Fat head: More on Inflammation, Fatty Acids, Neurology, and the Strange Diabetes Drug that...

[NNadir]

Protects Neurons.

Last night I wrote a post about http://www.democraticunderground.com/discuss/duboard.php?az=view_all&address=228x56901">The (Possible) Relationship Between Fish Oil Consumption and Alzheimer's Risk.

The post was all over the place and happily the few responses in it were all about walnuts and their relationship to fish oil.

I'm all over the place intellectually, so I like things that way. Mostly I think about nuclear energy, but I do a little work with medicinal chemistry on the side, and for whatever reason, I find myself thinking about the chemistry of fatty acids. (I had a cosmetics gig going for a while that involved fatty acids - it doesn't get better than that - feel younger with fat.)

Actually - irrespective of what you might hear from diet snake oil salesmen - a certain amount of fat is essential, although generally, when it needs it, your body can make fats pretty easily from stuff that isn't fat.

Like the sugar glucose, fat plays an important role in brain chemistry.

I came across a paper tonight where glucose chemistry and fat chemistry come together, because of the diabetes drug rosiglitazone (GSK's Avandia). Rosiglitazone has been controversial of late because of some suspicion about its effect on heart attacks. This risk is unproven, but yet, much as - as I may have indirectly indicated in my thread last night - there are many biochemical mechanisms in which drugs designed for one thing, like the COX-2 inhibitor Vioxx which was designed to reduce inflammation and pain, effect another, positively or negatively. (Aspirin, which is a Cox-2 and a Cox-1 inhibitor has a beneficial effect on heart disease.)

Inflammation is very much involved the paper I referenced last night suggested in Alzheimer's.

The paper I read tonight suggests the same thing. Here's the abstract: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T09-4PYR41Y-2&_user=1082852&_coverDate=06%2F30%2F2009&_alid=1027534323&_rdoc=12&_fmt=high&_orig=search&_cdi=4857&_sort=d&_docanchor=&view=c&_ct=190&_acct=C000051401&_version=1&_urlVersion=0&_userid=1082852&md5=244832480d3e9f50429f8e96aaeed23a">Neurobiology of Aging 30 (2009) 920–931

Here's a quote from the introduction:

Aged animals exhibit an inflammatory phenotype with evidence of an impaired capacity of aged mice to elicit a functional T helper type 2 cell response (Smith et al., 2001). The evidence suggests that the inflammatory phenotype extends to the brain; thus an age-related increase in hippocampal concentration of proinflammatory cytokines, accompanied by decrease in anti-inflammatory cytokines has been described (Maher et al., 2005; Martin et al., 2002; Nolan et al., 2005). This apparent imbalance in pro- and antiinflammatory cytokines contributes to the deficit in LTP, because restoring the balance, for example by eicosapentaenoic acid (EPA) (Lynch et al., 2007; Martin et al., 2002), leads to an improved ability of aged rats to sustain LTP. A key contributor to the age-related deficit in LTP is the increase in IL-1 concentration (Lynch and Lynch, 2002) and consistent with the evidence that IL-1 is derived largely from activated microglia (Davies et al., 1999; Li et al., 1997; Minogue et al., 2003), an age-related increase in microglial activation has been documented (Griffin et al., 2006). Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors, which are key regulators of lipid and glucose metabolism, energy homeostasis and adipocyte and macrophage differentiation (Kliewer et al., 1999).

LTP is "Long Term Potentiation" and the neurobiology of this effect is related to long term memory, which is impaired of course in diseases like Alzheimer's.

Eicosapentaenoic acid is a highly unsaturaged fat, found in fish oil, and, as I now suspect at the behest of the commentator in my last thread, in walnuts.

The paper is a long drawn out affair, but what I glean is that PPAR inhibitors do in fact, help a fat head remain a fat head - a fat head being a good thing apparently which certainly makes my fat head happy. Interestingly the mechanism seems to involve gene expression regulation. Despite all the hype about the human genome project that was supposed to cure all disease, very few pharmaceuticals work, when you get right down to it, by gene regulation at the end of the day, so this is interesting.

