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Life sciences · Journal article
Metabolism · November 1, 2026
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Obesity-related adipose tissue dysfunction is characterized by reduced β3-adrenergic receptor (β3AR) expression, resulting in impaired catecholamine-dependent lipolysis and limiting the efficacy of β3AR agonists. The discovery of impaired β3AR/cyclic adenosine monophosphate (cAMP) signaling caused by concurrent β3AR downregulation (limiting cAMP production) and phosphodiesterase 4 (PDE4) upregulation (enhancing cAMP degradation) necessitated the development of TMDU-3 as a multi-isoform PDE inhibitor targeting PDE4, PDE1, PDE3, and PDE10. TMDU-3 robustly restored downstream cAMP-mediated phosphorylation events, including lipolytic activation, and concomitantly increased upstream β3AR expression in white adipose tissue (WAT) from obese mice. Despite a 5-fold increase in WAT mass, TMDU-3 normalized the WAT lipid composition. Moreover, TMDU-3 enhanced thermogenesis in brown adipose tissue, corrected serum accumulation of various lipids, and more effectively reduced circulating monounsaturated fatty acids than the β3AR agonist mirabegron. These findings demonstrate that multi-target PDE inhibition represents a β3AR-independent strategy superior to β3AR agonism in ameliorating obesity-associated metabolic dysfunction.