AP on CDK?

[Jaegernaut]

Would AP be a waste on the CDK diet? Or should it only be taken on refeed days?

 

[borobulker]

Would AP be a waste on the CDK diet? Or should it only be taken on refeed days?

Check the info that Mulletsoldier posted over at bb.com...

Quote:
Originally Posted by wada
I've read the claims...I've tried AP/Pslin...enjoy the pumps..however, I still question the ability of it's claims:

1) to Upregulate Glut-4 receptors selectively only in Muscle cells and not adipose

2) How does AP selectively inhibit PPAR gamma (which by inference AP has to be an allosteric inhibitor for FFAs, PGs, LTs)...according to the claims, this is not proven, they just measured mRNA expression of the PPAR)

3) the drug class Thiazolidinediones (used in Diabetes) binds to PPARs and actually increases insulin sensitivity/decrease resistance. How can USP labs claim to INHIBIT PPAR gamma yet increase insulin sensitivity SELECTIVELY in skeletal muscle...

Just curious as to see if there are any theoretical pathways that would make sense...to put the puzzle pieces together.

1) The clinical data (albeit in IDDM/NIDDM and rat models) reflects as such; though it is impossible to state AGU is not occurring. However, with that being said, fuel provision is of secondary concern when lipid metabolism - and therein proliferation and differentiation - is being directly controlled.

2) Berberine directly activates AMPk in peripheral tissues, via mitochondrial respiration inhibition; thereby creating a fluctuation in the extracellular AMP:ATP ratio, and creating a demand for AMPk in respects to glucose phosphorylation for energy provision. Data has reflected a 6-16h increase in AMPk levels. This is important for the following reason: AMPk directly inhibits co-activator p3000, inhibits PEPCK through transcription, ACC (and thereby inhibits malonyl-cOA) both at transcriptional and post-translational, as well exerting transcriptional control over PPAR-y, and its target enzyme CPT-1. AMPk, and therefore AP (data reflects a direct and immediate regulation of AMPk in skeletomuscular tissue), selectively regulates PPAR-y via transcriptional factor control, and by the inhibition of co-activation factors, rather than direct site-binding. It selectively regulates PPAR-y, due to p3000 being an AMPk substrate; direct binding is not necessary.

3) Actually, and ironically enough, the most recent data is proposing that Thiazolidinediones' Insulin Sensitizing effect is via mechanisms independent of PPAR-y regulated gene transcription; in actuality, and to therefore answer your question, TZDs are now being shown to directly and acutely increase phosphorylation of AMPk. Whereas previous studies into TZD administration postulated that TZD mediated decreases in Insulin resistance were due to adipogenesis induction (and thereby decreased levels of FA, and storage of TGs - direct precursors to Insulin insensitivity), it is now being realized their action is via AMPk induction in skeletal muscle. As a result, Berberine is especially attractive as alternative NIDDM/IDDM, due to its weight loss induction via transcriptional control over the PPAR target enzyme CPT-1; thereby increasing mitochondrial B-Oxidation of FAs, rather than decreasing it. This anti-lipogenic action, combined with increased glucose uptake in myocytes, inhibition of cholesterol and TG synthesis, and more efficient response to energy demands, creates a recomposition effect on tissue via preferential use of energy.

Further, this Berberine mediated AMPk phosphorylation has (as of yet, at least) been most prominent in skeletal muscle. As stated, AMPk is a more direct regulator of the glucose metabolism pathway than that of PPAR-y (direct upregulation of GLUT4 translocation, and more direct control over lipogenesis); in this respect, the secondary pathways of PPAR-y become irrelevant, as they are more or less circumvented by AMPk. Berberine decreases mitochondrial respiration, thereby increasing the AMP:ATP ratio, increasing AMPk phosphorylation and inducing intracellular glycolysis; thereby having an additive effect on Insulin sensitivity.

Finally, to answer your first question in a round about manner, the inhibition of mitochondrial respiration via Complex-I has only been noted in L6 myotubes, and not adipocytes. In this respect, the response to intracellular glucose demand is not specific, but merely the respiratory response of AMPk; in this light, the AMP:ATP ratio modulation by Berberine, and therefore increased phosphorylation of AMPk is myocyte specific, rather than GLUT4 specificity.

The insulemic pathway is far more diverse than PPAR-y mRNA expression, or even PPAR-regulated gene transcription factors. A more direct approach to Insulin/Glucose modulation was necessary due to the additive effects on adipose posed by PPAR-modulating medications. In all respects, AMPk is the key regulator of energy expenditure pathways. Once the true role of AMPk mediated, Insulin-independent glucose metabolism is elucidated, PPAR-y/a modulation becomes of secondary concern (though, it is still important to keep in mind AMPk mediated PPAR-a induction in skeletal muscle, leading to increased FA oxidation, and thereby increases in stamina and endurance). I hope that was exact enough. j/k.

 

[borobulker]

More...

So everybody is on the same page, I'll review some of the relevant terms here.