It is clear however that genetics will increasingly play a role in health care, in some ways good - possibly involving drug design, treatment design, and even direct drug mechanics - and in some ways that may seem horrifying, at least to our generation, and in other ways that will reduce to bigotry, and bigotry is never justified.

Well, I thought this interesting, so posted it here.

[Hannah Bell]

1. *English* walnuts. also flaxseed. in addition to fatty fish. farmed won't do;

lower levels due to feed differences.

[NNadir]

2. Well, given that overfishing is leading to extinctions and depletions around the world,

along with dams and other pollution systems, I guess we can leave the "eat fish" plan out of Alzheimer's risk minimization...

...if what you say about farmed fish is true.

[Hannah Bell]

3. just lower levels of eicosapentaenoic acid & a different ratio of fatty acids.

There's no absolute requirement to eat wild fish. The body can make epa from other fatty acids, just takes more work.

[NNadir]

6. Not all kinds of fatty acids are synthesized in humans.

Synthesis of fatty acids with odd numbers of carbon atoms is unknown in humans, but it is known in mammals: One source of such acids is cow's milk. Interestingly these acids are metabolized to pyruvate, and thus can be used to make glucose, making the glucogenic. One cannot make glucose from fatty acids with even numbers of carbons.

I read on Wikipedia though that the body can in fact, make EPA from linolenic acid, although not efficiently.

It would be an interesting area of research to see if there is a correlation between people who have enzymes well suited for such synthesis are more likely to suffer from disease states, AD or hypercholesterolemia, or other syndromes of this type.

[Hannah Bell]

9. Eicosapentaenoic acid can be synthesized from alpha-linolenic acid, e.g.:

1: Nutr Metab Cardiovasc Dis. 2007 Jul;17(6):457-61. Epub 2006 Sep 26.
Levels of the n-3 fatty acid eicosapentaenoic acid in addition to those of alpha linolenic acid are significantly raised in blood lipids by the intake of four walnuts a day in humans.Marangoni F,

BACKGROUND AND AIMS: Ingestion of alpha linolenic acid (ALA), with the richest source among dry fruits such as walnuts, is associated with cardiovascular prevention. The aim of this study was to selectively evaluate the effects of moderate walnut consumption on the levels of ALA and its metabolic derivatives in human blood. METHODS AND RESULTS: After a 2-week run-in period, 10 volunteers consumed 4 walnuts per day (in addition to their habitual diet) for 3 weeks. Fatty acid profiles, with special attention to levels of ALA and long chain polyunsaturated fatty acids (LC-PUFA), were assessed in blood drops collected from fingertips. The data indicate that the administration of a few walnuts a day for 3 weeks significantly increases blood levels, not only of ALA (from 0.23+/-0.07 SD to 0.47+/-0.13 SD), but also of its longer chain derivative eicosapentaenoic acids (EPA) (from 0.23+/-0.37 to 0.82+/-0.41) with levels remaining elevated over basal values after washout. CONCLUSION: The findings of this pilot study indicate that plant ALA in appropriate food items favourably affects the n-3 LC-PUFA status.


pub med

[NNadir]

10. Well thanks for that. That is interesting and is consistent with the Wikipedia reference.

I'll pick up the paper the next time I'm in the library.

Strictly, as I read the abstract, this does not prove that linolenic acid is a metabolic precursor to EPA, however. A possible mechanism might involve some constituent of walnuts, maybe not linolenic acid, that has an agonist effect on an EPA synthesizing enzyme, for instance, that produces EPA from another substance.

Strictly the proof would be available from an isotope labeling experiment. For instance, one could ask volunteers to eat C-14 labeled linolenic acid and follow the fate of the C-14. A well defined labeling experiment might offer, as well, some mechanistic insight to the question.

I'm sure that producing labeled walnuts would be problematic.

[BadgerKid]

11. I believe I've read conversion of ALA is impaired

in people eating Western diets, and therefore to get adequate EPA and especially DHA, one should consume those directly.

