Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation
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 r...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001862 |
| _version_ | 1797342244557029376 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Da Mi Kim |
| collection | DOAJ |
| description | 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 Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). 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 ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. 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. |
| first_indexed | 2024-03-08T10:30:30Z |
| format | Article |
| id | doaj.art-6f8f999d1d354a3685b42a6470e37fe0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-08T10:30:30Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-6f8f999d1d354a3685b42a6470e37fe02024-01-27T06:54:36ZengElsevierMolecular Metabolism2212-87782024-01-0179101852Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammationDa Mi Kim0Jong Han Lee1Quan Pan2Hye Won Han3Zheng Shen4Sahar Eshghjoo5Chia-Shan Wu6Wanbao Yang7Ji Yeon Noh8David W. Threadgill9Shaodong Guo10Gus Wright11Robert Alaniz12Yuxiang Sun13Department of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Marine Bioindustry, Hanseo University, Seosan 31962, South Korea; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College Medicine, Houston, TX 77030, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA; Agilent technologies, Aanta Clara, CA 95051, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USA; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College Medicine, Houston, TX 77030, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USA; Texas A&M Institute for Genome Sciences and Society, Department of Cell Biology and Genetics, Texas A&M University, College Station, TX 77843, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USADepartment of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA; Tlaloc Therapeutics Inc., College Station, TX 77845, USADepartment of Nutrition, Texas A&M University, College Station, TX 77843, USA; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College Medicine, Houston, TX 77030, USA; Corresponding author. Department of Nutrition, Texas A&M University, College Station, TX 77843, USA.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 Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). 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 ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. 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.http://www.sciencedirect.com/science/article/pii/S2212877823001862MacrophageGHSRMeta-inflammationMacrophage polarizationInsulin resistanceObesity |
| spellingShingle | 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 Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation Molecular Metabolism Macrophage GHSR Meta-inflammation Macrophage polarization Insulin resistance Obesity |
| title | Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation |
| title_full | Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation |
| title_fullStr | Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation |
| title_full_unstemmed | Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation |
| title_short | Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation |
| title_sort | nutrient sensing growth hormone secretagogue receptor in macrophage programming and meta inflammation |
| topic | Macrophage GHSR Meta-inflammation Macrophage polarization Insulin resistance Obesity |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001862 |
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