Potent Anti-adipogenic Activity of Cyclopeptide Mallotumide A on Murine 3T3-L1 Adipocytes

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value of approximately 1 nM in preadipocytes. Notably, mature adipocytes maintained nearly 100% viability at concentrations from 0.001 to 1 nM, defining a nontoxic range to investigate the compound's modulation of lipid metabolism and differentiation. Treatment of preadipocytes with 1 nM Mallotumide A throughout the 10 day adipogenic differentiation process inhibited maturation into late-stage adipocytes and abolished lipid droplet accumulation. This effect was driven by the sustained downregulation of the master adipogenic regulators C/EBPα and PPARγ across both the early and late stages of differentiation. The disruption of these core transcriptional drivers subsequently reduced the expression of lipogenic enzymes, including pyruvate carboxylase, acetyl-CoA carboxylase 1, and fatty acid synthase, thereby preventing the maturation of the adipocytes. Mallotumide A also impaired growth signaling by reducing Akt protein. In contrast, stress-activated kinases, including JNK and p38, were not affected. The impaired differentiation was not attributed to apoptosis induction, as neither caspase-3 protein level nor caspase-3/7 activity was altered. The analysis of oxygen consumption profiles revealed that Mallotumide A did not significantly impair major mitochondrial bioenergetic parameters. However, in immature adipocytes, Mallotumide A moderately reduced mitochondrial spare respiratory capacity while maintaining normal basal and ATP-linked respiration. Collectively, these findings indicate that Mallotumide A predominantly targets both the early and late stages of differentiation. This effect is mediated through the downregulation of key adipogenic regulators and lipogenic enzymes, alongside the partial modulation of mitochondrial metabolism.

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