Mitochondria: Fuel, Fluxxx and Heat (NSFW)

Buddha Bar (Sex Lounge)
Credit: Youtube.com

Fuel and Fluxxx...

Why do we store fat? Why do we eat?  A scientist who wrote about reproduction, fuel, photoperiods and fecundity wrote the below abstract...[1]

"While there is a relatively direct connection between
circulating levels of metabolic fuels and the GnRH [gonadotropin releasing hormone] pulse generator [in SCN behind the retina], this might not be the only energy-related pathway influencing the secretion of this neuropeptide. The overall control of energy balance is an immensely complex process and a number of pathways involved in it might secondarily influence the activity of GnRH neurons. Peripheral signals influencing energy balance and thus possibly GnRH secretion could come from the liver, pancreas, stomach, duodenum or adipose tissue, and these signals could be sent to the brain via the vagus nerves or by hormones such as leptin, insulin, insulin-like growth factor 1 or ghrelin. These hormones could act directly on the neural circuits controlling the GnRH neurons or they could act by modulating the availability of metabolic fuel. Likewise, the neuropeptides regulating GnRH secretion in the forebrain could also include galanin, orexin, the urocortins and endogenous opioids. Recent interest has focused on kisspeptin, the product of the KISS1 gene. The presence of kisspeptin is necessary for normal reproductive development and it can override the reproductively detrimental effect of mild food restriction."

Obviously how we expend fuel is highly complex and humans are ruled by a big, big, big, hungry, hot brains... Grow or growl? Feast or fast? F-ck or forage? Repair or repast?





HEAT: Cellular Bioenergetics Creates Wildly Explosive, Exothermic Reaction Generating Water



CALORIES IN  ≠  CALORIES OUT

...we are not neat bomb-calorimeters, but open, conserved, networked metabolic and energy systems...

Photos credit: [2].













The Evolution of Body Heat?

When oxidized, the great majority of our food and stored energy goes to the production of HEAT.      What governs this? It is multifactorial but adrenaline, thyroid, cortisol and mitochondria quality are just a few [2]. Active tissues contain more mitochondria. Heat makes us mammals and birds. We have hot bodies, precisely 37C for the great majority.


In the 'Hot Brain:  Survival, Temperature, and the Human Body' the authors theorized that temperature gave us advantages over eukaryotic infections (yeast, fungal origins -- we are eukaryotic) which plagued bird/reptile species which were not armed with high 37C temperatures or fever-inducing capabilities [3].  It is a very interesting theory. Control of thermoregulation (heat loss v. heat gain) is believed to have evolved in the brain of therapsids. Our sinuses are larger. Mammalian brains have a Circle of Willis where 4 arteries (internal carotids and vertebral arteries) provide a complete internal brain circulation with collaterals, such that despite blockage of one or more of the 4 major arteries circulation in the brain and to the body remains intact.  Unfortunately only 25-33% of us have a 'perfect' classic circle of Willis; others have degrees of narrowing or asymetry in certain areas or another. Photos courtesy: Hot Brain, pp. 44, 142.

Recently a microbiologist, Casadevall, from Albert Einstein had the same theory that the rise of mammals can be attributed to 'endothermy and homeothermy [which] are thought to contribute to mammalian resistance to mycosis by creating a thermal exclusionary zone that inhibits most fungal species. The remarkable resistance of mammals to mycotic diseases is probably a combination of a vertebrate immune system, with both innate and adaptive arms, and elevated body temperatures... The currently favored hypothesis for the demise of dinosaurs and end of the age of reptiles is a bolide impact approximately 65 million year ago with the possibility that other events, such as increased volcanism, contributed to disrupting the cretaceous ecosystem. That ecological calamity was accompanied by massive deforestation, an event followed by a fungal bloom, as the earth became a massive compost. Although one cannot know which spores were present at the time, the likelihood that pathogenic fungi existed at the K-T boundary is enhanced by the finding that the potential for pathogenicity probably arose independently several times in evolution...'[3]

'Although we do not know the timeline for the recovery of the planet climate, it is estimated that photosynthesis was shut down for 6 months and climate cooling persisted for at least 9 years, and the occurrence of a fungal bloom sufficient to have left fossil evidence implies that surviving animals were exposed to massive numbers of fungal spores. The darkened skies and cooler temperatures that accompanied the K-T cataclysm would have shielded the sun and reduced the ability of ectothermic creatures such as reptiles to induce fevers by insolation, a necessary activity for protection against fungal diseases. Hence, it is reasonable to posit that ectothermic creatures unable to induce behavioral fevers and in weakened states from environmental stress would have been at a severe disadvantage relative to small mammals with their innate thermal exclusionary zones for fungal growth. Further complicating the situation for reptiles is that eggs can be vulnerable to fungal attack, whereas mammalian progeny would be protected in placentae.'[3]

I think it has merit. We generate a lot of HEAT and it comprises a cr*pload of our total energy losses (as many in NY know without electricity due to Storm Sandy and no heat to fight night time drops to freezing temperatures). As Casadevall reported  'the mammalian lifestyle is energetically costly.'






Mitochondria: Water (H2O) = 286 kJ of P-O-W-E-R

Many obesity researchers appear to forget these multiple evolutionary and hormetic factors in their Big Pharma funded, tenure-track equations. One did not (though partly Joslin funded which is Big Pharma).


In a Nature article, Tseng et al discuss mechanisms to find a drug target to increase cellular bioenergetics and energy expenditure as an anti-obesity strategy [2]. (But... Drug targets are always silly, no?) They discuss PPAR-delta, AMPK and several other pathways with potential promise.  A succinct explanation of how mitochondria produce energy on demand by harnessing the energy from the formation of water in the cellular bioenergetics of mitochondrial metabolism of fuel is provided. They define bioenergetics as the 'Studies the flow of chemical bond energy within organisms. In a living cell, the principal reactions of fuel metabolism take place in the mitochondria, where food energy is released,oxygen is consumed, and water and carbon dioxide are produced.'

All life on earth utilizes the energy formed from water formation to power pathways and metabolism. Remember the Calvin Cycle/Photosynthesis where carbs (glucose) are formed from air (CO2), and energy of the sun? In the mitochondria, the opposite reaction occurs. Energy from the exothermic reaction of water forming from air (O2) and the enzymatic burning of fuel (oxidizable food, glucogen, glucose, fat) result in HEAT and ATP. When one mole of H2O is created from one H2 (hydrogen) and half O2 (oxygen), 286 kJ of power are released (in other words, 68 kcal, which is about one small potato).... FROM FORMATION OF ONLY ONE MOLE OF WATER.

CO2 1/2 O2  =   one mole H2O (~18 grams water = 3.5 teaspoons)  =  286 kJ

Photo Credit: The Art, Mystery and Science of Water

Fuel Efficiency of Our Mitochondrial Cellular Respiration

With cellular respiration, instead of an enormous, exothermic explosion (like a hydrogen bomb), the electrons and protons are added step-wise on a gradient known as the electron transport chain (ECT) in plants and animals.  A biological mitochondrial 'battery' is created with the 'anode' on the inner mitochondrial membrane side and the 'cathode' on the other.  Heat is energy released when oxygen is the final proton acceptor and coupled to the enzyme (F1F0-ATPase) that forms ATP, the universal currency of cellular energy in the body. When the protons fall across the proton channel, ATP is formed.  We use ATP as fuel every minute every day for all cellular work, then recycled back to ADP.  In one day, it is estimated that our mitochondria may produce our own weight in ATP [5].

