2. Brain nutritional requirements
1. Energy needs
2. Structural needs
• Glucose is an obligatory metabolic fuel for
the brain.
• Hypoglycemia always represents an emergency
that signals the inability of the brain to meet its
energy needs.
2
3. Glucose homeostasis
• Requires the tight regulation of glucose utilization
by liver, muscle and white or brown fat, and
glucose production and release in the blood by
liver.
• The major goal of maintaining normal glycemia is
to ensure a sufficient flux of glucose to the brain.
• Glucose homeostasis is controlled by hormones,
mainly glucagon and insulin, and by autonomic
nervous activities that control the metabolic state
of liver, muscle and fat tissue but also the secretory
activity of the endocrine pancreas. 3
4. Glucose homeostasis
• Activation or inhibition of the sympathetic or
parasympathetic branches of the autonomic
nervous systems are controlled by glucose-excited
or glucose-inhibited neurons located mainly in the
brainstem and the hypothalamus.
• Activation of these neurons by hyper- or
hypoglycemia represents a critical aspect of the
control of glucose homeostasis.
• Loss of glucose sensing by these cells as well as by
pancreatic β-cells is a hallmark of type 2 diabetes.
4
5. Glucose and brain
• Impaired glucose homeostasis (type 2
diabetes) may be caused by initial defects in
brain glucose sensing.
Thorens B. Diabetes Obes Metab. 13 (S1) : 82-8, 2011.
• Lower brain glucose metabolism is present
before the onset of clinically measurable
cognitive decline in people at risk of
Alzheimer's disease.
5
6. Brain hypometabolism
• May contribute to the neuropathologic
cascade leading to cognitive decline in AD.
• Reasons unclear, but may include defects in
brain glucose transport, disrupted glycolysis,
and/or impaired mitochondrial function.
• Aging appears to increase the risk of
deteriorating systemic control of glucose
utilization.
Cunnane S et al. Nutrition 27(1):3-20, 2011
6
7. The vicious cycle
• Declining brain glucose
uptake is a risk factor for AD,
and the reduced synaptic
functionality (and hence
reduced energy needs) in AD
further decreases brain
glucose metabolism.
• How can we break this cycle?
• One possibility is to induce
mild, sustainable ketonemia.
8. Keton bodies
• Produced from fatty acids
by the liver.
• Released into the
circulation to provide
energy to tissues that are
not able to directly
oxidize fatty acids when
glucose is not available.
• Brain cannot oxidize fatty
acids.
•
9. Fatty acids as energy source
• The brain cannot use LC fatty acids for
energy because they are completely
albumin-bound and cannot cross the
blood-brain barrier.
• Not all medium-chain fatty acids are
bound to albumin. The unbound
medium-chain fatty acids can cross the
blood-brain barrier
9
10. The ketogenic diet
• high-fat, adequate-protein, low-carbohydrate diet
• used primarily to treat difficult-to-control
(refractory) epilepsy in children.
• mimics aspects of starvation by forcing the body to
burn fats rather than carbohydrates.
• effective in AD? No controlled studies
Gasior M et al. Behav Pharmacol. 2006;17:431-9.
• Effective in other disorders?????
– ketogenic diet meal planner
http://www.stanford.edu/group/ketodiet/mealplnr.xls
10
11. Fatty acids
• One carboxyl and one
methil group.
• Different chain lenght.
• Different unsaturation
degree
(saturated, monounsat
urated, polyunsaturate
d)
11
14. Brain “structural” needs: n-3 PUFAs
• Membrane PL of nervous cells are
extremely rich in docosahexaenoic acid
(C22:6 n-3, DHA)
A. Eilander et al
Prostaglandins Leukot
Essent Fat Acids 76,189–
203, 2007.
DHA is fundamental in brain development and
function 14
15. In the newborn
• Breast fed children have a better cognitive
development than children fed with low
DHA-containing infant formula.
M. Fleith et al Crit Rev Food Sci Nutr 45,205–229, 2005.
• Supplementation with DHA e AA in the
first 4 months of life increases the Mental
Development Index.
E.E. Birch et al. Dev Med Child Neurol 42,174–181, 2000
15
16. In ageing
• High fish or DHA intake
reduces the cognitive
decline and the risk of AD
M.G. Morris et al. Arch Neurol 62, 1849–
1852, 2005.
• DHA concentration in
plasma PC is inversely
related to the risk of
dementia
E.J. Schaefer et al. Arch Neurol 63,1545–
1550, 2006.
16
17. Why do n-3 PUFAs improve brain
function?
1. Modification of membrane PL composition
and fluidity
• Fluidity of synaptic membranes regulate
nervous transmission.
• DHA containing PL are more flexible.
• Ageing decreases DHA concentration in
synaptic membranes.
17
S. Yehuda World Rev Nutr Diet 92, 37–56, 2003
18. Why do n-3 PUFAs improve brain
function?
2. Modulation of receptors, ionic channels, G
proteins, membrane proteins.
3. Biosynthesis of
active metabolites.
DHA is the precursor
of neuroprotectin (NPD1)
H.Y. Kim J Biol Chem 26,18661–18665, 2007. 18
W.J. Lukiw et al. J Clin Invest 115, 2774-2783, 2005.
19. Neuroprotectin D1 (NPD1)
• Inhibts the expression of pro-inflammatory
genes.
• Inhibits pro-apoptotic proteins.
• Induces anti-apoptotic proteins.
H.Y. Kim J Biol Chem 26,18661–18665, 2007
• NPD1 and DHA reduce the synthesis and
aggregation of not soluble β-Amiloid peptides.
Lim GP et al. J Neurosci. 2005;25: 3032-40.
19
20. Why do n-3 PUFAs improve brain
function?
4. Stimulation of neurogenesis increasing stem cells
differentiation
E. Kawakita et al. Neuroscience 139, 991–997, 2006
5. Activation of sintaxin-3, protein stimulating the growth
of dendritis
F. Darios e B. Davletov. Nature 440,813–817, 2006
6. Increased synthesis of synaptic membranes
R.J. Wurtman et al Brain Res 1088, 83–92, 2006
20
21. Where does DHA come from?
• The most of DHA in the
brain comes from the
dietary intake (fish). A
small percentage is
synthetised by liver. In the
brain, DHA is synthetised
by astrocytes only.
21
22. How can DHA cross the blood-
brain barrier?
• Ingested DHA is available to the blood
in various forms, the major being TG
and PL bound to lipoproteins, and free
DHA and lyso-PC bound to albumin.
• The BBB appears to preferentially take
up DHA esterified in lyso-PC
22
• Lagarde M et al. J Mol Neurosci. 2001;16:201-4 .
23. Lipid peroxidation
• Isoprostans are the product
of lipid peroxidation
induced by free radicals.
• DHA peroxidation
produces F4-
neuroisoprostans.
• F4-NP concentration in
spinal fluid is higher in AD
patients.
• AD is related to oxidative
damage. And other
disorders?
23
P. Montuschi et al. FASEB J 1791–1800, 2004.
24. Dietary prevention of cognitive
decline
• Factors causing cognitive decline and its
progression toward AD are still unclear.
• Researches indicate that cognitive decline
and AD can be prevented by dietary
habits.
N-3 PUFAs (DHA) and antioxidants
24
V. Solfrizzi et al. Expert Rev Neuroather 8, 133-158, 2008
25. The Mediterranean diet can protect
can protect the brain
• Olive oil antioxidants
• High fruit and vegetables intake
antioxidants
F.Panza et al. Public Health Nutr 7, 959-963, 2004
• High fish consumption DHA
S. Lamijn et al Neurology 62, 275-280, 2004.
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