No abstract

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

Starzenie się jest złożonym i wieloetapowym procesem, angażującym mechanizmy na poziomie molekularnym, komórkowym i tkankowym. Podczas procesu starzenia się obserwowany jest rozwój przewlekłego, sterylnego stanu zapalnego, który jest określany terminem inflammaging, czyli zapalenie starcze. Zapalenie starcze jest wymieniane jako czynnik ryzyka wystąpienia i progresji chorób przewlekłych, nie tylko tych związanych z wiekiem. Ponadto, zapalenie starcze sprzyja wzrostowi zachorowalności i śmiertelności oraz wpływa na jakość życia osób starszych. Do rozwoju zapalenia starczego przyczynia się starzenie komórkowe oraz zaburzenia w regulacji aktywacji inflamasomów, pracy mitochondriów, autofagii i mitofagii, działania systemu ubikwityna – proteasom i odpowiedzi na uszkodzenia DNA. Powyższe procesy wzajemnie na siebie oddziaływają oraz są modulowane poprzez komórkowe szlaki sygnałowe uczestniczące w regulacji odpowiedzi zapalnej tj.: szlak mTOR, RIG-I, Notch, TGF-b, Ras, oraz regulacja aktywności sirtuin. Szczególną uwagę przypisuje się czynnikowi transkrypcyjnemu NF-kB. Celem pracy jest przedstawienie procesów oraz szlaków sygnałowych leżących u podstaw zapalenia starczego z uwzględnieniem badań klinicznych i eksperymentalnych.

No abstract

AbstractThe ketogenic diet has been shown to be very effective in managing drug-resistant epilepsy, treatment of obesity, improving symptoms of diabetes and reducing cardiovascular risk. Growing evidence supports the use of the ketogenic diet as an alternative or additional therapy in many types of cancer, polycystic ovary syndrome, acne, and neurological diseases. The rationale for the use of the ketogenic diet in brain diseases is based on its neuroprotective properties. But mechanisms responsible for these effects are only partially explained. It is possible that stimulation of macroautophagy (hereafter termed autophagy) may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Autophagy is a key mechanism for maintaining cell homeostasis and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Autophagy has become a subject of intensive research as a promising target for neuroprotective strategies, which are urgently needed in our aging population, in which the burden of age-related diseases is constantly increasing. The ketogenic diet may induce autophagy in brain cells through at least a couple of mechanisms: downregulation of mTORC1, activation of AMP-activated kinase, elevation of free fatty acids, activation of Sirtuin 1 and an increase of HIF1α expression. The aim of this study was to verify the hypothesis that the ketogenic diet affects the level of autophagy in the mouse brain. Thirty 9-weeks-old male mice were divided into three groups and fed with one of two differently composed ketogenic chows (KA, KB) or with standard rodent chow (SD) for 4 subsequent weeks. Western blotting (LC3, p62) and confocal microscopy (LC3 puncta) were employed to monitor autophagy in hippocampal and cerebrocortical samples. The Western blot results revealed an increased level of LC3 II protein - a marker of autophagosomes, in the hippocampus and frontal cortex of mice treated with ketogenic diet. The size of this effect was dependent on the composition of the diet. This observation was confirmed by the evaluation of the number of LC3 puncta with immunofluorescence microscopy. This study reports for the first time the upregulation of autophagosome synthesis in the brain of animals fed with the ketogenic diet. Our results make a significant contribution to the understanding of the mechanisms of ketogenic diet action. This research is supported by the National Science Center grant no 2017/01/X/NZ3/00984.

Physical activity impacts brain functions, but the direct mechanisms of this effect are not fully recognized or understood. Among multidimensional changes induced by physical activity, brain fatty acids (FA) appear to play an important role; however, the knowledge in this area is particularly scarce. Here we performed global metabolomics profiling of the hippocampus and the frontal cortex (FC) in a model of voluntary running in mice. Examined brain structures responded differentially to physical activity. Specifically, the markers of the tricarboxylic acid (TCA) cycle were downregulated in the FC, whereas glycolysis was enhanced in the hippocampus. Physical activity stimulated production of myristic, palmitic and stearic FA; i.e., the primary end products of de novo lipogenesis in the brain, which was accompanied by increased expression of hippocampal fatty acid synthase (FAS), suggesting stimulation of lipid synthesis. The changes in the brain fatty acid profile were associated with reduced anxiety level in the running mice. Overall, the study examines exercise-related metabolic changes in the brain and links them to behavioral outcomes.

AbstractObesity associates with plethora of dysfunctions including changes in the brain structures, like hippocampus which is particularly susceptible to metabolic or inflammatory alterations. The is a need to expand knowledge about the obesity related brain changes in order to enable development of new therapeutic interventions, that would support not only weight loss but also could help to restore the after-effects of obesity in the brain. In the present report we evaluated the hippocampal efficiency of obese rats. In order to induce obesity 4 weeks old male rats were fed with a chow that mimics human western diet for 12 weeks (model of diet induced obesity). Then the cognitive functions (water maze), neurogenesis (BrdU detection) and global proteomic changes (MS/MS analysis) were analyzed in separate cohorts of animals. Obese rats had worsen cognitive flexibility than normal rats, but the spatial learning and long term memory were unaffected. The number of BrdU/NeuN positive cells was lowered in obese animals suggesting decreased hippocampal neurogenesis. The analysis of proteins revealed that about 120 proteins significantly differed between hippocampi of obese and normal rats. Neuronal calcium sensor 1 (NCS-1) which participates in mechanisms involving synaptic plasticity and acquisition of spatial memory was decreased in obese rats. Neuromodulin and vinculin, required for synaptic plasticity also decreased in these animals. Impaired neurogenesis was associated with decreased level of: receptor-type tyrosine-protein phosphatase zeta and cytoplasmic dynein 1 light intermediate chain 2, which play crucial roles in controlling axonal growth and neuronal migration. Altogether the data show that proteomic changes related to obesity associate with impaired hippocampal functioning. The same set of experiments was performed on the additional cohort of obese animals subsequent to weight loss to examine if the observed brain changes persist if obesity is reversed. This research is supported by Nutricia Foundation, grant no. RG 1/2017.

Physical activity impacts brain functions, but the direct mechanisms of this effect are not fully recognized or understood. Among multidimensional changes induced by physical activity, brain fatty acids (FA) appear to play an important role; however, the knowledge in this area is particularly scarce. Here we performed global metabolomics profiling of the hippocampus and the frontal cortex (FC) in a model of voluntary running in mice. Examined brain structures responded differentially to physical activity. Specifically, the markers of the tricarboxylic acid (TCA) cycle were downregulated in the FC, whereas glycolysis was enhanced in the hippocampus. Physical activity stimulated production of myristic, palmitic and stearic FA; i.e., the primary end products of de novo lipogenesis in the brain, which was accompanied by increased expression of hippocampal fatty acid synthase (FAS), suggesting stimulation of lipid synthesis. The changes in the brain fatty acid profile were associated with reduced anxiety level in the running mice. Overall, the study examines exercise-related metabolic changes in the brain and links them to behavioral outcomes.