Abstract
The effects of spiramycin on adipogenesis and high fat diet (HFD)-induced obesity were investigated. Potential mechanisms contributing to these effects were elucidated. The inhibitory effect of spiramycin on adipocyte differentiation was assessed using 3T3-L1 preadipocyte cells, in which several parameters involved in AMPK signal pathways and lipid metabolism were examined. To further investigate the pharmacological effects of spiramycin in vivo, we examined several obesity-related parameters in HFD-induced obese mice. Spiramycin significantly inhibited preadipocyte differentiation by attenuating intracellular lipid accumulation. Spiramycin also reduced the expression of adipogenic master regulators (PPARγ, C/EBPα, and SREBP1c) and their downstream target genes (FAS, aP2, and GLUT4) in 3T3-L1 cells. In addition, AMPK phosphorylation was increased by spiramycin treatment in 3T3-L1 cells during early differentiation. Notably, HFD-induced obese mice administered spiramycin showed substantial decreases in body weight gain, serum leptin levels, adipose tissue mass, and hepatic lipid accumulation. Moreover, the decreased levels of GPT and GOT in the serum indicated that spiramycin attenuated hepatic injury caused by HFD. Taken together, these results demonstrate for the first time that spiramycin effectively attenuates HFD-induced obesity and hepatic steatosis by inhibiting adipogenesis.
Highlights
Obesity is associated with serious human diseases, including type 2 diabetes, hyperlipidemia and cancer [1]
To investigate the effect of spiramycin on adipogenesis in 3T3-L1 preadipocytes, post-confluent 3T3-L1 cells were induced by differentiation medium (DM) including MDI in the presence of spiramycin
On day 6 after differentiation (Day 6; S1A Fig), spiramycin-treated preadipocytes showed a dose-dependent reduction in Oil red O-stained lipid droplet formation in comparison with that of non-spiramycin-treated positive control cells (Fig 1A, 0 vs. 2.5–20 μM spiramycin)
Summary
Obesity is associated with serious human diseases, including type 2 diabetes, hyperlipidemia and cancer [1]. Adipocytes store excess energy in the form of triglycerides and release energy as glycerol and fatty acids [3]; altered adipocyte function is associated with metabolic disorders. Multiple transcription factors involved in inducing adipogenesis are sequentially activated [7, 8]. During this early stage of adipogenesis, CCAAT/enhancer-binding protein (C/EBP)β and δ induce expression of peroxisome proliferator-activated receptor (PPAR) γ, which induces C/EBPα, which plays a critical role in sterol regulatory element-binding protein (SREBP) 1c expression during the later stages of adipogenesis. Adipocytes control lipid metabolism through lipogenic proteins (e.g. fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC)) and lipolytic enzymes (e.g. hormone-sensitive lipase)
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