may-lead-to-novel-obesity-treatment/
- https://www.sciencedirect.com/science/article/pii/S2212877823001862#:~:text=GHSR%20is%20a%20critical%20regulator,systemic%20inflammation%20and%20insulin%20resistance.
マクロファージのプログラミングとメタ炎症における栄養感知成長ホルモン分泌促進受容体 Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation
Da Mi Kim, Jong Han Lee, Quan Pan, Hye Won Han, Zheng Shen, Sahar Eshghjoo, Chia-Shan Wu, Wanbao Yang, Ji Yeon Noh, David W. Threadgill, Shaodong Guo, Gus Wright, Robert Alaniz, Yuxiang Sun
Molecular Metabolism Available online: 12 December 2023
DOI:https://doi.org/10.1016/j.molmet.2023.101852
Highlights
•Macrophage GHSR controls meta-inflammation under obesity by regulating macrophage programming.
•In vivo, myeloid-specific Ghsr deficiency (Ghsr-MφKO) attenuates diet-induced systemic inflammation and insulin resistance.
•In eWAT and liver, Ghsr-MφKO reduces diet-induced macrophage infiltration and lipid deposition, showing elevated LAMs.
•In macrophages, GHSR remodels M1 polarization, reprograms metabolic pathways, and stimulates NF-κB nuclear translocation.
•Mechanistically, GHSR promotes M1-macrophage polarization by modulating PKA-CREB-IRS2-AKT2 pathway.
Abstract
Objective
Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global LysM
Methods
LysM–Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For overexpression or Insulin receptor substrate 2 (
Results
We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM–Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM–Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway.
Conclusions
These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity.
Graphical abstract
GHSR is a critical regulator of meta-inflammation. Macrophage GHSR controls immune homeostasis and insulin sensitivity under obesity by regulating macrophage infiltration and polarization. 1. In vivo, myeloid-specific Ghsr deficiency reduces systemic inflammation and insulin resistance. 2. In eWAT and liver, myeloid-specific Ghsr deficiency decreases macrophage infiltration and pro-inflammatory macrophage polarization, thus reducing tissue inflammation, adipose hypertrophy, and hepatic lipid accumulation. 3. Mechanistically, GHSR promotes M1-macrophage polarization by modulating PKA-CREB-IRS2-AKT2 pathway.
