P1‐135: Ovarian hormone loss induced decline in glucose availability and shift to alternative substrates in brain

Abstract

Background: Reproductive senescence is associated with decline in brain mitochondrial function. Further, enzymes for ketogenic/fatty acid metabolism were significantly increased, indicating shift towards a ketogenic phenotype. Herein, we investigated impact of reproductive senescence and ovarian hormone loss on brain substrate system. Methods: Aging female mice underwent FDG-MicroPET/Micro-CT imagin g, followed by analyses of brain bioenergetic substrates and their transporter profile. 6-month Female mice were also ovariectomized and underwent FDG-MicroPET/Micro-CT imagin g. Initial analysis was conducted to assess whole brain glucose uptake. ROI analyses were conducted in collaboration with Drs. Chen and Reiman and colleagues.Results:Age-related decline in brain glucose uptake was statistically significant at 9-month-of-age in the female mouse brain. Pathway analyses identified a concomitant decline in hexokinase activity, neuronal glucose transporter (GLUT3) expression and increased neuronal monocarboxylate transporter expression (MCT2), indicating a decline in glucose metabolism and increased transport of alternative fuels, ketone bodies or/and lactate in brains. However, MCT1 in BBB and astrocytes significantly decreased at 12-month-of-age, indicative of decreased transport of alternative substrates. Because these changes occurred during the period of reproductive senescence, we investigated regulation of substrate transport system by ovarian hormones. Contrary to expectation, the GLUTs increased in the absence of ovarian hormones. However, the increase in glucose transporters did not result in an increase in brain glucose uptake as brain glucose uptake was significantly decreased in OVX-female brain. These data indicate that despite the increase in GLUTs, the function of these transporters was compromised. Regional analyses indicated that glucose metabolism was significantly decreased in thalamus, consistent with hypometabolism in ApoE4-carriers. Estrogen treatment at the time of OVX prevented decline in transporters and brain glucose uptake to sustain brain metabolism.Conclusions:Reproductive senescence is associated with a decline in transporters for both glucose and ketone bodies, adaptive responses to increase substrate transporters is thwarted by post-translational modifications. Within 5 weeks of ovarian hormone loss, which translates into 2-3 years of human life span, thalamic hypometabolism developed, which is evident in ApoE4 Latino carriers, at-risk for AD. Estrogen treatment at the time of ovariectomy prevented declines in transporter expression and function, evidenced by brain glucose uptake.