Abstract
Cilostazol is a selective inhibitor of phosphodiesterase type 3 (PDE3) that increases intracellular cyclic adenosine monophosphate (cAMP), which plays a critical role in the development of the beige phenotype and the activation of its thermogenic program in white adipose tissue (WAT). We investigated the metabolic effects of PDE3B inhibition with cilostazol treatment in the adipose tissue of high-fat diet (HFD)-fed mice. Seven-week-old male C57BL/6J mice were randomly assigned to either the cilostazol or control group. The control group was divided into two groups: the chow diet and HFD. The expression of uncoupling Protein 1 (UCP1) and other brown adipocyte markers was compared. In the HFD-fed cilostazol group, C57BL/6J mice displayed improvements in systemic metabolism, including improved glucose tolerance and lipid profile, but only modest effects on body weight were observed. In the visceral WAT of HFD-fed cilostazol-treated mice, cAMP/protein kinase A (PKA) signaling pathways were activated, resulting in the "browning" phenotype, smaller fat deposits, and enhanced mRNA expression of UCP1 and other brown adipocyte markers. PDE3B appears to be an important regulator of lipid metabolism, insulin sensitivity, and thermogenic programs in adipose tissues. An increase in intracellular cAMP via PDE3B inhibition with cilostazol treatment promoted the browning of visceral WAT.