A small‑molecule HDAC/PDE modulator activates human adipocyte UCP1 and resolves inflammatory signaling

Abstract

Background: Obesity-associated inflammation in white adipose tissue (WAT) drives insulin resistance and type 2 diabetes. While UCP1-mediated thermogenesis is a therapeutic target, most browning agents lack anti-inflammatory activity. We aimed to identify small molecules that induce browning and suppress inflammation in human adipocytes. Methods: Human cohorts and cell line models were analyzed for inflammatory markers. We generated an in-house multicomponent reaction (MCR)-based chemical library and developed a proprietary high-throughput screening platform to identify UCP1 activators in human adipocytes. Lead compound CDC1011 was evaluated for effects on thermogenesis, mitochondrial respiration, glucose uptake, glycolysis, lipolysis, NF-κB signaling, cytokine secretion, and monocyte chemotaxis. Mechanistic studies assessed cyclic-nucleotide signaling, phosphodiesterase (PDE) inhibition, histone deacetylase (HDAC) modulation, and docking-based predictions. Results: CDC1011 induced UCP1 expression and mitochondrial respiration, enhanced glucose uptake and lipolysis, and suppressed NF-κB activation, cytokine secretion, and monocyte recruitment. Mechanistically, CDC1011 elevated cAMP/PKA and cGMP signaling via PDE inhibition and attenuated HDAC activity, reprogramming adipocytes toward a thermogenic, anti-inflammatory phenotype. Conclusions: CDC1011 is a first-in-class small molecule with dual thermogenic and anti-inflammatory actions in human adipocytes, offering a promising pharmacological strategy for obesity-related metabolic disorders.