Chronic high fat diet lowers male detrusor mitochondrial fatty acid oxidation while females are protected

Abstract

IntroductionObesity increases the prevalence of bladder dysfunction in both males and females. The bladder's mucosal and detrusor smooth muscle layers are involved in bladder signaling and contraction, respectively. The underlying causes of obesity‐induced bladder dysfunction in males and females are poorly understood. Mitochondrial dysfunction is common in the heart, liver and skeletal muscle with high fat diet (HFD). This study will characterize sex differences in mitochondrial respiration in bladder mucosal and detrusor layers. Additionally, we will determine the impact of long‐term HFD on bladder mitochondrial respiration in male and female mice.MethodsMale and female mice (n=7/group, 20–24 wks) were used to assess bladder mitochondrial sex differences. A second group of male and female mice (10 wks, n=5–7/group) were fed a control (10% kcal fat) or HFD (45% kcal fat) for 24 weeks. Bladders were collected, weighed and separated into mucosal and detrusor layers. Tissues were cut into strips, permeabilized, and placed in an OROBOROS Oxygraphy‐2K to measure respiration using a modified version of the creatine kinase energetic clamp. Substrates (pyruvate/malate, glutamate, L‐octanoylcarnitine/malate, or succinate/rotenone) were added followed by increasing concentrations of phosphocreatine to allow for substrate‐specific bioenergetic analyses across a physiological span of ATP free energies. Respiratory conductance was calculated for each substrate based on the rate of change in respiration for a given increase in ATP free energy.ResultsBladder respiration and respiratory conductance in the presence of L‐octanoylcarnitine/malate in mucosal and detrusor tissue was significantly decreased in males (p<0.05). Respiration and respiratory conductance remained unchanged between sexes in the presence of pyruvate/malate, glutamate, and succinate/rotenone. Chronic HFD increased body weight and decreased the bladder to body weight ratio in both sexes (p<0.05). In HFD males, mucosal respiration and respiratory conductance were decreased in the presence of L‐octanoylcarnitine/malate (p<0.05). In contrast, pyruvate/malate, glutamate, and succinate/rotenone did not change HFD male respiration and respiratory conductance. In HFD females, respiration and respiratory conductance were unchanged in presence of pyruvate/malate, glutamate, and L‐octanoylcarnitine/malate. However, HFD female mucosal layer had decreased respiration with succinate/rotenone but no change in respiratory conductance.ConclusionsMale mice have lower baseline fatty acid metabolism within the bladder's detrusor smooth muscle layer compared to females. With chronic HFD, male fatty acid metabolism within the mucosal and detrusor muscle layers is further lowered whereas female mice are protected. Ongoing studies will determine if excess lipids accumulate within the bladder and if we can rescue fatty acid metabolism with co‐factors such as L‐carnitine or acetyl‐CoA. Understanding bladder metabolic and bioenergetic sex differences will help to create more effective treatments for bladder dysfunctionSupport or Funding InformationNIDDK DiaComp, ECU SBRP, APS UGSRFThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.