Clinicians and Coaches: ROCK YOUR MICROBIOME & NUTRIGENOMIC MEDICINE w/ The Results & Outcome Academy Conference in 3 weeks

Check out the updated site: TheGutInstitute.Com has launched!

INVITATION TO COACHES AND PRACTITIONERS

Registration and More Details

Clinicians and Coaches:

ROCK YOUR MICROBIOME and NUTRIGENOMIC MEDICINE 

w/ The Results & Outcome Academy Conference

In 3 weeks!

How to Grow Your Practice by Incorporating Microbiome & Nutrigenomic Medicine

Cost: VIRTUALLY FREE AND WORTH $2497
Date: Dec 10th and 11th, 2016
Location: Double Tree Hotel, Berkeley Marina, California

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What Clinicians and Coaches Will Get!

• You will walk away with swag worth over $1000 – so the conference is virtually FREE
• Knowledge on how to build your business
• Cutting-edge, personalized gut and nutrigenomic protocols for your clients
• A deep connection with new lifelong friends and future collaboration partners
• Part of a growing emerging international community who are at the forefront of functional medicine for methylation and microbiome medicine

This an event like no other. We are bringing together leading practitioners, functional medicine providers, and health coaches to create a collaborative community.
This will be transformational experience - if you plan to come and just sit in the seat and take notes – then this is not for you… You will not leave the same as you came

Registration and More Details

Registration and More Details

This is Dr. Anh, and on behalf of Drs. Grace and Erika, I want to say “THANK YOU!” so much for your interest in our upcoming event, Microbiome and Nutrigenomic Medicine w/ Business Acumen live training!

NEW SITE  TheGutInstitute.Com for the latest in microbiome, gut flora, science, podcasts and more!

Paleo and PPAR For Max Longevity

Mitochondria, DNA and Our Hearts

Nick Lane (author, Power Sex Suicide) also discussed how a small cost exists for the mitochondria to each contain, replicate, and maintain their own set of mtDNA. The costs must be worth the expense and final outcomes for cellular energetics, survival and, ultimately, longevity.

All day everyday 24/7 our bodies are correcting DNA damage, mutations and breakage in mitochondria and in the prime control center, the nucleus. DNA repair requires optimal functioning of crucial enzymes, critical hormone pathways, the presence of co-factors, and the absence of ROS and other oxidative stressors.

We employ ALL of these strategies at TYP for optimum regression of obstructive heart disease as detected, identified and calculated on EBT calcium scoring.


The TYP Program includes:
--Paleo eating (Read Dr.Davis' Cordain interview for TYP: HERE)
--Paleo exercise (eg, functional hypertrophy)
--Lp(a) identification and correction (17-25% of population carries)
--Homocysteine identification and correction
--Small dense LDL particle quantification and correction
--Hormone dysregulation and optimization to youthful levels (Vitamin D, Thyroid, INSULIN, DHEA, Melatonin, Estrogen, Progesterone, Testosterone, Cortisol, etc)
--Antioxidants with anti-inflammatory properties: High dose Omega-3, Niacin Vitamin B3 1-2 g/day, Vitamins ADE K1 K2 MK-7 MK-4, Vitamin C, Phosphatidylcholine, B-vitamins, Minerals Mg Zn Se etc, etc


Everyone who correctly identifies the 'problem' and correctly fixes the 'problem' achieves reductions in calcium scores in 1-3yrs. The side effects reported are: better senses (seeing, smelling, balance, reflexes), vitality, energy, weight loss, lower BP/glucose/resting pulse, improved cholesterol, glowing skin/hair/nails, etc. Besides plaque regression/stabilization and long-term heart protection (statins, optional *WINK*)... Oh BTW ... Maximum longevity, cancer protection, easy weight loss, body fat recomposition...looking H-A-W-T and Paleo-appealing *HA*, obesity-resistance, and being idiot-proof (ok... j/k!) are additionally guaranteed.

...Who doesn't desire a degree of that?

