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A gestational ketogenic diet alters maternal metabolic status as well as offspring physiological growth and brain structure in the neonatal mouse.

Sussman D, Ellegood J, Henkelman M - BMC Pregnancy Childbirth (2013)

Bottom Line: To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth.An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5.The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada. dafna.sussman@utoronto.ca.

ABSTRACT

Background: The use of the ketogenic diet (KD) among women of child-bearing age has been increasing, leading to increased interest in identifying the diet's suitability during gestation. To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth. Since ketones have been reported to play a role in cerebral lipid and myelin synthesis, it is particularly important to investigate the diet's impact on brain anatomy of the offspring.

Methods: To fill this knowledge gap we imaged CD-1 mouse neonates whose mothers were fed either a standard diet (SD) or a KD prior to and during gestation. Images were collected at postnatal (P) 11.5 and 21.5 using Magnetic Resonance Imaging (MRI). Maternal metabolic status was also tracked during lactation, by following their body weight, blood glucose, ketone, cholesterol, and triglyceride concentrations.

Results: The KD dams exhibit a significant reduction in maternal fertility and litter size, as well as a high risk of developing fatal ketoacidosis by mid-lactation. To increase survival of the KD dams and offspring, fostering of P2.5 pups (from both KD and SD litters) by SD-foster dams was carried out. This resulted in stabilization of blood ketones of the KD dams, and aversion of the fatal ketoacidosis. We also note a slower and smaller weight loss for the KD compared with the SD dams. The average fostered KD pup exhibits retarded growth by P21.5 compared with the average fostered SD pup. An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5. The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla.

Conclusion: A gestational ketogenic diet deleteriously affects maternal fertility and increases susceptibility to fatal ketoacidosis during lactation. Prenatal and early postnatal exposure to a ketogenic diet also results in significant alterations to neonatal brain structure, and results in retarded physiological growth. These alterations could be accompanied by functional and behavioural changes in later postnatal life.

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T-statistics map overlaid on top of the final average registered P11.5 and P21.5 brain images, highlighting voxels with statistically different deformation (FDR ≤ 15%). Blue regions are statistically smaller, whereas red regions are statistically larger in relative volume in the SD compared with the KD brain. Shown are three cross-sectional views of the average P11.5 brains, along with the corresponding cross-sections at P21.5, for comparison.
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Figure 2: T-statistics map overlaid on top of the final average registered P11.5 and P21.5 brain images, highlighting voxels with statistically different deformation (FDR ≤ 15%). Blue regions are statistically smaller, whereas red regions are statistically larger in relative volume in the SD compared with the KD brain. Shown are three cross-sectional views of the average P11.5 brains, along with the corresponding cross-sections at P21.5, for comparison.

Mentions: At each of the two time-points, an average of the 30 high b-value diffusion weighted images of the SD and KD pups were geometrically aligned with one another, and saved within a common coordinate system. The overlapping images were then used to construct a single consensus average image by first undergoing linear (6 parameter, followed by a 12 parameter) alignment through a series of rotations, translations, scales, and shears. Then, an iterative non-linear alignment procedure created local deformations in each image, thereby bringing all images into alignment. All registrations were performed using a combination of ANTS algorithm [26] and mni_autoreg tool [27]. The collection of all linear and non-linear deformations across each image formed a deformation field, which contained the transformation from each embryo image to the consensus average image. The Jacobian matrix was calculated for every point in the deformation field, and the determinant of the Jacobian was then calculated for each image voxel (i.e. 3D pixel). The log-transform of these determinants were computed, assigning positive values to the determinants that were >1 and negative values to those <1. Smoothing was applied to the resulting values using a 0.2mm FWHM Gaussian kernel, to improve normal distribution and facilitate the following t-statistics. Analysis of these results using t-statistics allowed to identify whether the KD group significantly differed from the SD group of brains in any particular 3D region. The results from this deformation-based analysis are reported as a structural brain image overlaid with the voxel’s t-statistics, as shown in Figure 2 by the red and blue scale-bars in regions that were significantly different. This analysis accounted for multiple comparisons through a False Discovery Rate (FDR) technique [28,29], as reported along with each image. To quantify whole-structure volume changes, brain regions were segmented from the final average image using a pre-existing atlas [30]. The inverse deformation field from the registration was then applied to back propagate the atlas onto the original unregistered images, allowing the regional volume differences to be calculated. Only regions that were significantly different at an FDR of <15% in this region-based analysis are reported in the results. FDR was calculated based on all 62 regions in the atlas.


