Durgesh Kumar1,2, Sanket Kumar Pandya2,3, Salil Varshney1,2, Kripa Shankar1, Sujith Rajan1,2, Ankita Srivastava1,2, Abhishek Gupta1, Sanchita Gupta1,2, Achchhe Lal Vishwakarma4, Amit Misra3, Anil N Gaikwad5. 1. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 2. Academy of Scientific and Innovative Research, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 3. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 4. Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 5. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. anil_gaikwad@cdri.res.in.
Abstract
BACKGROUND/ OBJECTIVES: Chronic low-grade inflammation/meta-inflammation in adipose tissue leads to obesity-associated metabolic complications. Despite growing understanding, the roles of immune cell subsets, their interrelationship, and chronological events leading to progression of obesity-associated insulin resistance (IR) remains unclear. METHODS: We carried out temporal immunometabolic profiling of adipose tissue from C57BL/6 mice fed a high-fat diet (HFD) for 4, 8, 12, 16, and 20 weeks. We used clodronate sodium liposomes (CLODs) to deplete macrophages and disodium cromoglycate sodium liposomes (DSCGs) to stabilize mast cells. RESULTS: In the temporal HFD settings, mice showed progressive glucose intolerance, insulin resistance, and adipose tissue senescence. Histochemistry analysis of epididymal white adipose tissue (eWAT) using picro-sirius red and Masson's trichrome staining showed extensive collagen deposition in the 16th and 20th weeks. Flow cytometry analysis of the stromal vascular fraction (SVF) from eWAT revealed T-cell subsets as early-phase components and pro-inflammatory macrophages, as well as mast cells as the later phase components during obesity progression. In our therapeutic strategies, macrophage depletion by CLOD and mast stabilization by DSCG attenuated obesity, adipose tissue fibrosis, and improved whole-body glucose homeostasis. In addition, mast cell stabilization also attenuated senescence (p53 and X-gal staining) in eWAT, signifying the role of mast cells over macrophages during obesity. CONCLUSION: New-generation mast cell stabilizers can be exploited for the treatment of obesity-associated metabolic complications.
BACKGROUND/ OBJECTIVES: Chronic low-grade inflammation/meta-inflammation in adipose tissue leads to obesity-associated metabolic complications. Despite growing understanding, the roles of immune cell subsets, their interrelationship, and chronological events leading to progression of obesity-associated insulin resistance (IR) remains unclear. METHODS: We carried out temporal immunometabolic profiling of adipose tissue from C57BL/6 mice fed a high-fat diet (HFD) for 4, 8, 12, 16, and 20 weeks. We used clodronate sodium liposomes (CLODs) to deplete macrophages and disodium cromoglycate sodium liposomes (DSCGs) to stabilize mast cells. RESULTS: In the temporal HFD settings, mice showed progressive glucose intolerance, insulin resistance, and adipose tissue senescence. Histochemistry analysis of epididymal white adipose tissue (eWAT) using picro-sirius red and Masson's trichrome staining showed extensive collagen deposition in the 16th and 20th weeks. Flow cytometry analysis of the stromal vascular fraction (SVF) from eWAT revealed T-cell subsets as early-phase components and pro-inflammatory macrophages, as well as mast cells as the later phase components during obesity progression. In our therapeutic strategies, macrophage depletion by CLOD and mast stabilization by DSCG attenuated obesity, adipose tissue fibrosis, and improved whole-body glucose homeostasis. In addition, mast cell stabilization also attenuated senescence (p53 and X-gal staining) in eWAT, signifying the role of mast cells over macrophages during obesity. CONCLUSION: New-generation mast cell stabilizers can be exploited for the treatment of obesity-associated metabolic complications.
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