1. Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression.
- Author
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Lee HW, Karki R, and Han JH
- Subjects
- Animals, Mice, 3T3-L1 Cells drug effects, Adipocytes drug effects, Adipocytes metabolism, Adipogenesis drug effects, Adipose Tissue, White drug effects, Adipose Tissue, White metabolism, Diet, High-Fat adverse effects, Mice, Inbred C57BL, Mitosis drug effects, Signal Transduction drug effects, Cell Proliferation drug effects, Citrates pharmacology, Citrates therapeutic use, Forkhead Box Protein O1 antagonists & inhibitors, Forkhead Box Protein O1 metabolism, Obesity drug therapy, Obesity metabolism, Ribosomal Protein S6 Kinases, 90-kDa antagonists & inhibitors, Ribosomal Protein S6 Kinases, 90-kDa metabolism
- Abstract
Background: Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (-)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood., Purpose: This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements., Methods: Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo., Results: Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G
0 /G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro., Conclusions: These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity., Competing Interests: 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. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy, (Copyright © 2024 Elsevier GmbH. All rights reserved.)- Published
- 2024
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