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. 2022 Aug 22;14(16):3440.
doi: 10.3390/nu14163440.

A High-Fat Diet Modifies Brain Neurotransmitter Profile and Hippocampal Proteome and Morphology in an IUGR Pig Model

Natalia Yeste  1 , Jorge Pérez-Valle  1 , Ana Heras-Molina  2 , José Luis Pesántez-Pacheco  3 , Esteban Porrini  4 , Antonio González-Bulnes  5 , Anna Bassols  1
Affiliations

A High-Fat Diet Modifies Brain Neurotransmitter Profile and Hippocampal Proteome and Morphology in an IUGR Pig Model

Natalia Yeste et al. Nutrients. .

Abstract

Intrauterine Growth Restriction (IUGR) hinders the correct growth of the fetus during pregnancy due to the lack of oxygen or nutrients. The developing fetus gives priority to brain development ("brain sparing"), but the risk exists of neurological and cognitive deficits at short or long term. On the other hand, diets rich in fat exert pernicious effects on brain function. Using a pig model of spontaneous IUGR, we have studied the effect on the adult of a long-term high-fat diet (HFD) on the neurotransmitter profile in several brain areas, and the morphology and the proteome of the hippocampus. Our hypothesis was that animals affected by IUGR (born with low birth weight) would present a different susceptibility to an HFD when they become adults, compared with normal birth-weight animals. Our results indicate that HFD affected the serotoninergic pathway, but it did not provoke relevant changes in the morphology of the hippocampus. Finally, the proteomic analysis revealed that, in some instances, NBW and LBW individuals respond to HFD in different ways. In particular, NBW animals presented changes in oxidative phosphorylation and the extracellular matrix, whereas LBW animals presented differences in RNA splicing, anterograde and retrograde transport and the mTOR pathway.

Keywords: brain; high-fat diet; hippocampus; intrauterine growth restriction; metabolism; neurotransmitters; pig.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
NeuN immunostaining on the hippocampus of one year-old pigs born with normal birth weight (NBW) or low birth weight as result of IUGR (LBW) and fed a control diet (Ctrl, A,B) or an HFD diet (C,D). Representative images show the mature neurons immunostained with the NeuN antibody. Panels are magnifications of the CA1 (a1–d1) and DG (a2–d2) areas shown using black boxes. Scale bars: 1000 µm (A–D), and 250 µm (a1–d1, a2–d2).
Figure 2
Figure 2
DCX immunostaining on the DG of the hippocampus of one year-old pigs born with normal birth weight (NBW, (A)) or low birth weight as result of IUGR (LBW, (B)) and fed a control diet (Ctrl) or an HFD diet (identified as 1 or 2, respectively). Representative images show the immature neurons immunostained with the DCX antibody. Scale bars: 250 µm.
Figure 3
Figure 3
Venn diagram of differentially abundant proteins in the hippocampus of pigs. (A) Number of proteins identified by birth weight, diet and its interaction (Birthweight*Diet). (B) Number of proteins identified by comparing HFD vs. Ctrl in NBW and LBW groups.
Figure 4
Figure 4
Heatmap of differentially abundant proteins in the hippocampus of pigs in the four analyzed groups (NBW subjected to a control diet (C) or HFD; LBW subjected to a control diet (C) or HFD). Sex of the individual (M, F) is indicated. Numbers indicate the TMT labeling reagent and F indicates the TMT labeling reaction.
Figure 5
Figure 5
Functional classification of differentially abundant proteins identified in pigs comparing the effect of an HFD diet in NBW and LBW animals by Slim-GO analysis of the Molecular function and biological processes ontologies. (left hand) Molecular Function: A, binding; B, catalytic activity; C, molecular adaptor activity; D: molecular function regulator; E, molecular transducer activity; F: structural molecule activity; G, transporter activity. (right hand) Biological Process: A, biological regulation; B, cellular processes; C, developmental process; D, localization; E, locomotion; F, metabolic process; G, multicellular organismal process; H, response to stimuli; I, signaling; J, biological adhesion; K, growth.
Figure 6
Figure 6
Voronoi diagram sections obtained with Reactome showing the main pathways regulated by an HFD in NBW and LBW groups. Intensity of yellow color indicates abundance of DAPs in a specific pathway. The complete Voronoi picture and images with enlarged letter size is shown in Supplementary Figure S1.
Figure 7
Figure 7
KEGG diagram for the mTOR pathway (hsa04150) with the differentially abundant proteins identified in LBW animals subjected to an HFD marked by red squares.
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