A gestational ketogenic diet alters maternal metabolic status as well as offspring physiological growth and brain structure in the neonatal mouse.

Sussman D, Ellegood J, Henkelman M - BMC Pregnancy Childbirth (2013)

T-statistics map overlaid on top of the final average registered P11.5 and P21.5 brain images, highlighting voxels with statistically different deformation (FDR ≤ 15%). Blue regions are statistically smaller, whereas red regions are statistically larger in relative volume in the SD compared with the KD brain. Shown are three cross-sectional views of the average P11.5 brains, along with the corresponding cross-sections at P21.5, for comparison.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231349&req=5

Figure 2: T-statistics map overlaid on top of the final average registered P11.5 and P21.5 brain images, highlighting voxels with statistically different deformation (FDR ≤ 15%). Blue regions are statistically smaller, whereas red regions are statistically larger in relative volume in the SD compared with the KD brain. Shown are three cross-sectional views of the average P11.5 brains, along with the corresponding cross-sections at P21.5, for comparison.
Mentions: At each of the two time-points, an average of the 30 high b-value diffusion weighted images of the SD and KD pups were geometrically aligned with one another, and saved within a common coordinate system. The overlapping images were then used to construct a single consensus average image by first undergoing linear (6 parameter, followed by a 12 parameter) alignment through a series of rotations, translations, scales, and shears. Then, an iterative non-linear alignment procedure created local deformations in each image, thereby bringing all images into alignment. All registrations were performed using a combination of ANTS algorithm [26] and mni_autoreg tool [27]. The collection of all linear and non-linear deformations across each image formed a deformation field, which contained the transformation from each embryo image to the consensus average image. The Jacobian matrix was calculated for every point in the deformation field, and the determinant of the Jacobian was then calculated for each image voxel (i.e. 3D pixel). The log-transform of these determinants were computed, assigning positive values to the determinants that were >1 and negative values to those <1. Smoothing was applied to the resulting values using a 0.2mm FWHM Gaussian kernel, to improve normal distribution and facilitate the following t-statistics. Analysis of these results using t-statistics allowed to identify whether the KD group significantly differed from the SD group of brains in any particular 3D region. The results from this deformation-based analysis are reported as a structural brain image overlaid with the voxel’s t-statistics, as shown in Figure 2 by the red and blue scale-bars in regions that were significantly different. This analysis accounted for multiple comparisons through a False Discovery Rate (FDR) technique [28,29], as reported along with each image. To quantify whole-structure volume changes, brain regions were segmented from the final average image using a pre-existing atlas [30]. The inverse deformation field from the registration was then applied to back propagate the atlas onto the original unregistered images, allowing the regional volume differences to be calculated. Only regions that were significantly different at an FDR of <15% in this region-based analysis are reported in the results. FDR was calculated based on all 62 regions in the atlas.

Bottom Line: To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth.An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5.The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada. dafna.sussman@utoronto.ca.

ABSTRACT

Background: The use of the ketogenic diet (KD) among women of child-bearing age has been increasing, leading to increased interest in identifying the diet's suitability during gestation. To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth. Since ketones have been reported to play a role in cerebral lipid and myelin synthesis, it is particularly important to investigate the diet's impact on brain anatomy of the offspring.

Methods: To fill this knowledge gap we imaged CD-1 mouse neonates whose mothers were fed either a standard diet (SD) or a KD prior to and during gestation. Images were collected at postnatal (P) 11.5 and 21.5 using Magnetic Resonance Imaging (MRI). Maternal metabolic status was also tracked during lactation, by following their body weight, blood glucose, ketone, cholesterol, and triglyceride concentrations.

Results: The KD dams exhibit a significant reduction in maternal fertility and litter size, as well as a high risk of developing fatal ketoacidosis by mid-lactation. To increase survival of the KD dams and offspring, fostering of P2.5 pups (from both KD and SD litters) by SD-foster dams was carried out. This resulted in stabilization of blood ketones of the KD dams, and aversion of the fatal ketoacidosis. We also note a slower and smaller weight loss for the KD compared with the SD dams. The average fostered KD pup exhibits retarded growth by P21.5 compared with the average fostered SD pup. An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5. The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla.

Conclusion: A gestational ketogenic diet deleteriously affects maternal fertility and increases susceptibility to fatal ketoacidosis during lactation. Prenatal and early postnatal exposure to a ketogenic diet also results in significant alterations to neonatal brain structure, and results in retarded physiological growth. These alterations could be accompanied by functional and behavioural changes in later postnatal life.

Show MeSH
Related in: MedlinePlus