Efeito da dieta cetogênica rica em triheptanoína sobre a memória e o transporte de glicose cerebral em camundongos jovens e idosos

Abstract

The aging brain presents reduced glucose uptake and utilization, a process known as hypometabolism. This hypometabolism underlies impairment seen in cognitive function in the aged. Nonetheless, the aging brain preserves the capacity of ketone body utilization. Ketogenic diet (KD), a food regimen with severe carbohydrate restriction (~20g/d) and high-fat composition, emerges as an approach to counterbalance hypometabolism. However, KD could compromise the Tricarboxylic Acid Cycle (TAC), impairing energy metabolism. Here, we hypothesize that KD supplementation with an anaplerotic triglyceride, the triheptanoin, could improve TAC and improve memory in aged mice. The aim was to evaluate whether the ketogenic diet supplemented with triheptanoin ameliorates cognitive function in the aged. This thesis consists of an introduction, a literature review on the bioenergetic basis of the aging brain process, KD, memory, and anaplerosis, and an article named “Triheptanoin, an odd-medium-chain triglyceride, impacts brain cognitive function in young and aged mice”. In the article, C57/BL6 adult (12 weeks) and aged (22-month-old) mice were given (1) KD, (2) KD supplemented with triheptanoin, and (3) control diet for 12 weeks. Y-maze test, which evaluated spontaneous alternation (spatial working memory) and time spent in the previously closed arm and, novel object recognition test (NORT) accessed mice memory. Acetylcholinesterase (AChE) activity was measured in the prefrontal lobe, brain, and cerebellum. GLUT3 expression from the frontal lobe was analyzed by the western blot method. KD reduced spontaneous alternation in aged mice (aged CTRL = 52,5 ±5,2%; aged KD = 46,6 ± 7,7%; aged DC+T7 = 57,2 ±6,5%), led to lower AChE activity in adults and aged, besides lower GLUT3 expression in the prefrontal lobe (aged CTRL = 0,975±0,010; aged KD = 0,760±0,016; aged KD+T7 = 0,962±0,029 U/mg protein) and cerebellum (aged CTRL = 0,284±0,011; aged KD = 0,169±0,008; aged KD+T7 = 0,160±0,001 U/mg protein) of aged mice and, parieto-temporal-occipital lobe of adult mice (adult CTRL = 0,716±0,026; adult KD = 0,623±0,001; adult KD+T7 = 0,902±0,003 U/mg de protein). Furthermore, KD decreased GLUT3 expression in the frontal lobe of adult mice (adult CTRL = 100±14,5; adult KD = 72,9±6,5; adult KD+T7 = 68,2±9,1 % relative expression). Triheptanoin supplementation prevented memory impairment e showed similar AChE activity and GLUT3 levels compared to controls. Our data suggest a potential role of triheptanoin in brain bioenergetic, cognitive function. In conclusion, KD worsened cognitive and cholinergic function in aged mice, effect not observed in mice supplemented with triheptanoin.