I don't have a link on hand, though.

[pnwmom]

4. Since you like to read widely, I thought you might be interested

in this interview of a Harvard researcher who is interested in the brain chemistry of people with autism. (And who is increasingly convinced that autism is a chronic disease process and not simply hard-wired before birth.)

http://www.alternative-therapies.com/at/web_pdfs/herbert_long.pdf

She is also interested in how many autistic people have digestive problems, one of the major ones being gluten intolerance. Gluten intolerance leads to fat malabsorption . . . which connects back to your interest in fat and the brain.

[tabatha]

5. Coconuts and Alzheimer's

Yep, the right kind of fats are important for health - brain function, tissue repair, etc. Also, some nutrients such as CoQ10 work better with fat present.

Grass-fed animals have a higher amount of Omega3 than animals on other feed. Hence, prior to industrialized farming, man was probably able to get adequate Omega3 from both meat and fish.

From everything I have read, the fats in olive oil, flaxseed oil, avocados, coconuts, nuts and seeds are probably the best. The excerpt at the end was from a link in an article about coconut and Alzheimer's disease, below (the end of the article has a list of references):

http://coconutoil.com/AlzheimersDiseaseDrMaryNewport.pdf
(for some reason it takes a long time to load)

High carbohydrate diets and Alzheimer's disease.
Henderson ST.

Accera Inc. and Institute for Behavioral Genetics, University of Colorado, 1480 30th Street, Boulder, CO 80303, USA. [e-mail]

Alzheimer's disease (AD) is a common, progressive, neurodegenerative disease that primarily afflicts the elderly. A well-defined risk factor for late onset AD is possession of one or more alleles of the epsilon-4 variant (E4) of the apolipoprotein E gene. Meta-analysis of allele frequencies has found that E4 is rare in populations with long historical exposure to agriculture, suggesting that consumption of a high carbohydrate (HC) diet may have selected against E4 carriers. The apoE4 protein alters lipid metabolism in a manner similar to a HC diet, suggesting a common mechanism for the etiology of AD. Evolutionarily discordant HC diets are proposed to be the primary cause of AD by two general mechanisms. (1) Disturbances in lipid metabolism within the central nervous system inhibits the function of membrane proteins such as glucose transporters and the amyloid precursor protein. (2) Prolonged excessive insulin/IGF signaling accelerates cellular damage in cerebral neurons. These two factors ultimately lead to the clinical and pathological course of AD. This hypothesis also suggests several preventative and treatment strategies. A change in diet emphasizing decreasing dietary carbohydrates and increasing essential fatty acids (EFA) may effectively prevent AD. Interventions that restore lipid homeostasis may treat the disease, including drugs that increase fatty acid metabolism, EFA repletion therapy, and ketone body treatment.

http://www.ncbi.nlm.nih.gov/pubmed/15082091

I once read a book about two Germans who hid out in the wilds of South West Africa (now Namibia) during World War II, and one of them died because he had inadequate fat intake.

[NNadir]

7. That looks like an interesting paper.

I'll pick it up if I continue to think about this issue.

Thanks.

[tabatha]

8. There is no shortage of stuff on the web.

See some links below. I bet someone could write a book condensing and summarizing all of these findings into a useful reference book for those less inclined to know about the bio-chemistry, or don't have the time to do the research - I would buy such a book.

Another area of interest is the effect of food on genes - in some case, there can be gene alteration:
http://www.physorg.com/news139054245.html


