Effects of a Phosphodiesterase inhibitor on the Browning of Adipose Tissue in Mice

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.

Effects of allicin on human Simpson-Golabi-Behmel syndrome cells in mediating browning phenotype

“…Allicin is known to increase intracellular cAMP by inhibiting phosphodiesterase activity in isolated human platelets (66,67) or by increasing adenylate cyclase activity in the human bronchial epithelial cell line (68). In adipose tissue, PDE3 inhibitors increase intracellular cAMP levels, thereby enhancing lipolysis (69). The present results showed a significant up-regulation of PDE3B in ALLI_CTRL and cAMP_CTRL (Supplementary Table 1), resulting in an increase in intracellular cAMP and downstream genes involved in lipolysis, such as LIPE and PLIN1, and in browning, such as TBX1 and UCP1 (Supplementary Table 1).…”

Gut microbiota turn up the heat after bariatric surgery

“…Like the sympathetic nervous system, licoricidin recruited the protein kinase A (PKA) signalling pathway in primary subcutaneous white adipocytes as shown through phosphoblots of PKA substrates including cyclic AMP response element binding protein (CREB). Interestingly, the tripling of intacellular cAMP levels by licoricidin treatment did not appear to be due to the inhibition of phosphodiesterases 3 and 4 which is known to promote thermogenesis in epididymal white fat [20,21] and subcutaneous white fat [22], respectively. Instead, through a combination of confocal microscopy on primary subcutaneous white adipocytes, pull-down assays on beta-3 adrenergic receptor-overexpressing human embryonic kidney (HEK) cells and bioinformatic analysis, licoricidin was shown to bind to transmembrane 3 (TM3), TM6 and TM7 of the beta-3 adrenergic receptor.…”

The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis

“…It Is noteworthy that the Increase In cAMP triggered by cilostazol treatment affects norepinephrine, thus increasing fat metabolism and exothermic reactions, and consequently increasing energy consumption. Cilostazol can increase uncoupling protein 1 (UCP1) in adipocytes [ 91 ]. Regulating the expression of UCP1 and PGC1α through cAMP-responsive element binding (CREB) and increasing free fatty acid release through lipolysis are used as fuel for thermogenesis in mitochondria [ 92 ].…”