Abstract
Obesity is a worldwide public health problem, which is associated with various severe diseases including diabetes, hypertension, atherosclerosis, and cancer. Recent studies have revealed that combination treatment of several different compounds using low doses is effective to reduce side effects. Thus, there is a need to develop an efficient inhibitor for reducing lipid droplets with a divergent target/pathway. Ser/Thr protein phosphatase PPM1D is involved in cellular metabolic processes and is a promising target for anti-obesity treatment. We have previously developed a potent and specific PPM1D inhibitor, SL-176. In this study, we demonstrated that significant reduction of lipid droplet formation in adipocytes by the PPM1D specific inhibitor, SL-176. Using Oil-red O staining and fluorescent imaging of lipid droplet, we found that treatment of SL-176 significantly suppressed lipid droplet formation of 3T3-L1 cells both in amount and in size. SL-176 also repressed mRNA and protein expression of PPARγ and C/EBPα, adipogenic markers, at nontoxic conditions. Thus, SL-176 is a unique and potent inhibitor of lipid droplet formation that acts via PPM1D, a novel target toward inhibiting adipocyte differentiation.
Highlights
Obesity, a significant risk factor for multiple diseases including diabetes, heart disease, hypertension, and cancer, is becoming a global public health problem
To analyze whether the PPM1D inhibitor SL-176 suppresses lipid droplet formation in adipocytes, 3T3-L1 preadipocytes were induced to differentiate into adipocyte in the absence or presence of SL-176
Quantitative analysis showed that treatment with 15 μM of SL-176 significantly decreased the amount of lipid droplets to 32% compared with control cells (Fig 1C)
Summary
A significant risk factor for multiple diseases including diabetes, heart disease, hypertension, and cancer, is becoming a global public health problem. Most compounds have unknown mechanisms and unknown target pathways of inhibitory activity for lipid droplet formation. We report a novel and potent inhibition activity of adipocyte differentiation by SL-176, which suppresses PPM1D phosphatase activity and leads to down-regulation of the PPARγ pathway.
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