• Mitochondria in the human heart.
  Lemieux H, Hoppel CL. J Bioenerg Biomembr. 2009 Apr 8.
  Center for Mitochondrial Disease, Department of Pharmacology and Medicine, School of Medicine, Case Western Reserve University
  The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of
  (1) methods to understand mitochondrial function, with particular emphasis on integrated function,
  (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and
  (3) possible applications of this knowledge in the treatment of patients with cardiac disease.
  PMID: 19353253
• Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis.
  Puddu P, Muscari A et al. Cardiology. 2005;103(3):137-41.
  It is now widely accepted that oxidant stress and the ensuing endothelial dysfunction play a key role in the pathogenesis of atherosclerosis and cardiovascular diseases. The mitochondrial respiratory chain is the major source of reactive oxygen species as byproducts of normal cell respiration. Mitochondria may also be important targets for reactive oxygen species, which may damage mitochondrial lipids, enzymes and DNA with following mitochondrial dysfunction. Free cholesterol, oxidized low-density lipoprotein and glycated high-density lipoprotein are further possible causes of mitochondrial dysfunction and/or apoptosis. Moreover, in patients with mitochondrial diseases, vascular complications are commonly observed at an early age, often in the absence of traditional risk factors for atherosclerosis. We propose that mitochondrial dysfunction, besides endothelial dysfunction, represents an important early step in the chain of events leading to atherosclerotic disease.
• Mitochondrial integrity and function in atherogenesis.
  Ballinger SW, Runge MS et al.
  Circulation. 2002 Jul 30;106(5):544-9.
• The role of mitochondria in ischemic heart disease.
  Ferrari R.
  J Cardiovasc Pharmacol. 1996;28 Suppl 1:S1-10. Review.

Pimp Your PPARs! For Obesity Resistance

The family of PPAR nuclear receptors (NRs) are one of the ultimate controllers of inflammation, growth, proliferation, nutrient sensing, metabolism, and most importantly energy homeostasis. Remember, energy IN does not equal energy OUT. G-Flux post.

The medical literature only recently in the last 10-15 yrs exploded with information about these regulators of life. One of the newest elucidated pieces of the puzzle is that PPAR-Delta controls mitochondrial metabolism (uncoupling) in brown fat (our 'good' storage fat...keeps us warm when we shiver and many MANY other good things). The authors from the east coast remark, "Interestingly, the nuclear receptor PPARdelta not only mediates the actions of PGC-1alpha but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism... In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. " Pan D et al. Cell. 2009 Apr 3;137(1):73-86.


Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease.
Robinson E, Grieve DJ.
Pharmacol Ther. 2009 Mar 24.

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.
Chinetti G, Fruchart JC, Staels B.
Inflamm Res. 2000 Oct;49(10):497-505. Review.

Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: simultaneous activation of PPARalpha, PPARgamma, and PPARdelta.
Evans JL, Lin JJ, Goldfine ID.
Curr Diabetes Rev. 2005 Aug;1(3):299-307. Review.

Peroxisome proliferator-activated receptors and the control of inflammation.
Cabrero A, Laguna JC, Vázquez M.
Curr Drug Targets Inflamm Allergy. 2002 Sep;1(3):243-8. Review.

Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.
Touyz RM, Schiffrin EL.
Vascul Pharmacol. 2006 Jul;45(1):19-28. Epub 2006 Jun 16. Review.

Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.
Marx N, Duez H, Fruchart JC, Staels B.
Circ Res. 2004 May 14;94(9):1168-78. Review.

Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.
Guan Y.
J Am Soc Nephrol. 2004 Nov;15(11):2801-15. Review.

Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism.
Latruffe N, Vamecq J.
Biochimie. 1997 Feb-Mar;79(2-3):81-94. Review.

Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis.
Gouni-Berthold I, Krone W.
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Dec;5(6):513-23. Review.

Pleiotropic actions of PPAR gamma activators thiazolidinediones in cardiovascular diseases.
Takano H, Hasegawa H, Zou Y, Komuro I.
Curr Pharm Des. 2004;10(22):2779-86. Review.

Dead and Gone...the Old Me

When you've stepped into a new realm of extreme longevity and optimal fitness and health, how do you feel?

Like the old self is gone?

When I attend weddings for relatives and old friends, it's seriously scary/odd how people don't recognize you. Because internally you are the SAME person, but physical transformations can be overwhelmingly out of proportion. Blown away. Can't comprehend. No one has any idea that a more vital, energy-filled, blasting life can be awaiting them.

Movement with a little intensity, vitamin D/A/E/K, fish oil, seafood/grassfed meat, omega-3 eggs, wheat-free (semi-dairy/legume-free), low carb is the only way to go. It's not hard. At ALL. In fact, it's purely incomprehensibly curious to NOT engage in this T.Y.P. HEDONIA-lifestyle.

The Old Me...GONE...certainly that's how I feel now -- engaged a year now...! Yep, been about a year on TYP and can't imagine feeling how lethargic, slow, sluggish, mentally fogged I was before. Asthmatic, scratchy skin, poor reflexes, SAD (seasonal affective disorder), cold extremities like semi-Reynaud's, and the list goes on-and-on... Beyond one year, I've continued to lose body fat, increased energy and improved fitness -- mental as well as physical.

Also... can't suppress the emerging sense of . . .
--Agelessness
--Invincibility
--Mental vigor

Travelling on this road too long...

No more stress now -- I'm straight

Now I get it now, I take time to think

Before I make a mistake

Just for my family's sake

That part of me left yesterday

The harder me is strong today

No regrets I'm blessed to say

The old me is dead and gone away

T.I. featuring Justin Timberlake
DEAD AND GONE
Courtesy of Youtube.com

The TrackYourPlaque program embodies fully the tools to engage comprehensively in the path toward infinite good health and reversal of many disease states -- diabetes, heart disease, peripheral vascular disease, erectile dysfunction, carotid artery disease, strokes, hypertension, obesity, hypothyroidism.

We're launching TYP 2.0 shortly in the next week or two. You'll truly be able to TRACK the wonderful progress in CAC score, lesion/volume/score, weight, BMI, Body Fat %, Lp(a), TC-TG-HDL-LDL, TSH, free T4, free T3, anti-TPO, CRP, fibrinogen, homocysteine, uric acid, creatinine, ALT, HDL2b, large small HDL, large small LDL, VLDL, IDL, etc. Supplement dose and durations can be entered eventually and tracked as well. These are the ULTIMATE tools for evaluating health and assessing improvements and trends.

I can hardly wait...

The next generation of TYP will be so exciting!!! I'm so glad y'll be there...

Currently we add our personal data HERE and soon will be greatly expanded.

Bliss out... let me kick it to ya! Grasp it!

Hearts of Stone, Arteries of Glass

A recent Wall Street Journal article "Defending Against Disease -- With Vitamin D New Studies Suggest It Isn't Just Bones That Might Benefit" by the wonderful Melinda Beck highlights benefits of Vitamin D3. In TYP, we've known the benefits for years :) but it's nice to see the rest of the world catching up.

The benefits of Vitamin D3 are potent, powerful immunomodulation -- to the point where autoimmune diseases, viral and bacterial infections and cancer are effectively reduced. What is the value for heart disease and diabetes prevention? In hemodialysis patients, great lessons are can be learned. Nephrologists often describe patients with severe (stage 5) chronic kidney disease (CKD) patients on hemodialysis as having 'hearts of stone, blood vessels of glass.' Unfortunately over 70% of chronic hemodialysis patients have coronary artery disease (and Lp(a)). What medical science shows is that Agatston coronary calcification scores can be dramatically reduced when vitamin D is replenished and calcium is restricted. Sevelamer (Renagel) is a calcium-free, metal-free polymer phosphate binder. In 52-weeks, calcium restriction, a phosphate-binder and vitamin D resulted in one individual in a 21% reduction in Agatston CAC score (from 968 to 756; see Figure 2).

Average reduction in CAC at 6-mos in the Sevalamer group was 8% CAC score reduction/regression, whereas the Calcium-binder group exhibited an increase of CAC score of 10%. Interestingly, the study protocol encouraged discontinuation of Vitamin D once PTH was 150 therefore regression does not appear to be achieved further in the Sevelamer group between the 6-12 month period.

With chronic kidney disease, impaired activation of Vitamin D occurs which leads to degeneration of bones (renal osteodystrophy) and subsequent release of calcium and phosphate into the blood stream (ie, the building blocks of bone). To normalize phosphate and prevent precipitation of bony matrix in soft tissues (including the heart), phosphate binders are used. In the past, calcium carbonate was used -- cheap and effective. The problem was that calcium added to the mix created higher CAC scores and vascular calcification. Higher rates of mortality secondary to coronary artery disease, peripheral vascular disease and strokes were witnessed in the past. However now with newer calcium-free phosphate binders and Vitamin D (real and fake) as standard of medical care, vascular calcifications, aortic, valvular and coronary calcifications can be halted. In fact... even dramatically REDUCED. Wow... Dr. Davis, you R-O-C-K !

He's right about wheat toxicity... and he's right about the powers of vitamin D!

• Chertow GM, Burke SK, Raggi P; Treat to Goal Working Group. (Vitamin D !! and) Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002 Jul;62(1):245-52. PMID: 12081584
• Nunes JP. The case for dietary calcium restriction in patients with atherosclerosis.
  Med Hypotheses. 2005;65(3):521-4. Review.
  PMID: 15905041
• Wonderful review article from the Kidney.org (see above and below diagrams)
  Clinical Outcomes. in CKD Stage 5: The Impact of Mineral. and Bone Disorders

Why did these UCSF and Tulane researchers use EBT calcium scanning to 'track plaque'? There reasoning was 'The purpose of EBT imaging in our study was to investigate whether the treatments would contribute differently to calcium deposition in the arterial wall. Since the Agatston score is very sensitive to density, and is directly related to the calcium content of the plaque, this was considered the primary EBT end-point. The volumetric scoring method does not apply a scalar density factor but rather estimates the bulk of atherosclerosis [16], and was calculated for completeness. The median inter-scan variability is 8 to 10% for the Agatston score [17, 18] and 6 to 8% for the volume score [16].' Kidney specialists have known the value of EBT scanning (non-invasive, cheap, low-radiation) for YEARS because diagnostic tests which utilize iodine contrast dyes are harmful to kidneys. EBT requires no dyes and therefore maintains protection against kidneys. Additionally, clinical events track well with EBT and vascular calcifications.





Vitamin D used in the trial was one of the below per the investigator:

• 1,25-dihydroxy vitamin D3
• Synthetic analog, IV
• Synthetic analog, PO

EBT scoring measures up and predicts events in coronary disease patients with CKD:
Huybrechts KF, Caro JJ, London GM.
Modeling the implications of changes in vascular calcification in patients on hemodialysis.
Kidney Int. 2005 Apr;67(4):1532-8. PMID: 15780108

METHODS: Data on 179 patients on hemodialysis treated at one center in France included biochemical values during the year prior to study entry, patient characteristics, and cardiovascular events over an average of 4 years. As arterial calcification was evaluated ultrasonographically and quantified using a 0 to 4 score, an equation relating this to the electron-beam tomography (EBT)-based calcification score used in the trial was developed and applied to all patients. The estimated scores were then used in survival and Cox proportional hazards analyses of cardiovascular events in relation to the degree of calcification, controlling for other characteristics.

RESULTS: Mean age at inclusion was 54 years, dialysis vintage 70 months, average follow-up 49 months; 32% suffered an event. The calcification score, diabetes, C-reactive protein (CRP), diastolic blood pressure, gender, smoking and hypertension are independent predictors of cardiovascular risk. The resulting equation indicates that, relative to a calcification score below 400, the risk of an initial event increases 44% for a score of 600, and more than doubles for a score of 1000.




Heart protection has been demonstrated with Vitamin D in this CAD hemodialysis subgroup. Reduced clinical events and mortality are demonstrated and discussed below:

• Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R.
  Vitamin D levels and early mortality among incident hemodialysis patients.
  Kidney Int. 2007 Oct;72(8):1004-13.
  PMID: 17687259
• Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernán MA, Camargo CA Jr, Thadhani R.
  Activated injectable vitamin D and hemodialysis survival: a historical cohort study.
  J Am Soc Nephrol. 2005 Apr;16(4):1115-25.
  PMID: 15728786
• Cheng S, Coyne D.
  Vitamin D and outcomes in chronic kidney disease.
  Curr Opin Nephrol Hypertens. 2007 Mar;16(2):77-82. Review.
  PMID: 17293681
• Levin A, Li YC.
  Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease?
  Kidney Int. 2005 Nov;68(5):1973-81. Review.
  PMID: 16221197
• Wu-Wong JR, Melnick J.
  Vascular calcification in chronic kidney failure: role of vitamin D receptor.
  Curr Opin Investig Drugs. 2007 Mar;8(3):237-47. Review.
  PMID: 17408120
• Gesek FA, Desmond JS.
  Improved patient outcomes in chronic kidney disease: optimizing vitamin D therapy.
  Nephrol Nurs J. 2008 Mar-Apr;35(2 Suppl):5S-22S; quiz 23S. Review.
  PMID: 18505229

We also know that Vitamin D in just a single dose (100,000 IU D2... which is dose-equivalent to 33,333 IU natural D3) administered to elderly Scotland residents with Type 2 Diabetes significantly improves endothelial function with testing flow-mediated vasodilatation (FMD):

• Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD.
  Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels.
  Diabet Med. 2008 Mar;25(3):320-5.
  PMID: 18279409

Great reference for Vitamin D:
THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS (CME)
By Alex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD

Lp(a): Running With Scissors (Part 1)

I'm sure as a kid, your mother warned you over and over and over how dangerous running with sharp objects is...

Or sharp pencils... Or knives... Or chopsticks...

Or Lp(a)??! wtf??

Ben Harper and friends: THERE WILL BE LIGHT

Rome Concert Live

Courtesy of Youtube.com

I wish we could live forever...

Then melt into the sun

Melt into the sun

Time is gonna change you

Once it gets you on the run

Gets you on the run

--Chorus--

I've been running

Ever since

Ever since I was a child

Some call it free

And some call it wild

There will be
There will be
There will be a light
There will be a light
There will be
There will be
There will be a light
There will be a light

Why is Lp(a) elevated for some individuals? Why is it directly correlated with premature vascular disease (when BP is elevated)?

It's estimated there are potentially three families of factors that influence Lp(a) which affects about 17-25% of the general population:
(a) Structure and metabolism of very-low-density lipoprotein (VLDL) such as triglycerides, phospholipids, apoC-II, C-III, E, A-II and uric acid (which are of course ALL related to insulin)
(b) Thrombosis-related centering on platelets
(c) Acute phase reactions represented by 1 hr and 2 hr erythrocyte sedimentation rates (ESR) (in other words, immune system stimulation)
(I'd add a 4th factor in the formula (d) kidney dysregulation which is the site of Lp(a) catabolism and recycling/disposal in the human body)

Nakajima K, Hata Y. Intraindividual variations in lipoprotein (a) levels and factors related to these changes. J Atheroscler Thromb. 1996;2(2):96-106. PMID: 9225216



At TrackYourPlaque.com we have several reports addressing Lp(a). The challenge in controlling this one single, severe plaque-building factor can not be underestimated. It can be an unrelenting foe...

-Lp(a) Report I (2006): Lipoprotein(a): What it is, why it's important, and why you need to know if you've got it!

-Lp(a) Report II (2008): Unique Strategies for Lipoprotein(a) Reduction

-Lp(a) Lipoprotein Checklist



There appear to be distinct subpopulations affected by Lp(a) from my (anecdotal, untrained) nonscientific observations:

--high-carb consuming well known athletes (and unknown) who drop dead at endurance events of MIs (Brian Maxwell Northern Cal POWERBAR guru, Jim Fixx, and lucky survivor-Alberto Salazar)
--advanced stage chronic kidney disease (CKD)
--end-stage-renal-disease (ESRD) and dialysis patients
--individuals with kidney stones
--individuals with Metabolic Syndrome (MetSyn) with premature heart disease in the family tree (females affected before age 65; males affected before age 55)
--men with diabetes Type 2 and erectile dysfunction
--individuals with MetSyn who have survived cancer (a condition that really sets off acute phase reactions and the immune system to heal)
--youth and young children with MetSyn, esp PCOS or any other hormone derangements (ie, wheat addiction/prolactin, big-man-boobs, appear 4-mos pregnant and they are male )
--children with elevated insulin and apo B
--adults with elevated insulin and apo B (and this is much more toxic for women for some reason than men)
--women after menopause, esp if no hormone replacement occurs


Can we avoid the dangers of running with scissors (or chopsticks)?

I certainly believe so. (Heed the words of your mother)

Let's keep running... wild and free... until we melt with the sun...


Lp(a): PPAR-Delta... Dagger in the Heart of Lp(a) (Part II) coming soon...

'Wanted': Elite Heart Health NOW

There is a new summer blockbuster I'm looking forward to...(!!) 'Wanted' shortly will be released. Angelina Jolie plays a sort of 'trainer'... to a novice apprentice. All the tools to assassinate the target are provided, and he is 'invited' to lead a new life. Do we all have opportunities to transcend and create extraordinary goals? ...And achieve what we never dreamed? Would you know unless the first steps are taken? Do you need a trainer?

Shift time... Shift your destiny... and make every minute count.

Live like you mean it

Don't accept a 'normal' standard heart life (ie, 'conventional cardiovascular care')
Don't expect mediocrity
Don't wait for an AED defibrillator to be mandated for each home for a home myocardial infarction
Don't play with fire...

Protect a life, yours, and protect others, those who depend on you

Learn all the weapons to l-i-v-e... super-vital, plaque-free, extra-extended lives

Forge elite heart health and fitness now

'This is your destiny. Join us...' Morgan Freeman

Choose your destiny

Choose elite heart health now...And change your life forever...

Track Your Plaque (TYP 2.0):
--controls plaque
--controls weight and body fat
--controls TGs ('bad cholesterol') and small dense bullet-like LDL
--controls blood pressure
--controls inflammation and insulin
--controls glucoses
--controls heart rhythms
(These interventions also controls the same factors which cause strokes, ED, and most cancers.)

Do you need a trainer?

-G

Sarcopenia: 'Poverty of the Flesh' (Greek)

Sarcopenia is a clinical term referring to the loss of muscle mass, strength and function. Starting in our 30s - 40's we begin to lose lean skeletal muscle mass at an average rate of 5% annually. The value of skeletal muscle mass for heart protection cannot be underestimated. Muscle mass, movement, and many dietary components maintain a low inflammatory status in our bodies via the PPAR-Delta receptor and other critical mechanisms. Decline of mass may be age-related but more and more, dysfunction is a sign of the times -- as a society we engage in less and less physical/intense activities, eat more and more excessive nutrient-poor foods, and are prodigiously sedentary for extended periods of time with 'time-saving' devices. (We lost our TV remote control recently (we don't even watch much TV) and boy we've been a bit more active...) Figure 1. Identical twins of different body size and composition due to different training regimes (endurance running vs. field, including dynamic intense and resistance training. Rennie MJ. Body maintenance and repair: how food and exercise keep the musculoskeletal system in good shape. Exp Physiol. 2005 Jul;90(4):427-36. (the G. L. Brown Prize Lecture)



Movement appears more crucial for certain insulin-resistant individuals (including myself) due to our genes. Movement does not need be structured or scripted activity. All physical movement in essence is effective. This includes housekeeping, car washing, hunting/gathering... (even s..e..x..) counts. And movement appears to defy physics. The more movement engaged... and the more intense... the less effort later. (???!) Is that like life? The more we love 'n give... the more we l-i-v-e?





Variations in PPARD determine the change in body composition during lifestyle intervention: a whole-body magnetic resonance study. Thamer C, et al. J Clin Endocrinol Metab. 2008 Apr;93(4):1497-500.



