cl-316243 and cilostamide

Repeated activation of the beta 3 adrenergic receptor (β3AR) with the agonist CL 316,243 (CL) results in remodeling of white adipose tissue (WAT) characterized by increased mitochondrial enzymes and expression of uncoupling protein 1 (UCP1). β3AR activation also has profound acute metabolic effects including rapidly decreasing blood glucose, secondary to fatty acid-induced increases in insulin, and increasing energy expenditure. The acute (single dose) effects of β3AR activation have largely been examined in treatment naive animals and under room temperature housing conditions. The current study examined if repeated CL treatment would lead to an attenuation of acute metabolic effects of CL treatment under thermoneutral housing conditions and if this could be rescued with cilostamide, a phosphodiesterase inhibitor. We provide evidence demonstrating that the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not increases in energy expenditure, are attenuated in mice following repeated treatment with CL. This occurs in parallel with reductions in indices of protein kinase A signaling in WAT including the phosphorylation of hormone sensitive lipase. The findings of attenuated serum fatty acid, insulin, and blood glucose responses were confirmed in both high-fat fed and UCP1

Topics: Adipose Tissue; Animals; Blood Glucose; Dioxoles; Fatty Acids; Hypoglycemic Agents; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Phosphodiesterase Inhibitors; Quinolones; Thermogenesis; Uncoupling Protein 1

Obesity is linked to various diseases, including insulin resistance, diabetes, and cardiovascular disorders. The idea of inducing white adipose tissue (WAT) to assume characteristics of brown adipose tissue (BAT), and thus gearing it to fat burning instead of storage, is receiving serious consideration as potential treatment for obesity and related disorders. Phosphodiesterase 3B (PDE3B) links insulin- and cAMP-signaling networks in tissues associated with energy metabolism, including WAT. We used C57BL/6 PDE3B knockout (KO) mice to elucidate mechanisms involved in the formation of BAT in epididymal WAT (EWAT) depots. Examination of gene expression profiles in PDE3B KO EWAT revealed increased expression of several genes that block white and promote brown adipogenesis, such as C-terminal binding protein, bone morphogenetic protein 7, and PR domain containing 16, but a clear BAT-like phenotype was not completely induced. However, acute treatment of PDE3B KO mice with the β3-adrenergic agonist, CL316243, markedly increased the expression of cyclooxygenase-2, which catalyzes prostaglandin synthesis and is thought to be important in the formation of BAT in WAT and the elongation of very long-chain fatty acids 3, which is linked to BAT recruitment upon cold exposure, causing a clear shift toward fat burning and the induction of BAT in KO EWAT. These data provide insight into the mechanisms of BAT formation in mouse EWAT, suggesting that, in a C57BL/6 background, an increase in cAMP, caused by ablation of PDE3B and administration of CL316243, may promote differentiation of prostaglandin-responsive progenitor cells in the EWAT stromal vascular fraction into functional brown adipocytes.

Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic beta-3 Receptor Agonists; Adult Stem Cells; Animals; Biomarkers; Crosses, Genetic; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclooxygenase 2; Dioxoles; Enzyme Induction; Epididymis; Gene Expression Profiling; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Phosphodiesterase Inhibitors; Quinolones