Efficiency of the theoretical transfer of energy from oxidizable fuel to ATP and heat is pretty darn good: 39% ATP and 61% heat [5]. Mitochondria are energy rockstars. Obviously many biolgical factors determine true efficiency: iron status (cytochromes are composed of heme), ubiquinol, oxidative and inflammatory state, thyroid, HPA axis function, hormones, etc.

Plants (chloroplasts) get 3-6% efficiency from transfer of solar energy to the energy bonds of plant starches and fatty acids. Particular C4 plants can get 7-8% (sugarcane) and one super cyanobacteria strain Chlorobaculum tepidum achieves 10%. Various modern fuel efficiencies are approximately -- for coal (~20-30s%) and solar (20%). Photo credit: [5].



References

1. Climate change and seasonal reproduction in mammals. Bronson FH.Philos Trans R Soc Lond B Biol Sci. 2009 Nov 27;364(1534):3331-40.

2. Cellular bioenergetics as a target for obesity therapy.Tseng YH, Cypess AM, Kahn CR. Nat Rev Drug Discov. 2010 Jun;9(6):465-82. [Free PDF here]

3. The Hot Brain: Survival, Temperature, and the Human BodyCarl V Gisolfi, Francisco Mora Teruel. MIT Press (Bradford Book), 2000. [Free SCRIBD text here]

4. Fungi and the rise of mammals.Casadevall A. PLoS Pathog. 2012 Aug;8(8):e1002808.  [PDF]

5. http://highered.mcgraw-hill.com/sites/dl/free/0073525502/930160/mad25502_ch08.pdf

Phytanic Acid (Red Meat, Dairy, Seafood): Binds PPAR-α and RXR

'...Like all things come from the sun'
referencing all the food at the table,

daughter Natalie

ATB Sunset Girl

Courtesy: Youtube.com

Food, Sunlight and Nuclear Receptors

I've discussed RXR/RAR (carotenoids/ vitamin A receptor), VDR (vitamin D receptor) and PPAR-α (saturated fat/omega-3 receptor). These are a constellation of receptors found in the nucleus of all cells which control growth, maturation, reproduction, proliferation, apoptosis (cell suicide), autophagy (cell re-cycling) and inflammation.  Bioactive components of our food and hormone vitamin D from sunlight exposure (or organ meat consumption) bind and control nuclear receptors.

See prior posts:
PPAR -- Dagger in the Heart of CAD and all Chronic Conditions
Benefits of Grassfed Butter





Phytanic Acid Generates Carnitine

A recent study looked at the level of phytanic acid (PA), a
fatty acid found in red meat, dairy fat, and seafood which has activity on receptors known to control and regulate cancer, inflammation, triglycerides/cholesterol and even energy status in skeletal muscles. It may have several mechanisms for health regulation. One mechanism found is that phytanic acid is an agonist for several nuclear receptors including RXR and PPAR-α. I would not be surprised if it has affinity and binds other receptors as well.

We don't synthesize phytanic acid on our own; we can only source from food (animal based). Phytanic acid and its metabolite pristanic acid contribute to the activation of carnitine in peroxisomes which are later transported to mitochondria for fatty acid oxidation (burning and synthesis of energy, ATP). A lack of carnitine has been shown to lower mitochondrial processes and is significant factor in disease. Like phytanic acid, carnitine can mainly be sourced only from MEAT and seafood, not vegetables. We produce it but not very well. Many factors affect carnitine levels (kidney function, ACTH/cortisol, thyroid and diet. French authors write 'L-carnitine ensures regeneration of coenzyme A and is thus involved in energy metabolism. L-carnitine also ensures elimination of xenobiotic substances. Carnitine deficiencies are common.'  Photo credit: [1].

Do butter and bison do a body good?

YESSSSSS.




Chlorophyll Is Biotransformed into Phytanic Acid by Fish and Mammals

Apparently the chlorophyll content of the meat, seafood or dairy is what determines the amount of this important fatty acid, phytanic acid. 'PA (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid generated by the oxidation of the phytol side chain of chlorophyll in mammals. Because humans cannot release phytol from chlorophyll, PA in the human body comes from dairy products and ruminant fats in the diet' [2]. Shore-based food such as fish, salmon, molluscs, snails and krill have significant levels too since these consume smaller fish which consume chlorophyll from algae and green phytoplankton. Phytanic acid is also found in menhaden oils. There is a vague association with prostate cancer and levels of phytanic acid however the below authors discuss "the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk." Phytanic acid is metabolized in peroxisomes -- little fatty storage droplets where enzymes breakdown and metabolize fatty acids. Many of the metabolic breakdown products then go to the mitochondria to provide energy, intermediaries for the respiratory and energy producing complexes, and/or to absorb and quench ROS (reactive oxygen species, aka POLLUTION generated from energy production). If mitochondria are working awry, I suspect phytanic acid accumulation occurs because it is not being appropriately metabolized which could be genomic or post-genomic (Refsum syndrome).



Evolutionary Medicine: Mitochondrial Dysfunction

Many of our chronic diseases are a result of mitochondrial dysfunction -- our tiny nuclear power plants are on the 'blink'...often preferring glycolytic combustion over superior fatty-acid burning.  Mitochondria provide awesome power but can wreak untold destruction as well.

--compromised controls, directions and regulation for proper nuclear plant functioning (AMPK, cAMP)
--lacking power grid efficiency (leptin, insulin, cortisol, SIRT1, adiponectin, secretin, fertuin-A)
--malfunctioning or missing power plant cogs and parts (minerals, carnitine, AcCoA/pantothenic acid, omega-3)
--deficiency of buffering, recycling and containment of nuclear waste (coenzyme Q10/ ubiquinol)
--lacking managers and communicators (cell membrane stability and communication: omega-3 vitamins A B D E K2 thyroid cortisol estrogen progesterone DHEA pregnenolone testosterone saturated fat etc)
--excessive disruptions (high carb diets, endocrine disruptors, PCBs, heavy metals)





From Bacteria 4.5+ bya To Mitochondria

Other strategies to keep mitochondria free of breakdowns -- lifestyles and diet aligned with our evolutionary past from 4.5+ Billion Years Ago:

--lowish carbish (~150 grams or less net effective carbs I like...varying on goals, gut, adrenals, etc)
--saturated fat (~20% or more -- dietary or butt-sourced)
--low fructose
--low omega-6
--high omega-3
--high phytanic acid *wink*
--organic shore-based and grassfed/pasture-based fat and protein
--organic mineral rich plants, berries, nuts, meat/fish/fowl
--intermittent feast v. fast (seasonality)
--optimal hormesis status
--low pollution (air, water, mind)
--enjoyment of culture, music, arts, spiritual enlightenment
--engaging in community and social networks
--movement: rapid intense and languid continuous (yeah S*X counts)


Prior animal pharm:
You are only as strong as your weakest mitochondria...





Health and Food Connection

When I consume ghee (clarified butter), egg yolks, veggies, adequate starches and adequate grassfed beef, pork and lamb, I notice more and easy weight maintenance and improved muscle composition. Mental and physical performance are pretty excellent too. How do you break down food and its effects on mitochondria? Researchers are trying and it's a good thing....

Phytanic acid--an overlooked bioactive fatty acid in dairy fat?

Hellgren LI. Ann N Y Acad Sci. 2010 Mar;1190(1):42-9.