References:
1. “Ketone bodies, potential therapeutic uses,” RL Veech, B Chance, Y Kashiwaya, HA Lardy, GC Cahill, Jr., IUBMB Life, 2001, Vol. 51 No.4, 241-247
2. “Ketoacids? Good Medicine?” George F. Cahill, Jr., Richard L. Veech, Transactions of the American Clinical and Climatological Association,
Vol. 114, 2003.
3. “The therapaeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism,” Richard L. Veech, Prostaglandins, Leukotrienes and Essential Fatty Acids, 70 (2004) 309-319.
4. “Diminished glucose transport and phosphorylation in Alzheimer’s Disease determined by dynamic FDG-PET,” M Piert, et.al., The Journal of Nuclear Medicine, Vol.37 No.2, February 1996, 201-208.
5. “Glucose metabolism in early onset versus late onset Alzheimer’s Disease: an SPM analysis of 120 patients,” EJ Kim, et. al., Brain, 2005,
Vol. 128, 1790-1801.
6. “Cerebral glucose metabolism in Parkinson’s disease with and without dementia,” RF Peppard, et.al., Archives of Neurology, Vol. 49 No.12,
December 1992.
7. “Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease,” Brain, October 1990, Vol 113, part 5, 1405-23.
8. “Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study,” U Roelcke, et. al., Neurology, 1997, Vol. 48, Issue 6, 1566-1571.
9. “ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury,” Z Guo, et. al., Journal of Cerebral Blood Flow Metabolism, March 2000, Vol. 20 No. 3, 463-8.
10. “Combinations of medium chain triglycerides and therapeutic agents for the treatment and prevention of Alzheimer’s disease and other diseases resulting from reduced neuronal metabolism,” United States Patent 20080009467, Inventor Samuel T. Henderson, Accera, Inc., Broomfield,
Colorado (Ketasyn).
11. Nutrient analysis of coconut oil (vegetable), NDB No: 04047 – www.nal.usda.gov/fnic/foodcomp .
12. “Lipids in (human) milk and the first steps in their digestion,” M Hamosh, et. al., Pediatrics, 1985, Vol. 75, 146-150.
13. “Nutritional factors and serum lipid levels,” EH Ahrens, American Journal of Medicine, 1957, vol. 23, 928 (used hydrogenated coconut oil).
14. “Trans fatty acids and coronary artery disease,” NEJM, 1999, Vol. 340, 1994-1998.
15. “Effect of mixed fat formula feeding on serum cholesterol level in man,” SA Hashim, American Journal of Clinical Nutrition, 1959, Vol. 7, 30-34.
16. “Modified-fat dietary management of the young male with coronary disease: a five-year report,” JL Bierenbaum, JAMA, 1967, Vol. 202, 1119-1123.
17. “Cholesterol, coconuts and diet in Polynesian atolls-a natural experiment; the Pukapuka and Toklau island studies,” IA Prior, American Journal of Clinical Nutrition, 1981, Vol. 34, 1552-1561.
18. “Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia,” S.G. Hasselbalch, et.al, Am J Physiol, 1996,
Vol. 270, E746-51.
19. “Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia
in normal humans,” T. Veneman, et. al., Diabetes 43:1311-7 (1994).
20. “D-b-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease,” Y Kashiwaya, et. al. including RL Veech, PNAS, May 9, 2000, Vol. 97 No. 10, 5440-5444.
21. “High carbohydrate diets and Alzheimer’s disease,” Samuel T. Henderson, Medical Hypotheses, 2004, Vol 62, 689-700 (Another article of interest).
22. “Effects of b-Hydroxybutyrate on cognition in memory-impaired adults,” MA Reger, ST Henderson, et. al., Neurobiology of Aging, 2004,
Vol. 25, 311-314.
23. “Breastfeeding, infant formula supplementation, and Autistic Disorder: the results of a parent survey,” ST Schultz, et. al., International Breastfeeding Journal, 2006, Vol. 1 No. 16.
Other Important Resources
“Ketones: Metabolism’s Ugly Duckling,” TB VanItallie, TH Nufert, Nutrition Reviews, Vol 61, No 10, 327-341.
“Fuel Metabolism in Starvation,” GF Cahill, Jr., Annual Reviews in Nutrition, 2006, 26:1-22.
“Ketone Bodies as a Therapeutic for Alzheimer’s Disease,” ST Henderson, Journal of the American Society for Experimental NeuroTherapeutics,
Vol 5, 470-480, July 2008.

Now, back to reading my new book on Ecology.