Adiponectin Signaling Regulates Urinary Bladder Function by Blunting Smooth Muscle Purinergic Contractility

Abstract

Lower urinary tract symptoms (LUTS) affect [~] 50% of the population aged >40 years and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and anti-inflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. The role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN knockout mouse model (Adpn-/-). Adpn-/- mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome. ARTICLE HIGHLIGHTSLower urinary tract symptom (LUTS) is strongly associated with obesity and metabolic syndrome, however, the underlying molecular mechanisms are missing. Dysregulation of adipokine signaling could be the link for this association. Whether adiponectin, the most abundant adipokine, plays a role in regulating bladder function and dysfunction. Mice null for adiponectin exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle contractility, with corresponding metabolic and purinergic pathway changes. Dysregulation of adiponectin signaling might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.