Abstract
Phytanic acid is a multibranched fatty acid with reported retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist activity, which have been suggested to have preventive effects on metabolic dysfunctions. Serum level in man is strongly correlated to the intake of red meat and dairy products and the concentration in these products is strongly correlated to the chlorophyll content in the feed of the cattle. Available data suggest that phytanic acid is a natural agonist for RXR at physiological concentrations, while it is more likely that it is the metabolite pristanic acid, rather than phytanic acid itself, that acts as PPAR-alpha agonist. Animal studies show increased expression of genes involved in fatty acid oxidation, after intake of phytol, the metabolic precursor of phytanic acid, but it is at present not possible to deduce whether phytanic acid is useful in the prevention of ectopic lipid deposition. Phytanic acid is an efficient inducer of the expression of uncoupler protein 1 (UCP1). UCP1 is expressed in human skeletal muscles, were it might be important for the total energy balance. Therefore, phytanic acid may be able to stimulate energy dissipation in skeletal muscles. Phytanic acid levels in serum are associated with an increased risk of developing prostate cancer, but the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk. However, certain individuals, with specific single-nucleotide polymorphisms in the gene for the enzyme alpha-methylacyl-CoA racemase, might be susceptible to raised phytanic acid levels. PMID: 20388135

Phytanic Acid (Cheese, Butter) Human RCT

How does phytanic acid perform as a drug? In a tiny Denmark RCT, this was tested.  The control group however also received phytanic acid therefore the results were substantially diluted out IMHO. Methods: In a double-blind, randomized, 4 wk, parallel intervention study 14 healthy young subjects were given 45 g milk fat/d from test butter and cheese with 0.24 wt% phytanic acid or a control diet with 0.13 wt% phytanic acid. The outcomes were positive and associate with metrics that indicate improved mitochondrial functioning (better insulin sensitivity, more fat oxidation, decreased glycolysis).   The lipoprotein changes were impressive but unfortunately the study was too small for meaningful stats. HDL-cholesterol increased by 10% in only one month.  No drug achieves this... or without killing patients or raising BG and diabetes (particularly Crestor).  Is it all phytanic acid?  I dunno...  The researchers enriched the test dairy products by feeding the cows more green material. Subsequently the omega-3 to omega-6 profile in test butter and cheese also improved. They discussed, 'The test butter with the highest content of phytanic acid, also had the highest content of α-linolenic acid [omega-3] and a lower n-6:n-3 ratio of about 1.8. This is in agreement with the higher proportion of clover and grass in the green feeding regime.'   Notwithstanding the beneficial numbers, butter and cheese have other proven bioactive food components which improve heart health, inflammation, insulin resistance and cancer risks, principally, cholesterol, vitamin A/retinol, saturated fatty acids including butyrate, omega-3, taurine (if raw), stigmasterol (if raw; Wulzen factor), folate (5-MTHF) and vitamin K2 (menaquinones).

Results:
(a) HDL increase 10% 
(b) Insulin reduction 15%
(c) TG reduction 22% 

References

1.Verhoeven NM et al. Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. The Journal of Lipid Research, Vol. 39, 66-74, January 1998. [Free PDF here]

2. Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid.
Tang XH, Suh MJ, Li R, Gudas LJ.
J Lipid Res. 2007 Jan;48(1):165-76.

3. Novel branched-chain fatty acids in certain fish oils.
Ratnayake WM, Olsson B, Ackman RG.
Lipids. 1989 Jul;24(7):630-7.

4. Oxidative stress and mitochondrial dysfunction in Fibromyalgia. MINIREVIEW.
Cordero MD, Miguel MD, Carmona-López I, Bonal P, Campa F, Moreno-Fernández AM.
Neuro Endocrinol Lett. 2010 Apr 29;31(2):169-173.

5. Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury.
Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P.
J Alzheimers Dis. 2010;20 Suppl 2:453-73.

6. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease.
Cordero MD, De Miguel M, Moreno Fernández AM, Carmona López IM, Garrido Maraver J, Cotán D, Gómez Izquierdo L, Bonal P, Campa F, Bullon P, Navas P, Sánchez Alcázar JA.
Arthritis Res Ther. 2010;12(1):R17. Free PMC ArticleFree text

7. Connecting the Dots: Molecular and Epigenetic Mechanisms in Type 2 Diabetes.
Goh KP, Sum CF.
Curr Diabetes Rev. 2010 Jun 9.

8. Fetal programming of atherosclerosis: possible role of the mitochondria.
Leduc L, Levy E, Bouity-Voubou M, Delvin E.
Eur J Obstet Gynecol Reprod Biol. 2010 Apr;149(2):127-30.

9. Spinal cord repair in MS: does mitochondrial metabolism play a role?
Ciccarelli O, Altmann DR, McLean MA, Wheeler-Kingshott CA, Wimpey K, Miller DH, Thompson AJ.
Neurology. 2010 Mar 2;74(9):721-7.

10. Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.
Desbois AP, Smith VJ.
Appl Microbiol Biotechnol. 2010 Feb;85(6):1629-42.

11. Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases.
Chakravarthy MV, Booth FW.
J Appl Physiol. 2004 Jan;96(1):3-10. [Free PDF here]

12. Glycolysis: a bioenergetic or a survival pathway?
Bolaños JP, Almeida A, Moncada S.
Trends Biochem Sci. 2010 Mar;35(3):145-9.

13. Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: a fertility first hypothesis.
Corbett SJ, McMichael AJ, Prentice AM.
Am J Hum Biol. 2009 Sep-Oct;21(5):587-98.

14. Liver fattening during feast and famine: an evolutionary paradox.
van Ginneken VJ.
Med Hypotheses. 2008;70(5):924-8.

15. Biochem pages http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html

16. Carnitine: an overview of its role in preventive medicine.
Kendler BS.
Prev Med. 1986 Jul;15(4):373-90. Review.

17. [L-carnitine: metabolism, functions and value in pathology]
Jacob C, Belleville F.
Pathol Biol (Paris). 1992 Nov;40(9):910-9. Review. French.

18. The metabolism of phytanic acid and pristanic acid in man: a review.
Verhoeven NM, Wanders RJ, Poll-The BT, Saudubray JM, Jakobs C.
J Inherit Metab Dis. 1998 Oct;21(7):697-728. Review.

19. Phytanic acid--an overlooked bioactive fatty acid in dairy fat?
Hellgren LI.
Ann N Y Acad Sci. 2010 Mar;1190:42-9.

20. Effect of dairy fat on plasma phytanic acid in healthy volunteers - a randomized controlled study.  [Free PDF here.]
Werner LB, Hellgren LI, Raff M, Jensen SK, Petersen RA, Drachmann T, Tholstrup T.
Lipids Health Dis. 2011 Jun 10;10:95.

21. Bioactive food components, inflammatory targets, and cancer prevention.
Kim YS, Young MR, Bobe G, Colburn NH, Milner JA.
Cancer Prev Res (Phila). 2009 Mar;2(3):200-8.

(NSFW) Evolutionary Muscles, Skin, Fat

Fascinated Remix
(Offer Nissim, Courtesy of Youtube.com)

Questionable Trade-Off Between Sex and Longevity

I've wondered about this dichotomy -- can humans and other mammals have both sex and longevity? Nick Lane, author of Life Ascending, gives his deep, refined thoughts on this apparent contrast. 'The idea of a trade-off between sex and longevity was laid out by the British gerontologist Tom Kirkwood pictured exactly such a 'choice', on the economic grounds that ENERGY is limited and everything has a cost. The energetic cost of bodily maintenance must be subtracted from the energetic cost of sex, and organisms that try to do both simultaneously will fare less well than organisms that apportion their resources...'

