PMID- 38092245 OWN - NLM STAT- MEDLINE DCOM- 20240129 LR - 20240210 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 79 DP - 2024 Jan TI - Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation. PG - 101852 LID - S2212-8778(23)00186-2 [pii] LID - 10.1016/j.molmet.2023.101852 [doi] LID - 101852 AB - 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;Ghsr(f/f)). METHODS: LysM-Cre;Ghsr(f/f) and control Ghsr(f/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;Ghsr(f/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;Ghsr(f/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-kappaB 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. CI - Copyright (c) 2023 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Kim, Da Mi AU - Kim DM AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Lee, Jong Han AU - Lee JH AD - Department 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, USA. FAU - Pan, Quan AU - Pan Q AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Han, Hye Won AU - Han HW AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Shen, Zheng AU - Shen Z AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Eshghjoo, Sahar AU - Eshghjoo S AD - Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA; Agilent technologies, Aanta Clara, CA 95051, USA. FAU - Wu, Chia-Shan AU - Wu CS AD - Department 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. FAU - Yang, Wanbao AU - Yang W AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Noh, Ji Yeon AU - Noh JY AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Threadgill, David W AU - Threadgill DW AD - Department 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, USA. FAU - Guo, Shaodong AU - Guo S AD - Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. FAU - Wright, Gus AU - Wright G AD - Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA. FAU - Alaniz, Robert AU - Alaniz R AD - Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA; Tlaloc Therapeutics Inc., College Station, TX 77845, USA. FAU - Sun, Yuxiang AU - Sun Y AD - Department 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. Electronic address: Yuxiang.Sun@tamu.edu. LA - eng GR - P30 ES029067/ES/NIEHS NIH HHS/United States GR - R01 AG064869/AG/NIA NIH HHS/United States GR - R01 DK118334/DK/NIDDK NIH HHS/United States GR - R01 DK120968/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20231212 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (Receptors, Ghrelin) RN - 0 (Lipopolysaccharides) SB - IM MH - Mice MH - Animals MH - *Receptors, Ghrelin/genetics/metabolism MH - *Insulin Resistance/physiology MH - Lipopolysaccharides/metabolism MH - Inflammation/metabolism MH - Macrophages/metabolism MH - Mice, Knockout MH - Obesity/metabolism MH - Nutrients PMC - PMC10772824 OTO - NOTNLM OT - GHSR OT - Insulin resistance OT - Macrophage OT - Macrophage polarization OT - Meta-inflammation OT - Obesity COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/12/14 00:42 MHDA- 2024/01/29 06:42 PMCR- 2023/12/12 CRDT- 2023/12/13 19:27 PHST- 2023/10/11 00:00 [received] PHST- 2023/12/03 00:00 [revised] PHST- 2023/12/08 00:00 [accepted] PHST- 2024/01/29 06:42 [medline] PHST- 2023/12/14 00:42 [pubmed] PHST- 2023/12/13 19:27 [entrez] PHST- 2023/12/12 00:00 [pmc-release] AID - S2212-8778(23)00186-2 [pii] AID - 101852 [pii] AID - 10.1016/j.molmet.2023.101852 [doi] PST - ppublish SO - Mol Metab. 2024 Jan;79:101852. doi: 10.1016/j.molmet.2023.101852. Epub 2023 Dec 12.