Submitted on September 21, 2006
Accepted on January 31, 2007
Diet-induced ketosis increases capillary density without altered blood flow in rat brain
Michelle A Puchowicz1*, Kui Xu1, Xiaoyan Sun1, Andre Ivy1, Douglas Emancipator1, and Joseph C LaManna1
1 Anatomy, Case Western Reserve University, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: map10{at}case.edu.
It is recognized that ketone bodies such as R-beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) are energy sources for brain. As with glucose metabolism, monocarboxylate uptake by brain is dependent on the function and regulation of its own transporter system. We concurrently investigated ketone body influx, blood flow, and the regulation of monocarboxylate and glucose transporters (MCT1 and GLUT1, respectively) in diet-induced ketotic rat brain. Regional blood-to-brain BHB influx (μmol/g/min) increased by 40 fold with ketosis (4.8 ±1.8, plasma BHB) in all regions compared to non-ketotic groups (standard and no fat diets), with no changes in regional blood flow. Immunohistochemical staining revealed that GLUT1 density (number counted / mm2) in cortex was significantly elevated (40%) in the KG diet group compared to standard and no fat diets groups. MCT1 was also markedly up-regulated by 3-fold in the KG diet group compared to standard diet group. Forty percent of the brain capillaries stained positive for MCT1 in standard diet conditions; doubling with KG diet. Western Blot analysis on isolated microvessels from ketotic rat brain showed an 8-fold increase in GLUT1 and a 3-fold increase in MCT1 compared to standard diet group. These data suggest that diet-induced ketosis results in increased vascular density at the blood-brain barrier without changes in blood flow. The increase in extraction fraction and capillary density with increased plasma ketone bodies, indicates that there is a significant flux of substrates available for brain energy metabolism.