This change that occurred in evolution when mammals internalized pregnancy and increased child-rearing from a few weeks to a few years may explain how the priorities in energetics shifted. It reminds me of other predators... bears, wolves and coyotes. Just like them, we invest a great deal of resources into teaching, reinforcing, enrolling into chest club, swimming lessons, golf camp, piano lessons and other preparations necessary for optimal success in life. Actually we invest VERY LITTLE in sex but MUCH MUCHO MORE in maintenance phases. The higher up the supposed predator food chain, the balance is FAR shifted toward maintenance phases, less sex. Nick Lane's theory is that 'In all cases, though, there is a choice, and in animals that choice is normally controlled by the insulin hormones.'



Behavioral budgeting by wild coyotes: The influence of food resources

Coyotes and wolves are quintessential survivors and clever companions. Dogs are pretty close. My daughter is reading a wonderful series called 'Wolf Brother' by Michelle Paver.

Coyote populations display a very curious 'negative relationship between coyote abundance and population growth' as these authors noted. Though increased litter size occurs with food abundance, 'There was also a hint that mean litter size may be correlated with food conditions under which females are reared, as opposed to conditions leading up to specific reproductive seasons (Knowlton and Stoddart 1983).'

COYOTE POPULATION PROCESSES REVISITED, Knowlton and Gese


Energy balance of the female of the species explains a lot. Certainly gender-specific nutrigenomics play a role. We are definitely more sensitive to the insulin resistant, pro-inflammatory effects of glucocorticoids and n-6 PUFAs than our male counterparts. Vitamin D (e.g. duration photoperiods), probably as well, esp if you believe the female-forager theories and division of labor.

Prior post (read end): n-6 PUFAs Cause Inflammation and Cancer: Israeli Experience



Energy Balance: Relates to Priorities in Mammalian Physiological Functions (SEX v. maintenance v. decreased population growth)

Bronson describes energy balance affecting reproduction in all animals. If the priority is survival and forwarding genetic material to the next generation, this all makes incredible and wonderful sense. Everything appears clear in light of evolution.

Climate change and seasonal reproduction in mammals. PDF free.



Evolutionary Skin

Recently, I started bikram yoga and... oh boy. It's H-O-T. One hundred four degrees F to be precise, in 40% humidity which grows during the 90min sessions. Skin is a big excretory organ (bigger than the KIDNEYS... *wink*). Sweating is a stellar way to detox whether it is during exercise or in a sauna -- the Japanese and Korean spend a lot of time in sauna-like hot baths; the Greeks luxuriate in hot mineral baths. After the class starts, within 5-10min every person in the room is dripping bodily fluids. Every sweat gland gets a workout. Even. My belly button's. In fact, it's gross but I discovered my knees SWEAT too.


Under My Skin: Subcutaneous Fat

Subcutaneous fat stores are anatomically located under the skin. Pinch an inch or grab a slab? (after holidays, the later for me) The quantity and quality of our storage fat and skin fluxes with the same hormones that affect our muscles.

See NephroPal: Evolutionary Muscles and Skin



Heat Shock Hormesis

I've discussed hormesis and how cold showers relate in an earlier post. Being BIONIC. This winter I've enjoyed much less cold showers... which last... OHHHH... ~1.4 seconds long. *haa*

Hot bikram yoga is a much more preferable way for me to achieve hormesis because both cold and heat shock induce mTOR changes.



More Hormesis

Skin is our largest organ (yes, it is). Surface area ~ 27 sq ft (2.5 sq meter) and weighs about 9 lbs. Each square inch contains about 230 ft (70 m) of nerves and 16 ft (~5 m) of blood arteries and veins. More vitamin D synthesis occurs in our skin when we are heated (no sunlight involved, just temperature factors alone). According to the below authors "The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. The local level of each sexual steroid depends upon the expression of each of the androgen- and estrogen-synthesizing enzymes in each cell type, with sebaceous glands and sweat glands being the major contributors." I think we can have it both ways... sex/hormones... and quality, disease-minimized lifespans... (1) controlling insulin (2) keeping mitochondria happy. Hormones and hormesis are indeed key players for power, sex and survival.

Sexual hormones in human skin.

Happy Cows and Fish Oil

Here's an inspiring friend and buddy... Ms. Happy Cow like the rest of the happy cows in my neighborhood (see last photo from my camera). Everytime I run by one of the cows grazing on fresh clover and grass and absorbing full spectrum sunlight nearly all day, I have to resist the urge to put on... my dairy-maid outfit! And start milking! Here's the tribute to happy cows (and their DHA, EPA and CLA) which make ideas at the Animal Pharm (and my brain) possible...

This picture is courtesy of Bay Nature which showcases Mt. Diablo well in the background and more happy cows.

The benefits from dietary fat and protein sourced from grass- and clover-fed cows include hitting my favorite family of metabolic and proliferative switches in the mammalian kingdom... PPAR -- alpha gamma and delta! Not only does consumpation of dietary protein like beef and whey dairy protein activate mTOR and indirectly PPAR-delta, a natural fatty acid called conjugated linoleic acid (CLA) found only in the meat and milk of pasture-fed cows like the ones in the picture also directly binds PPAR receptors. Like many mysteries and secrets revealed by my MILFy buff girlfriends, CLA grows muscle to be defined, lean, and tight. Body fat significantly decreases and minimizes (but it aint a miracle -- you still need to work a little, ie lift and pump and eat right). What girl (or TYPer) wouldn't want that? Additionally CLA reduces cancer and reduces proliferation.

CLA is produced by the bacteria in the bellies of ruminants who consume grass or clover (not hay or grains).

Food sources of CLA (and Vits K2, D3, A, Butyric acid, EPA, DHA) :

--pasture-fed cowmilk (at most good health food stores: Organic Pastures $6.99/qt)

--raw pasture-fed cowmilk (see above --contains 'Wulzen Factor' = heat-labile stigmasterol which is an unsaturated plant sterol which lowers cholesterol)

--pasture-fed cowmilk cheese, butter, raw butter oil

--pasture-fed goat milk, dairy products

Protein sources with CLA (and DHA+EPA/aka 'fish oil'):

--pasture-fed beef

--pasture-fed lamb

--pasture-fed sheep

--pasture-fed goat

--pasture-fed bison, wild bison

--wild deer, elk, antelope

Of course I like CLA because also it potently binds and activates PPAR -- all of them. Alpha, gamma and beta/delta. This is why my muscles feel so wonderful and grow well (after like... some strain and pain... scrubbing those plaquey-toilets at home).

CLA raises muscle mass with resistance training in humans and reduces weight in the obese humans (and in rats):

• Lowery LM, et al. Conjugated linoleic acid enhances muscle size and strength gains in novice bodybuilders. Med Sci Sports Exerc. 30(5):S182, 1998.
• Pinkoski C, et al. The effects of conjugated linoleic acid supplementation during resistance training. Med Sci Sports Exerc. 2006 Feb;38(2):339-48.
• Tarnopolsky MA, Safdar A. The potential benefits of creatine and conjugated linoleic acid as adjuncts to resistance training in older adults. Appl Physiol Nutr Metab. 2008 Feb;33(1):213-27. Review.
• Blankson H, et al. Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr. 2000 Dec;130(12):2943-8.
• Gaullier JM, et al. Six months supplementation with conjugated linoleic acid induces regional-specific fat mass decreases in overweight and obese. Br J Nutr. 2007 Mar;97(3):550-60.
• Gaullier JM, et al. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr. 2005 Apr;135(4):778-84.
• Gaullier JM, et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr. 2004 Jun;79(6):1118-25.
• Risérus U, et al. Conjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial.
  Int J Obes Relat Metab Disord. 2001 Aug;25(8):1129-35.
• Eyjolfson V, et al. Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Med Sci Sports Exerc. 2004 May;36(5):814-20.
• Liu LF, et al. Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice. Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1671-82.
• Park Y, et al. Changes in body composition in mice during feeding and withdrawal of conjugated linoleic acid. Lipids. 1999 Mar;34(3):243-8.

