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Differential Regulation of Brown Adipose Tissue Activation by PDE3 and PDE4
Author(s) -
Kraynik Stephen M.,
Hinds Thomas R.,
Beavo Joseph A.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.666.7
Subject(s) - phosphodiesterase 3 , lipolysis , brown adipose tissue , phosphodiesterase , endocrinology , medicine , adipose tissue , microbiology and biotechnology , biology , adipocyte , chemistry , biochemistry , enzyme
Recent studies indicate that adult humans possess brown adipose tissue (BAT), though the impact of BAT on human energy expenditure is still unclear. The activation of key BAT processes by adrenergic stimulation, namely lipolysis and Ucp1 expression, are mediated through cAMP‐dependent signaling. Phosphodiesterases (PDEs) catalyze the breakdown of cyclic nucleotides, and therein control subsequent downstream effects. This makes PDEs attractive pharmacological targets to activate BAT in obese humans in order to potentially reduce fat stores. We have identified six different PDE subtypes in mouse interscapular BAT that can hydrolyze cAMP. We found that a combination of PDE3 and PDE4 inhibitors can highly synergistically stimulate basal cAMP, CREB‐phosphorylation and Ucp1 mRNA expression, whereas individual inhibitors were ineffective when used alone. However, a PDE3 inhibitor alone could shift the adrenergic agonist dose‐response curves for cAMP and Ucp1 mRNA to the left. Additionally, we found the same synergistic effect of PDE3 and PDE4 inhibitors on lipolysis in primary brown adipocytes, but in this case also identify PDE4 as a major regulator in the basal state. These results identify a functional synergy between PDE3 and PDE4 in the control of BAT function, and suggest that one must inhibit both in order to fully activate the tissue in the basal adrenergic state. Supported by NIH grant GM08392.