PPAR-y (gamma) stands for Peroxisome Proliferated Activated Receptor, and is a subclass in a family of receptor proteins that exert transcriptional control over lipid binding genes and enzymes. This essentially means that it controls the differentiation (unspecialized cells developing into specialized functions; such as preadipocytes differentiating into adipocytes), proliferation (rapid growth and multiplication) and accumulation (plasma triglycerides and FAs bonding to stored adipose) of lipids by regulating the mRNA expression of genes responsible for carrying out these effects.

ACC stands for acetyl-CoA-carboxylase, and is responsible for the carboxylation of Acetyl-CoA into Malonyl-CoA. This process highly regulates the storage of plasma triglycerides, and inhibits the B-Oxidation of FAs by cell mitochondria, as Malonyl-CoA directly inhibits CPT-1: The rate-limiting step for mitochondrial B-Oxidation.

Malonyl-CoA-decarboxylase performs the exact opposite function of ACC, and catalyzes the conversion of Malonyl-CoA back into Acetyl-CoA and a carbon dioxide emission. It therefore directly increases levels of CPT-1, and subsequently the B-Oxidation of FAs.

Now, all this is important for one, primary factor: AMPk (adenosine monophosphate kinase) exerts transcriptional (limits the mRNA expression of) control of PPAR-y, while also exerting post-translational control over its co-activation factors, as well as directly regulating levels of ACC, Malonyl-CoA-decarboxylase, and therefore levels of Malonyl-CoA and CPT-1. Now, why is that important? Because all of the aforementioned compounds directly regulate the storage of circulating triglycerides and fatty acid chains, and therefore regulate the differentiation and proliferation (growth) of lipids (fat). This is the exact opposite effect one desires when attempting to enter ketosis (Acetyl-CoA directly induces ketone body production by the liver as well) - one desires the inhibited synthesis of triglycerides and cholesterol, the increased B-Oxidation of fatty acids, and the decreased redepositing and accumulation of lipids. By raising AMPk (and research has directly shown ACC and MCD inhibition as well, while Corsolic Acid potently regulates PPAR-y mRNA expression in adipose) AP contributes significantly to effects which are beneficial to Ketosis.

Here is a shorthand legend:

PPAR-y: Peroxisome Proliferated Activated Receptor

Function: Diverse, but in an adipose tissue, lipid-specific respect, it exerts gene expression of lipogenic storage factors (genes which regulate the storage of lipids). Also keep in mind there are three subclasses of PPAR-y: PPAR-y1, PPAR-y2, PPAR-y3. It is Gamma 2 which is dominantly expressed in adipose tissue, and responsible for lipid storage.

ACC: Acetyl-CoA-Carboxylase

Function: Carboxylates Acetyl-CoA into Malonyl-CoA, which subsequently lowers levels of CPT-1, and therein the oxidation of Fatty Acids by mitochondria.

Malonyl-CoA-Decarboxylase

Function: Decarboxylates Malonyl-CoA into Acetyl-CoA and Carbon Dioxide, thereby raising levels of CPT-1 and increasing mitochondrial oxidation.

 

[Jaegernaut]

So that is a yes, should I continue to take it 3x a day and before meals or should I take it right before I run and right before I lift?

 

[Mulletsoldier]

So that is a yes, should I continue to take it 3x a day and before meals or should I take it right before I run and right before I lift?

Yes, definitely! From that same thread I explain here:

Ketosis is simply the process of your body hydrolyzing (chemical breakdown via the interjection of a water molecule to form two end products, or the reaction of a substrate with water) stored triglycerides (fatty acid chains combined with a glycerol, and the body's primary source of stored adipose) to be used as fuel; Ketosis is the recognition by your body of chronic starvation. It therefore causes lipolysis (breakdown of stored triglycerides into respective fatty acids and glycerol molecules) in order to provide fuel in the absence of glucose (your body uses these as fuel via B-Oxidation). AP is beneficial, because it will expedite (speed up) this process due to its direct interconnectivity with many of the above mentioned processes.

a) It increases levels of CPT-1. CPT-1 is the rate-limiting (controls the rate at which a process can occur) enzyme of B-Oxidation (the oxidizing of fatty acids to be used as fuel), and increasing it increases the amount of lipids your mitochondria will use as fuel. This is important, because even during Ketosis where lipolysis (break up of TG into FAs) is occurring, if you do not oxidize (burn) the FAs, they will simply redeposit.

b) On the note of redepositing, AMPk inhibits the accumulation and synthesis of TGs and cholesterol. Why is this beneficial, and tied into the above point? Because if the redepositing of lipids is inhibited, they will be forced to circulate the bloodstream continually; with the increasing of CPT-1, the possibility is increased they will subsequently be oxidized.

Now, as I said, R-ALA is not an anti-lipogenic (compound which inhibits the accumulation, differentiation, or biosynthesis of lipids) and would not assist as greatly as AP would on a "carb-up" during Ketosis. The primary goal of Ketosis is releasing stored triglycerides into the bloodstream to be oxidized: AP accomplishes this. The fundamental step to remaining in Ketosis is low blood sugar levels: AP accomplishes this.