Muller et al studied how if human vascular cells also may carry CLA as ruminant tissues do... guess what he found? Müller A, et al. Detection of conjugated dienoic fatty acids in human vascular smooth muscle cells treated with conjugated linoleic acid. Biochim Biophys Acta. 2005 Dec 15;1737(2-3):145-51.

"Conjugated linoleic acids (CLA) have attracted scientific interest due to their potential beneficial effects on atherosclerosis. Recent studies demonstrated that conjugated metabolites of CLA are found in tissues of CLA-fed animals and cultured cells treated with CLA. This observation has gained in importance since it has recently been shown that these metabolites of CLA exert specific biological activities...Examination of fatty acid composition of total cell lipids ...revealed a significant isomer-specific formation of conjugated metabolites of CLA such as CD16:2, CD20:2 and CD22:2 in human coronary artery smooth muscle cells treated with various CLA isomers. Different CD16:2/CLA ratios between various CLA isomers as observed in the present study indicate that fatty acid metabolism is differently affected by the configuration of the double bonds. In conclusion, the observation from the present study suggests that the effects of CLA in vascular cells might not only be mediated by CLA itself but also by its conjugated metabolites."


Of course synthetic CLA is artificially created with hydrogenated cheap industrial veggie oils which is not likely to be as beneficial (longterm) as naturally derived CLA from whole foods.

RELATED LINKS:

• Higher concentrations of vitamin E, CLA, long change omega-3 fatty acids in pasture fed cow milk. Leiber F, et al. A study on the causes for the elevated n-3 fatty acids in cows' milk of alpine origin. Lipids. 2005 Feb;40(2):191-202. PMID: 15884768


• Grain (corn) feeding lowers CLA and content of other important nutrients like Butyric acid (4-carbon fatty acid) in the fat of cow milk. Stockdale CR, et al. Influence of pasture and concentrates in the diet of grazing dairy cows on the fatty acid composition of milk. J Dairy Res. 2003 Aug;70(3):267-76. PMID: 12916820


• Beef meat considered a source of 'omega-3s' EPA/DHA when pasture fed. Mann NJ, et al. Feeding regimes affect fatty acid composition in Australian beef cattle. Asia Pac J Clin Nutr. 2003;12 Suppl:S38. PMID: 15023647


• Ponnampalam EN, et al. Effect of feeding systems on omega-3 fatty acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on human health. Asia Pac J Clin Nutr. 2006;15(1):21-9. PMID: 16500874

Atheroma Regression 101 -- Focus on HDL

Dr. Steve Nissen certainly deserves some respect. Not only does (a) he stick his neck out for the heart protection of Americans and (b) endorses CAC scoring/EBT for plaque/atheroma validation, he supports regression data in alignment with the Track Your Plaque goals for regression 60-60-60-60 already established by Dr. William Davis MD FACC. In a recent post-hoc analysis he reviewed data pooled from 4 major trials (ASTEROID, CAMELOT, REVERSAL, ACTIVATE) where plaque was diagnosed with angiography and tracked via IVUS over ~18 months (n=1455). The plaque volume % (PAV) decrements tracked well with i-n-c-r-e-a-s-i-n-g HDLs. And even more substantial reductions in total atheroma volume (TAV) were seen with more dramatic increases in HDLs.

The average 'regression' lead to an average 0.5 increase in PAV (2% increase and wide SD=15.7%) and a total atheroma volume reduction of 2.4 mm3 (only -0.2%; wide SD=17.4%). The authors note that in the ACTIVATE trial nearly 90% of patients were already on a statin and in fact their LDLs were less than 100 at baseline. Benefits for plaque stabilization and regression may have already been reaped prior to initiation for this sub-group which makes up 1/4 of the study. The duration of statin therapy was unknown.

These changes (avg plaque change: + 0.5)) were observed with the combination:
(1) LDL reduction (study avg=87.5 mg/dl final)
(2) increased HDL changes (the 'higher the better' with avg change=7.5% --the greatest regression was associated with HDL increases of 40% and HIGHER)
(3) lower LDL/HDL ratio (study ratio=2.1)

Average apo B was also significantly reduced from 131 mg/dl to 95 mg/dl (36% reduction) which was statistically correlated to changes in both PAV and total atheroma volume (p less than 0.001). The regression graph (see Figure and graph areas where PAV change is less than zero) lines up with TYP standard goals 60-60 for LDL and HDL.

TYP Goals (standard):
-LDL-C =60 mg/ml (see above arrow; higher?? see hard cardiac events)
-HDL-C = 40% increase to 60 mg/ml (study baseline avg = ~43 mg/dl; sorry--arrow wrong!)
-LDL/HDL ratio = 60/60 = 1.0


This regression data certainly emulates TYP to me!! The results truly seem to demonstrate the '60/60' vision...of a regressionist!! Like our beloved Dr. Davis :)



Often Dr. D achieves lipoproteins even beyond his standard goals. Many who follow TYP obtain LDLs lower than 60 and HDLs far higher than 60. Of course TGs fall far lower than 60 as well (often 40s) and of course apo B naturally drop as well (I'd conjecture less than 60).

So perhaps standard goals may be revised for those with 'stubborn' plaque.... based on this new information.

Who might benefit? The analysis showed that independent predictors of change in PAV were baseline PAV, the presence of diabetes and/or hypertension. For total atheroma volume, independent predictors of change were baseline TAV and BMI.

Refer to the L-sided endpoints of each graph in the Figure. The regression data certainly supports substantial size reductions of plaque occur with further improvements in LDL and HDL. HHHhhhhmmm..... Therefore, based on reported values of TYP'ers who experience regression/stabilization, the below standards may apply. At TYP, we are not LDL-centric. Small-LDLp centric extremely so, but never accuse us of LDL-mania...

Ultimate TYP (hypothetical) for Ultimate Regression:

-LDL-C = 60 mg/dl
-HDL-C = 60-80s mg/dl
-TG = 40-50 mg/dl
-TG/HDL ratio = ~50/83 = 48/80 = ~40/67 = 0.60
-LDL/HDL ratio = 60/80 = 0.75

-(? 60-60-60-0.60 ===> LDL-25(OH)D-apoB-TG/HDL-ratio)


The most significant contribution that Nissen made I believe was actually not mentioned in his comments or conclusions. In fact his conclusions from the data differed from mine regarding reduction of clinical events at 18 months and less than 18months after starting a Statin (or for ACTIVATE subjects, statin duration prior to the study longer than the rest of the test subjects). If you review Dr. Nissen's Table 6 below, you'll notice an interesting phenomenon. The best reduction of clinical events outcomes (obstructed events or events requiring re-vasc) supports actually a higher LDL-C (calculated) v. lower LDL-C at time 18 months for the group with a 'good' healthy HDL increase and LDL surprisingly g-r-e-a-t-e-r than average LDL=87.5 mg/dl.... hhhmmm... what could be going on here...? May stabilization (which translates best to reduced revasculariazations) require a little increase in % atheroma volume (though total plaque mass show decreases)?? The data may suggest this (see below 2 duplicated Table 6's).


Dividing out the study pop into 4 subgroups compared responses related to HDLs (and apo B) which appear to exhibit the highest association with clinical events. Perhaps when LDL is less than 87.5 mg/dl, the presence of small LDL still plays a HUGE role? Perhaps those individuals who experienced the most substantial INITIAL improvement in HDLs also had the greatest shift from Pattern B to Pattern A? Perhaps this shift explains the reduction in revascularizations (p=0.07) since these occur at higher frequency 6-12 months after a previous PTCA/stent. Rates of prior percutaneous intervention were in fact high in the study groups (71%, 30%, 81%, n/a). Could the first sub-group have had some plaque shrinkage but were still in the early stages of plaque-remodelling? Perhaps the first sub-group contained two distinct stages of regression -- one early (not stabilizied yet) and one late (stabilization + regression). Of course, the unstabilized will increase clinical events, especially if the presence of small LDL has not been addressed (ie, fish oil deficiency, vitamin D3 deficiency, carb-overloading). It only takes a few events or revascularizations to affect the data. Maybe there is a period of even 'fluffiness' of plaque (surface, core/internal) right before it stabilizes and regresses... synonymous with the changes occuring in the arteries where small LDL is shifting toward buoyant, more benevolent particles? Perhaps it's a phase... and we only have part of the snapshot...

What an amazing picture to behold though... Regression t-r-a-c-k-e-d in such a large population!

Let's thinc again... Perhaps the LDL-calculated based conclusions are bunk? Is LDL-calcuated really the 'lousy' cholesterol???

It's too bad the large trials failed to VAP or NMR the lipoproteins (or at least failed to report smLDL-particles).




Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K, Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. (Full PDF here)
Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.
JAMA. 2007 Feb 7;297(5):499-508.
PMID: 17284700

The conclusions that I draw from the data (though apparently non-statistically significant; who the heck was the statistician) is that human clinical events data support an approximately 50%+ decrease in revascularization-events in the group with higher LDL-C (read: lower small-LDLp) when compared with those with lower LDL-C (read: still high small-LDL in a subset of patients which may have contributed to higher clinical events requiring revascularization).

When plaque stabilizes, the echogenicity increases on ultrasound. Does this also contribute to mildly increased plaque volume? Perhaps? When you get a scab on a traumatic wound, does the scab appear thicker and heavier (esp if you're swimming!) before subsequently falling off after new pink epithelium grows?

Dr. Nissen notes:

"Greater percentage increases in HDL and lower levels of LDL (NOT) and LDL/HDL ratio in patients during treatment with a statin resulted in atheroma regression (BUT NOT HUMAN CLINICAL CAD/CVD EVENTS)...

...This is, to our knowledge the first time that increases in HDL levels have been shown to be an independent predictor of beneficial outcome with statin therapy."

Now Nissen is erudite.

He also looked at 'substantial' responders, meaning those with massive regression (b/c the above data otherwise makes little sense -- to statinators). And HDL-cholesterol undoubtedly must be raised for regression. Could Crestor have higher affinity for PPAR receptors or indirectly affect PPAR more?

His results when looking from a different perspective comparing Non-Responders v. Responders is even more intriguing than the above data. And holds more answers to the key to SUBSTANTIAL REGRESSION. Additionally this data is in direct compliance with TYP principles 60-60-60. Responders were assigned if significant volume/PAV% relative reduction of 5% or greater regression occurred (?about twice or more the average amount?).

Responders comprised 34% of the study population (n=370 were they all Crestor/ASTEROID??). Looking at this data (see Table 5 in the PDF), you'll notice immediately that huge increases in HDL and apo B occurred and likely lead to the dramatic PAV reductions in responders. In fact the difference between HDL improvements between Non-regression subjects and Substantial-Regression subjects was nearly 58% (6.5% v. 10.3%; wide SD 17.2%)) Remember average HDL change was 7.5%. Wow. I bet some of these individuals with massive plaque regression hit the TYP goals of 40% increase to HDL=60 mg/dl (perhaps combined with exercise/diet changes) and TG=60 mg/dl. For apo B, there was also wide variation apparently among the subjects, but also apo B dropped substantially by 40.9 mg/dl to an average of 90.1 mg/dl in the Regression group (almost close to TYP less than 60-70 mg/dl goals!). The median change was 34.8% (SD wide 25.0%) whereas the Non-regression median apoB change was only 25.7% (SD 24.8%).

Wouldn't it have been interesting to see if the Responders had reduced clinical events? Instead of just breaking down LDL-subsets?


Does Nissen know that Statins substantially affect PPAR???! And the regression benefits for regression may be attributed more strongly to PPAR than LDL? Evidently not... though he mentions VA-HIT and Helsinki Heart (he forgot DAIS) which are primary and secondary prevention trials that demonstrated reduced mortality and events with fibrates (PPAR-alpha agonists) especially in the diabetes subsets (ie, high insulin).

We discussed how statins both bind and indirectly affect plaque-mac PPAR earlier here.

The many pleiotropic benefits of statins are related to reduction in inflammation via Macrophage's PPAR activation at the plaque level in damaged endothelium:
--reduction in CRP
--plaque stabilization
--reduced oxLDL in plaque
--atheroma regression


Does this suggest that PPARs regress plaque...?

I do believe so


How do statins causes lipoprotein benefits via activation of Mac PPAR a and PPAR g ?

Nissen saw no significant contribution of statins on TGs on changes in PAV but TGs were statistically associated with improvement. The regression was attributed most strongly to vast HDL increases he reports (and to dramatic apoB and small-LDLp reductions which he didn't really address in the text) .

PPAR activation leads to these lipoprotein benefits:
--reduction in small-LDLp
--reduction in apoB
--reduction in TGs
--INCREASES IN HDL-C


So statins are like PPAR agonists? So statins work like food and food sensors?

What food item works the best as a PPAR agonist? What's my favorite supplement?




Bays et al nicely describes the benefits, MOA, and clinical implications of omega-3 fatty acids. Next to the NIACIN-king... fish oil R-O-C-K-S. Fish oil raises HDLs by an impressive 11-14% in clinical trials. The benefits are dose related, the higher the dose, the higher the HDLs. The lower the baseline HDL, the higher the potential increases.

Fish oils benefits for regression are three-fold:
(a) reduced systemic inflammation via PPAR
(b) increase HDLs via PPAR
(c) reduce apoB and insulin via PPAR

Another dimension of fish oil CAD benefits is its electro-stabilizing effects on cardiac conduction and prevention of arrhythmias.

Bays HE, Tighe AP, Sadovsky R, Davidson MH.
Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
Expert Rev Cardiovasc Ther. 2008 Mar;6(3):391-409. Review. (Full PDF here)
PMID: 18327998


Synergistically, Statins and Fish oil can work together to stabilize and regress plaque. The authors eloquently review how both have separate mechanisms which complement and accelerate the conversion of small-LDLp to IDL than to large non-atherogenic LDL.

Synergism... I like that...

What are other mechanisms to raise and maximize HDL?

Depending on the degree of plaque, the more the below are achieved, the greater the increase in HDLs...
--stop all wheat
--stop all grains
--minimize all fruit
--stop all HFCS garbage
--consume adequate high-quality protein 1 g/kg
--consume Hg-free seafood
--consume EPA+DHA
--consume nuts/seeds
--intermittently fast
--exercise, some HIT (high intensity training -- only after medical clearance -- of course)
--get lean muscle mass
--abdominal fat loss
--decrease IR (see above)
--tobacco cessation
--maintain good sleep

-BG

PPAR-Delta: Dagger in the Heart of CAD

(Proteins = amino acids)

PPAR-Delta is part of the family of peroxisome proliferator-activated receptors (PPARs). This receptor family is responsible for cueing in environmental nutrients. In evolutionary terms, survival depended on nutrients in the environment and the ability for the human body to adapt to low nutrients vs. plentiful nutrients it is hypothesized to determine inflammatory status, growth, reproduction and development. Nutrient factors like dietary fats and protien bind or regulate PPAR receptors, thus these receptors have been termed 'nutrient sensors.'

How is this wonderful transcriptional 'switch' turned on? What degrades its amazing anti-inflammatory and muscle/metabolism-building functions? PPAR-Delta works through the mTOR pathway which reminds me enormously of the Norse god THOR which shares similar attributes -- invincibility, strength and virility. Can PPAR-Delta be the dagger in the heart of heart disease?

FIGURE (below)
Therapeutic targets of PPARδ in the metabolic syndrome. Receptor activation improves multiple aspects of the metabolic syndrome through tissue- and cell-specific effects. In skeletal muscle, PPARδ regulates fatty acid transport and oxidation, thermogenesis, and the formation of slow-twitch muscle fibers, resulting in enhanced endurance performance. It likewise activates fatty acid transport and oxidation as well as thermogenesis in adipose tissue, retarding weight gain. PPARδ regulates the availability of BCL-6, an inflammatory suppressor protein released upon ligation of PPARδ, thereby functioning as an “antiinflammatory switch” to control macrophage-elicited inflammation and atherogenesis. In the liver, PPARδ activation suppresses glucose production by upregulating the pentose phosphate shunt. PPARδ activation also improves atherogenic dyslipidemia by raising serum HDL cholesterol levels via unclear mechanisms. Additionally, PPARδ activation in the heart enhances contractile function and may improve cardiomyopathy.

PPAR delta: a dagger in the heart of the metabolic syndrome.
Barish GD, et al. Howard Hughes Medical Institute, Salk, La Jolla CA. J Clin Invest. 2006 Mar;116(3):590-7.
Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis. PMID: 16511591

Synthetic analogues of chemicals that bind PPAR-Delta are being elucidated. In animal (and human) studies, their extreme benefits have been shown on lipids as well as reductions in insulin and improvement in insulin sensitivity. Barish et al summarize much of the current research on PPAR-Delta, including astounding trends in reductions in small dense atherogenic LDL, increases HDL, lowering of TGs, as well as the drops in insulin.

"High-affinity PPARδ ligands have revealed an important role for PPARδ in lipoprotein metabolism. Treatment of insulin-resistant obese rhesus monkeys with the PPARδ-selective agonist GW501516 resulted in a dramatic 79% increase in HDL-C, a 56% decrease in triglycerides, and a 29% decrease in LDL cholesterol (33). The profound increase in HDL cholesterol levels correlated with an increase in number, not size, of HDL particles and was accompanied by increased serum levels of the HDL-associated apolipoproteins apoA-I, apoA-II, and apoC-III (33). In addition, fasting insulin levels declined by up to 48% in the PPARδ drug–treated animals (33). Obese and nonobese mice similarly develop an increase of up to 50% in HDL cholesterol levels when treated with PPARδ agonists (34, 35). The mechanism by which PPARδ activation raises HDL cholesterol levels remains to be elucidated, but studies to date indicate that expression of the reverse cholesterol transporter ABCA1 is enhanced in some tissues upon exposure to PPARδ agonists, including human and mouse macrophages as well as human intestinal cells and fibroblasts (33, 35). Additional work suggests that PPARδ activation reduces intestinal cholesterol absorption via downregulation of the Niemann-Pick C1–like 1 gene (NPC1L1) (35). NPC1L1 is a key mediator of intestinal cholesterol absorption and a putative target for the clinically used cholesterol absorption inhibitor ezetimibe (ZETIA). "

However, like all synthetic, fake analogues which try to copy and mimic our own natural endogenous nutritional factors (Dr. Davis recently discussed) that we consume or make on our own, these agents so far are not the 'magic bullet' researchers hoped for. In this trial, there are questionable effects on colon carcinogenesis in APCmin mice with one synthetic analogue GW501516 (and other cancer lines). This reminds me of other failed clinical trials where synthetic vitamins or hormones caused poor outcomes (CARET, WHI, etc). Natural ligands seem to be the most optimal binders to our natural receptors.

"Moreover, PPARδ agonists enhanced β-oxidation in 3T3-L1 preadipocytes by 50% (39). Most importantly, PPARδ ligands retard weight gain in models of high-fat diet–induced obesity (39, 40). These results suggest that PPARδ synthetic drugs may be therapeutic as antiobesity agents. Short-term (4-month) treatment of obese rhesus monkeys with variable doses of GW501516 did not affect body weight, however, so it remains to be determined whether long-term administration of PPARδ drugs will control body weight in monkeys and humans (33)."

The key may be perhaps... muscle. Isn't the heart one of the most important muscles? It beats every second of every minute of our lives, right? Nearly 100,000 times per day.

Metabolic 'remodeling' in the muscles activates PPAR-Delta; fasting, exercise training, and diabetes can affect it. The end result is prevention of obesity/weight gain and potently sensitizing glucose uptake.

"Skeletal muscle is a key metabolic tissue, accounting for approximately 80% of insulin-stimulated glucose uptake. It is composed of heterogeneous myofibers that differ in their metabolic and contractile properties, including oxidative slow-twitch (type I), mixed oxidative/glycolytic fast-twitch (type IIA), and glycolytic fast-twitch (type IIB) forms
(41). Oxidative myofibers preferentially express enzymes that oxidize fatty acids and contain slow isoforms of contractile proteins, whereas glycolytic myofibers predominantly metabolize glucose and are composed of fast contractile protein isoforms (41, 42). Skeletal muscle is highly
plastic, adapting to environmental challenges by regulating the composition of slow- and fast-twitch myofibers. Interventions including endurance exercise, physical inactivity, and metabolic diseases such as type 2 diabetes mellitus can induce the trans-differentiation of myofibers (43)."

"PPARδ’s regulation of metabolic and fiber type status has several physiological implications. First, the presence of an increased proportion of oxidative slow-twitch fibers is predicted to decrease skeletal muscle fatigability. For example, increased endurance in marathon runners is linked to a higher proportion of oxidative slow-twitch fibers in their skeletal muscles. Mice with muscle-specific VP16-PPARδ transgenes have strikingly higher treadmill endurance capacity, running twice as long and far as wild-type mice (WOW -- super-mice! PPAR-Delta doubles the distance!) (48). Second, oxidative fibers have a tremendous impact on fatty acid homeostasis. Both obesity and insulin resistance are linked to a decrease in the proportion of oxidative slow-twitch fibers in skeletal muscle (52–56). Muscle-specific VP16-PPARδ transgenic mice, which have a higher proportion of oxidative slow-twitch fibers, are resistant to high-fat diet–induced obesity (48). Activation of PPARδ during high-fat feeding (In Lab language, translates to 'HIGH CARB' lab chow -- c-a-r-b is the context to concentrate on.) increases disposal of lipid in skeletal muscles, preventing the storage of excess fat in adipocytes and weight gain (39, 40, 49)."

PPAR-Delta activation may be the most heart-protective of all the PPAR receptor subtypes -- PPARalpha and PPARgamma have primary tissue expression, however PPARdelta is expressed strongly ubiquitiously.

Undoubtedly, this receptor has the most power to shield the heart from shifting to inferior energy sources (glucose) and developing inelasticity and stiffness in heart muscle fibers. What has been shown to activate PPAR-Delta? Protein intake (see end), fatty acid intake, movement (see end). What has been shown definitely to de-activate PPAR-Delta? The amount of unliganded receptors appears to predict the inflammatory status, according to Takahashi S, et al. (New therapeutic target for metabolic syndrome: PPARdelta. Endocr J. 2007 Jun;54(3):347-57). Paraplegia (see later). In other words, long periods of physical inactivity and sedentary lifestyles allow this pivotal anti-inflammatory 'switch' to be turned off (which can later lead to heart disease, heart failure, MetSyn, insulin resistance, and even cancer in vitro here and here).

A future blog topic is cardiac energetics (and other laws of physics). Our heart and skeletal muscles prefer combusting fatty acids, not glucose, for energy. Glycogen (glucose stored in muscles) is more like kindling and twigs to a fire. What fuels a nice roaring fire? Nice l-o-g-s... For burning PHAT (!!) flaming fires, our bodies go to temporarily-stored fatty acids in skeletal muscles... then next it goes to WAT (white adipose tissue) found in centrally-located fat, ie toxic wheat-bellies (that Dr. Davis frequently refers to). PPAR-Delta again is responsible for regulating the 'switch' to preferred fuel metabolism!

"Fatty acid oxidation is the primary source of energy in the postnatal heart (67). Impaired fatty acid oxidation and a shift to reliance on glucose metabolism are hallmarks of myocardial diseases such as cardiac hypertrophy and congestive heart failure (67). As in skeletal muscle, PPARδ is a critical regulator of fatty acid oxidation in cardiac tissue. Cheng et al. showed that cardiac-specific deletion of PPARδ suppresses the expression of oxidative genes (68). This leads to impaired fatty acid oxidation and a reciprocal increase in glucose oxidation, along with fat accumulation in cardiomyocytes (68). Moreover, PPARδ-selective agonists increase fatty acid oxidation via the induction of oxidative genes in isolated neonatal as well as adult rat cardiomyocytes (69) (Table 1). The PPARδ-dependent maintenance of basal fatty acid oxidation is crucial for normal cardiac mechanics. PPARδ-null hearts are characterized by decreased rates of contraction and relaxation, increased left ventricular end-diastolic pressure, and decreased cardiac output, factors associated with the onset of cardiac failure (68). Indeed, mice with cardiac-specific deletion of PPARδ develop age-dependent cardiac lipotoxicity, cardiac hypertrophy, end-stage dilated cardiomyopathy, and decreased survival (68). The protective role of PPARδ in the heart has been confirmed by in vitro studies showing that PPARδ agonists attenuate phenylephrine-induced cardiac hypertrophy. While phenylephrine suppresses fatty acid oxidation in cardiomyocytes, concomitant activation of PPARδ reverses these effects (70). Although PPARδ may directly increase the transcription of fatty acid oxidative genes, at least 1 study suggests that effects could also be indirect. Planavila and colleagues showed that PPARδ interacts with and blocks NF-κB–mediated suppression of fatty acid oxidation in cardiomyocytes (71). PPARδ-dependent antagonism of NF-κB could be particularly important during sepsis, when endotoxins decrease cardiac fatty acid oxidation and initiate cardiac failure (71, 72)."

FIGURE. PPARδ: an inflammatory switch. In the absence of ligand, PPARδ-RXR heterodimers bind to consensus PPAR DNA response elements (PPREs) and repress target gene expression by recruiting corepressors and associated repressive proteins including B cell lymphoma-6 (BCL-6) (top). (VITAMIN A, RETINOIDS, CAROTENOIDS BIND RXR) Upon addition of PPARδ ligand (bottom left), PPARδ-RXR heterodimers undergo a conformational shift. This dismisses the corepressor complex, including BCL-6, in exchange for a complex of coactivator proteins and results in enhanced PPARδ target gene expression. BCL-6, an inflammatory suppressor protein, is thereby liberated to repress inflammatory gene expression.

Some natural nutrients and endogenous substances that bind or activate PPARdelta are listed below. What are the side effects of these receptor agonists? Vitality, strength and virility. No cancer, no heart disease, etc.

Fish oil (yeah my favorite) -- DHA, EPA -- n-3 PUFAs

Vitamin D, Vitamin A -- heterodimer with PPARs via VDR and RAR/RXR

Monounsaturated fatty acids (ie, olive oil)

Walnuts, Almonds (n-3 PUFAs, MUFAs)

Saturated fatty acids (our own adipose depots as burned with resistance training/exercise; consumed)

Eicosanoids -- Prostacyclin (PGI2), carbaprostacycline (cPGI2)

Protein -- indirectly activates PPARdelta via mTOR signalling

Physical movement -- especially resistance training with weights

Eat protein... MAKE PROTEIN, ie, muscles!

Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E392-400. PMID: 18056791

Inactivity trains our muscles to degrade and die off. Eight hours of sedentary activity can lead to our most important muscle, the heart, to effectively atrophy. Whereas, use of muscles signals to the body to build m-o-r-e muscles. The resulting adaptations to movement are (1) muscle growth (2) increased synthesis of more mitochrondria (fuel-burning furnaces) (3) higher increases in glucose uptake and transporters for glucose (which thereby ameliorate insulin resistance).

• Dreyer HC, Glynn EL, Lujan HL, Fry CS, DiCarlo SE, Rasmussen BB. Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway. J Appl Physiol. 2008 Jan;104(1):27-33. Epub 2007 Sep 20. PMID: 17885021
• Röckl KS, Witczak CA, Goodyear LJ. Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life. 2008 Mar;60(3):145-53. Review. PMID: 18380005 Link to full article here (see below for 2 great figures).
  
  SUMMARY by Rockl et al: "Exercise is of critical importance for people with insulin resistance or diabetes. Our current understanding is that one of the many benefits of an acute bout of exercise is an insulin-independent increase in the glucose uptake capacities of skeletal muscle. Important chronic adaptations to exercise training are the increase of mitochondria and thus oxidative capacities in skeletal muscle, the transformation of muscle fiber types, and the increase in GLUT4 protein expression.
  Contractile activity and insulin are the most potent and physiologically relevant stimuli of glucose transport in skeletal muscle. While significant progress has been made in elucidating the insulin signaling pathway leading to GLUT4 translocation, identification of the signals mediating contraction-stimulated glucose transport has proved challenging. A growing body of data suggests that multiple signaling cascades mediate the metabolic effects of contraction. While the proximal signals leading to contraction- and insulin-stimulated glucose transport are clearly distinct, emerging studies have shown a reconnection or convergence of these signals at AS160.
  Exercise training induces an increase of oxidative capacity, fiber type changes, and elevated GLUT4 protein levels in skeletal muscle; adaptations which are of critical importance to lower free fatty acids, improve glucose uptake, and decrease the risk of insulin resistance and diabetes. Again, multiple signaling pathways appear to act synergistically to mediate adaptive responses to exercise training. In particular, AMPK and calcineurin have evolved as major candidates for mediating exercise-training adaptations. PGC-1 may be a point of convergence for both pathways. While considerable progress has been made in decoding molecular mechanisms around these molecules, more research will be needed to test their physiological role in skeletal muscle adaptations to exercise training. "
  
  
  Figure: Proposed model for the signaling pathways mediating insulin and contraction-induced skeletal muscle glucose transport. Insulin and contraction-mediated glucose transport occurs by translocation of glucose transporter 4 (GLUT4) from intracellular locations to the plasma membrane. Insulin binding leads to phosphorylation of the insulin receptor with subsequent activation of insulin receptor substrate 1/2 (IRS-1/2) and phosphatidylinositol 3-kinase (PI3-kinase). Downstream of PI3-kinase the protein kinases, Akt, which then regulates activation of Akt Substrate of 160 kD (AS160), and atypical protein kinase C (aPKC), have been identified to mediate insulin stimulated GLUT4 translocation. Contraction stimulated glucose uptake is mediated by multiple signaling pathways including aPKC, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), LKB1, and AMP-activated protein kinase (AMPK).