Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression

Phytomedicine. 2024 Jun:128:155551. doi: 10.1016/j.phymed.2024.155551. Epub 2024 Mar 20.

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 G0/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.

Keywords: Adipogenesis; FoxO1; Hydroxycitric acid; Mitotic clonal expansion; Obesity; RPS6KA1.

MeSH terms

  • 3T3-L1 Cells / drug effects
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipogenesis / drug effects
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Cell Proliferation* / drug effects
  • Citrates* / pharmacology
  • Citrates* / therapeutic use
  • Diet, High-Fat / adverse effects
  • Forkhead Box Protein O1* / antagonists & inhibitors
  • Forkhead Box Protein O1* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitosis / drug effects
  • Obesity* / drug therapy
  • Obesity* / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa* / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa* / metabolism
  • Signal Transduction / drug effects

Substances

  • Citrates
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • hydroxycitric acid
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse