Saturday, July 30, 2016

Lifestyle and Ursolic Acid Amplifies Energy for Cellular Function and Regeneration.

Exercise and fasting via beta hydroxybutyrate ( signaling, direct priming of oxidative phosphorylation and histone acetylase inhibition to increase BDNF transcription)  increase nuclear transcription factors of BDNF et al and are promoted by PPAR gamma agonist such as Ursolic acid via peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α.

BHB beta hydroxybutyrate is the transcriptional link allowing PGC1α and NCOR1 to co-promote or co-repress oxidative phosphorylation .

More fasting, exercise and high fat low carb diet promotes mitochondrial metabolism via BHB nuclear transcription of BDNF et al and increased PgC1a or decreased NCOR1 an amplifying or silencing partner effecting the mitochondria.

Ursolic acid, amplifies fasting and exercise effects of BDNF leading to increased fatty acid oxidation and energy production by mitochondria.  The effect in muscles is 30% more strength in 8 weeks and I suspect increased nerve and brain metabolism and function.  One important function of brain energy is to protect the brain!  What is the most potent nuclear transcription growth factor to prevent brain disconnection syndrome?  BDNF brain derived neurotrophic factor.  BDNF also inhibit heart and muscle disconnection syndrome that leads to heart failure and age related sarcopenia.

Introduction

Energy is vital to all living organisms. In humans and other mammals, the vast majority of energy is produced by oxidative metabolism in mitochondria [1]. As a cellular organelle, mitochondria are under tight control of the nucleus. Although the majority of mitochondrial proteins are encoded by nuclear DNA (nDNA) and their expression regulated by the nucleus, mitochondria retain their own genome, mitochondrial DNA (mtDNA), encoding 13 polypeptides of the electron transport chain (ETC) in mammals. However, all proteins required for mtDNA replication, transcription, and translation, as well as factors regulating such activities, are encoded by the nucleus [2].
The cellular demand for energy varies in different cells under different physiological conditions. Accordingly, the quantity and activity of mitochondria are differentially controlled by a transcriptional regulatory network in both the basal and induced states. A number of components of this network have been identified, including members of the nuclear receptor superfamily, the peroxisome proliferator-activated receptors (PPARs) and the estrogen-related receptors (ERRs) [34 and 5].

The Yin-Yang co-regulators

A well-known inducer of mitochondrial oxidative metabolism is the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) [6], a nuclear cofactor which is abundantly expressed in high energy demand tissues such as heart, skeletal muscle, and brown adipose tissue (BAT) [7]. Induction by cold-exposure, fasting, and exercise allows PGC1α to regulate mitochondrial oxidative metabolism by activating genes involved in the tricarboxylic acid cycle (TCA cycle), beta-oxidation, oxidative phosphorylation (OXPHOS), as well as mitochondrial biogenesis [6 and 8] (Figure 1).
Figure 1. PPARs and ERRs are major executors of PGC1α-induced regulation of oxidative metabolism. Physiological stress such as exercise induces both the expression and activity of PGC1α, which stimulates energy production by activating downstream genes involved in fatty acid and glucose metabolism, TCA cycle, β-oxidation, OXPHOS, and mitochondrial biogenesis. The transcriptional activity of PGC1α relies on its interactions with transcriptional factors such as PPARs (for controlling fatty acid metabolism) and ERRs (for regulating mitochondrial OXPHOS).
The effect of PGC1α on mitochondrial regulation is antagonized by transcriptional corepressors such as the nuclear receptor corepressor 1 (NCOR1) [9 and 10]. In contrast to PGC1α, the expression of NCOR1 is suppressed in conditions where PGC1α is induced such as during fasting, high-fat-diet challenge, and exercise [9 and 11]. Moreover, the knockout of NCOR1 phenotypically mimics PGC1α overexpression in regulating mitochondrial oxidative metabolism [9]. Therefore, coactivators and corepressors collectively regulate mitochondrial metabolism in a Yin-Yang fashion.
However, both PGC1α and NCOR1 lack DNA binding activity and rather act via their interaction with transcription factors that direct the regulatory program. Therefore the transcriptional factors that partner with PGC1α and NCOR1 mediate the molecular signaling cascades and execute their inducible effects on mitochondrial regulation.


Joseph Thomas (Tony) Liverman, Jr.

Tuesday, July 26, 2016

Time Restricted Feeding née Intermittent Fasting Increases Fat Metabolism, Prevents Obesity and Reduces Inflammatory Cytokines

Time restricted feeding of calories for 8 or 12 hours of a high fat diet resulted in lower obesity rates in mice.

Insulin levels were reduced (and therefore less needed) by time restricted feedings.  The respiratory exchange ratio of the time restricted feeding high fat diet group was lower than the normal diet group meaning greater fat metabolism despite less energy expenditure.  They burned more fat and more calories with less exercise and less fat gain.  (Lower insulin increased fat burning and metabolic rate independent of exercise.)

Diabetic humans who fast 12 or more hours daily despite a crappy diet and no exercise should have better A1c, less obesity and less inflammatory cytokines.

Circadian metabolic clock genes cycle from the first bite of food for approximately one half of the circadian light dark cycle.

Conjecture:  time restricted feeding is 80% of obesity prevention, 10% calorie restriction and 10% exercise.

Time-restricted feeding reduces adiposity in mice fed a high-fat diet

Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet–induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8 hours during the dark cycle was initiated when high-fat diet–fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet–induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance.

Saturday, July 23, 2016

BDNF and Inflammation Control Reverse Cognitive and Mood Disorders

Mental Health a metabolic and inflammatory solution.

Inflammation of brain and hypo metabolic brain metabolism leads to brain network disruption on both functional parts of the human brains, emotional and cognitive.

Therefore the equation health plus BDNF minus inflammation is globally the way to improve metabolism, mood and memory.

Why?

 See article below on reversing dementia, a profound brain dysfunction or brain network disconnection syndrome, for your review.  Particularly, I want you to focus on the table that lists the strategies, tactics and projects to link the why, how and what of metabolic brain regeneration.  To wit depression, mania, dementia and psychosis are inflammatory and brain cell  hypo-metabolic states.  Effective treatments increase BDNF (SSRIs, Exercise, Slow paced breathing, cognitive behavioral therapy and fasting) and reduce inflammation ( melatonin, DHA, Ubiquinol, lithium, fasting/autophagy)

Can "normal" persons increase resilience to cognitive or mood dysfunctions?

Remember BDNF is inversely proportional to addiction.

Reversal of cognitive decline: A novel therapeutic program - AGING Journal


Monday, July 11, 2016

Heart Failure Stages Correlate to Dysfunction in Fatty Acid Metabolism; Overnutrition, Obesity and Diabetes

The bio marker associated directly with heart failure stage is a fatty acid acylcarnitine which  indicates that the heart cell and other muscles are "relatively" unable to metabolize fatty acids due to their mitochondrial energy weakened state.


Fasting and other activities that produce beta hydroxybutyrate improve cell mitochondria and their function inclusive of short, medium and long chain fatty acid metabolism requiring the CCA enzyme to allow mitochondrial metabolism of smaller carbon subunits or fragments.  Beta hydroxybutyrate is already a short 2 carbon fragment that is processed mainly by the liver into the first used fuel and therefore is the preferred fuel of mitochondria.

How does exercise improve heart failure? 
Why is high intensity interval exercise superior to endurance exercise which is superior to brief aerobic exercise?
EXERCISE related KETOSIS.

If one thinks of a pump handle well, beta hydroxybutyrate is the energy put in to prime the energy pump.  It is an energy signal and also a supplement to augment cell function.

Having fuel or energy allows the cell to be primed and able to use longer chained fatty acids for metabolism.  
The normal heart primarily uses fatty acids for energy.
The normal brain almost exclusively uses glucose for energy.
Both can use lactate and beta hydroxybutyrate as alternative energy sources.
Beta hydroxybutyrate is the preferred fuel of both.
Beta hydroxybutyrate increases BDNF and brain function.
Beta hydroxybutyrate increases muscle mass and function.

Ursolic acid increases cellular fatty acid metabolism and also produces beta hydroxybutyrate from the liver.

Diabetes is associated with inhibition of glucose metabolism and increased fatty acid intermediate metabolites such as acylcarnitine.  In effect diabetic cells display insulin resistance with refusal to import more intracellular glucose but unexpectedly imports or manufactures more fatty acids.  This results in marbling of muscle, fatty liver, fatty pancreas, fatty heart and their resulting dysfunctions, sarcopenia, steatohepatitis, beta cell dysfunction/diabetes, heart failure and increased bio marker of fatty acid metabolism dysfunction- acylcarnitine.  This is a mild acquired form of carnitine-acylcarnitine  deficiency physiology a severe inborn error of metabolism in newborns.

Affected newborns are unable to metabolize longer chain fatty acids and have seizures, irregular heart beat, low ketones, low blood sugar, fatty liver, cardiomyopathy.  This is caused by genetic errors in the newborn.  The obvious cause of this acquired physiology is OVER NUTRITION and the obvious treatment is INTERMITTENT FASTING or under nutrition from exogenous sources (food and calorie laden beverages.).  Fat cells get larger and increase in number but fat cell storage is not the problem.  Insulin resistance and abnormal energy signaling in lean body cells is the problem.

Insulin resistance leads to both elevated blood glucose as the cells resists intracellular transport of more toxic glucose while at the same time becoming saturated with elevated stored lipids and its lipotoxic cellular effects.

To improve the cells of the lean body one must metabolize via beta oxidation accumulated fatty acids and restore normal insulin sensitivity.  

Within three days of fasting, insulin resistance is reduced by approximately 70%. Most of that occurs within 24 hours.  

Once the acute insulin sensitivity dysfunction is decreased, 12 or more hours of fasting per day will maintain the improved insulin sensitivity.

Is it not obvious that avoiding insulin requiring foods will result in less  energy storage as fat and further improve insulin sensitivity making the basal or fasting insulin rate fall?

(Eating fat does not significantly increase insulin, an energy storing hormone.  Eating more fat, and therefore less carbohydrate, results in higher resting metabolic rates.  Eg.  Adding 10 grams of coconut oil to a measured normal diet resulted in a resting metabolic rate of 106% of baseline.)

What are the high glycemic foods that require the most insulin?  Processed carbohydrates like flour, high fructose corn syrup and sugar are the most obvious.

Additionally, one cannot lose stored body fat unless one reduces insulin, an energy storing hormone. The breakdown of fat for burning is inhibited by insulin, an energy storing hormone.

The solution appears obvious and has been verified by circadian scientists, timed-restricted-feeding and its corollary timed-restricted-fasting.  Fasting 12 or more hours reduces liver glycogen and restores insulin sensitivity.  The effect of fasting is to reduce glycogen stored in the liver and muscles.  When glucose level is below 100, the liver stores glucose first, as glycogen and fat,  then glucose levels rise within the normal range of 100-140 stimulating the release of insulin and the muscles store glucose as glycogen and fat and fat cells store glucose as fat.  Insulin is an integral part of energy storage.  Fasting reduces insulin and depletes liver glycogen, and muscles use their stored energy until the next meal.  If the fasting interval is extended, excess energy can be released from fat stores in fat cells but only if insulin, a storage hormone, is reduced.  Normalizing insulin levels to the low range of normal is desirable.  

If one reduces insulin and insulin resistance which allows fat burning, weight loss from calorie restriction does not slow down metabolism.  Further high fat low carb diets are associated with increased metabolic rates.  It has been noted by Dr. Jason Fung and possibly others that bariatric surgery is different from calorie restricted weight loss because basal metabolism is maintained AND that this result is due to fasting.  He questions the need for surgery if fasting is the mechanism for fat loss and avoiding processed carbohydrates is the cause of insulin resistance, excess fat storage and obesity.  At an even smaller fractal level, cellular metabolic health is promoted by circadian clock genes of metabolism.  When the fast is broken by the first bite or consumption of calories the clock begins for the feed cycle.  

Is there an optimum duration for the feed cycle? Probably until the liver and muscles have a full tank of stored fuel as glycogen and fat.

Is there an optimum duration for the fast cycle? Probably longer than the feed cycle due to the speed of refueling over speed of energy use and the abundance of stored calories in body fat.  As the metabolically healthy adult is fat burning ketones after 12 hours indicating glycogen depletion from the liver, 12 hours is the lower limit.  

Action:  Low carb higher fat diet consumed within 4-12 hours, high intensity interval exercise, 12-16 hours of fasting with or without Ursolic acid 200 mgs three times daily and weekly resistance exercise.

Caveat:  High cortisol high stress causes insulin resistance and thwarts effect of feed fast cycle to promote cellular metabolic health.  Two minutes of slow paced breathing 5 seconds in and 5 seconds out for 2 minutes twice daily and or walking in nature and or 2 minutes of absolute silence using noise cancelling devices should reduce brain cortisol by stimulation of vagal nerve signals to the brain.

Net effect:  Beta hydroxybutyrate levels increase and BDNF brain derived neurotrophic levels increase.  The latter cannot be commercially measured but Elite Heart Rate Variability is a proxy measure.  Healthy aging is associated with high for age Heart rate variability index.

Disclaimer:  This information may not be suitable for individuals under medical care and treatment.  It is always recommended to consult with your personal physician before making these changes.



Metabolic Staging in Human Heart Failure Circulating Acylcarnitines and the Failing Heart’s Energetic Signature∗

Monday, July 4, 2016

Beta Hydroxybutyrate, Energy Signaller and "Super Efficient Fuel"

This is a recent hypothesis paper regarding SGLT2 positive and unexplained outcome improvements in Macrovascular disease complications of diabetes and metabolic syndrome by extension.  

Previous studies showed that Microvascular outcomes such as neuropathy, nephropathy and retinopathy improve with A1C control. But not Macrovascular.

Metabolic flexibility, the ability to variably use glucose or fatty acids according to glucose scarcity or abundance, is enhanced by BHB, beta hydroxybutyrate a super efficient fuel that also is an energy signaler or switcher analagous to a fuel injector for the mitochondria.

BHB is produced by exercise induced ketosis, fasting induced ketosis, Ursolic acid triglyceride metabolism derived BHB and coconut/MCT oil liver produced BHB.

Question: does BHB production predominate from somatic cells or liver cells?

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis | Diabetes Care