CONTEXT: We recently demonstrated that single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-delta gene (PPARD), i.e. rs1053049, rs6902123, and rs2267668, affect the improvement of mitochondrial function, aerobic physical fitness, and insulin sensitivity by lifestyle intervention (LI).

OBJECTIVE: The objective of the study was to determine whether the aforementioned PPARD SNPs influence the change in body composition and ectopic fat storage during LI.

DESIGN: A total of 156 subjects at an increased risk for type 2 diabetes were genotyped for rs1053049, rs6902123, and rs2267668 and participated in a LI program. Body fat depots, ectopic liver fat, and muscle volume of the leg were quantified using magnetic resonance spectroscopy and imaging.

RESULTS: With regard to body composition, carriers of the minor SNP alleles displayed reduced responses to LI, i.e. LI-induced reduction in adipose tissue mass (nonvisceral adipose tissue: rs1053049, P = 0.02; rs2267668, P = 0.04; visceral adipose tissue: rs1053049, P = 0.01) and hepatic lipids (rs1053049, P = 0.04; rs6902123, P = 0.001; independent of changes in adiposity) as well as LI-induced increase in relative muscle volume of the leg (rs1053049, P = 0.003; rs2267668, P = 0.009) were less pronounced in homo- and heterozygous carriers of the minor alleles as compared with homozygous carriers of the major alleles.

CONCLUSION: SNPs rs1053049, rs6902123, and rs2267668 in PPARD affect LI-induced changes in overall adiposity, hepatic fat storage, and relative muscle mass. Our findings provide a mechanistic explanation for the involvement of these genetic variations in the development of insulin resistance and type 2 diabetes. PMID: 18252792





All the PPAR receptors have similar ligands -- endogenous and exogenous fatty acids (short-chain, medium-chain, long-chain, MUFA, PUFA, SFA, etc) and eicosanoids (steroidal products from the prostaglandin cascade, including COX derivatives). They truly are pivotal controllers when all lifestyle and nutritional factors are optimized. Although such a wide-range of substances can bind and activate these receptors, Amino Acids (via the mTOR pathway) appear to be one the most potent stimulators of PPAR. Amino Acid sufficiency can determine and maximize all the functions of PPAR-Gamma (and Alpha and Delta) -- metabolism, maintenance and synthesis of muscle fibers, thermogenesis, burning fat, storing fat, and the overall balancing of energy. Not only can PPARs regulate diabetes/insulin resistance and heart disease, but with their optimization of function, PPARs can also reverse these conditions. PPARs ameliorate atherosclerosis. Both food and omega-3 trials and drug (alpha, gamma, delta) trials demonstrate this already.



Don't be sarcopenic... Build a wealth of heart protection in your flesh. How much meaningful movement do you have in your daily life?







Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Kim JE, Chen J. Diabetes. 2004 Nov;53(11):2748-56.



Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process. Rapamycin specifically disrupted the positive transcriptional feedback loop between CCAAT/enhancer-binding protein-alpha and peroxisome proliferator-activated receptor-gamma (PPAR-gamma), two key transcription factors in adipogenesis, by directly targeting the transactivation activity of PPAR-gamma. In addition, we demonstrate for the first time that PPAR-gamma activity is dependent on amino acid sufficiency, revealing a molecular link between nutrient status and adipogenesis. The results of our further investigation have led us to propose a model in which the mTOR pathway and the phosphatidylinositol 3-kinase/Akt pathway act in parallel to regulate PPAR-gamma activation during adipogenesis by mediating nutrient availability and insulin signals, respectively. It is interesting that troglitazone (a thiazolidinedione drug WHICH BINDS PPAR-Gamma) reversed the inhibitory effects of rapamycin and amino acid deprivation, implicating therapeutic values of thiazolidinedione drugs to counter certain side effects of rapamycin as an immunosuppressant. PMID: 15504954



(Diagram from here; Williamson DL, et al. Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. J Physiol. 2006 June 1; 573(Pt 2): 497–510. )

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).