With all the recent discussion regarding the various alpha/beta receptors in regard to adipose tissue reduction--particularly very recent discussions concerning specific targeting of certain beta receptors, the thought came to mind that generally we tend to focus on one avenue--that being lipolysis--when discussing methods of fighting the war against adipose tissue. As such, at least a brief focus is warranted on the other front of this war--namely lipoprotein lipase.

The physiologically active form of the enzyme LPL is found anchored to the endothelial cells of the capillary lumen, in and near tissues of its origin (it is also expressed in muscle cells). Because adipose tissue LPL exceeds that of skeletal muscle by three-to-tenfold in rat or mouse and one-to-fourfold in man, normal resting conditions in the healthy, fed, sedentary mammals favor fatty acid distribution to adipose tissue for storage. Generally, it has been observed that endurance exercise up-regulates LPL activity while resistance training decreases it. Interestingly, LPL has various interactions with other hormones and intracelluar factors:

Insulin: In vitro, insulin increases adipose tissue LPLA (LPLA=tissue specific regulation of LPL); however, physiologic insulin does not increase human adipocyte LPL; thus, while adipose tissue LPLA correlates with serum insulin levels and the degree of inulin sensitivity under a number of circumstances, it does NOT appear that insulin regulates LPL at the gene level.

Estrogen: may shift the flux of TG FA's from storage in adipose organ toward incorporation by muscles (decreases LPLA in adipose tissue)

Catecholamines: E decreased LPL translation and synthesis in mouse 3T3-L1 adipocytes via a trans-acting factor that binds to the 3' untranslated region of LPL mRNA.

Growth Hormone: stimulates a rise in LPL

Thyroid Hormones: decrease LPL activity (generally)

Cortisol*: in concert with insulin, promote intra-abdominal adipocyte LPLA and promote lipid accumulation there. Tissue culture studies show that cortisol increases AT LPLA but requires insulin for its action. (note: this is what I have been looking for in regards to cortisol's influence on fatty deposits--IMO, it is the most concise evidence yet)

Progesterone*: promotes filling of gluteofemoral adipocytes by stimulating LPLA in those cells

T: inhibits subq abdominal LPL but not femoral LPL.

TNFalpha: may inhibit LPLA

Leptin: studies have shown a .6 positive correlation with AT HR-LPLA (HR=heparin releasable)

Additionally, much like the alpha/beta issue in regards to lipolysis, LPL is also expressed in a site-dependent fashion, with fasting sub gluteal AT HR-LPLA being higher than abdominal in women, whereas in men subq abdominal LPL mRNA is about 3fold higher than glueteal. Further, at least one study has evidenced lower subq abdominal AT HR-LPLA than femoral in both sedentary and trained females (this fits well with the A2 scenearios).

Maintaining leaness is also a benefit in regard to LPLA in that in lean healthy persons without IR, AT HR-LPLA correlates with cell size (the smaller surface area, the less LPLA). Finally, a genetic component to LPLA activity has been identified showing that subq AT HR-LPLA varied in relation to a common DNA polymorphism: the presence of complete absence of the cut-site for the restriction enzyme Pvull located in intron 6 fo the LPL gene. And one more thing: the effect of exercise/resistance training on LPL is considerably less than than of feeding and fasting...again, more evidence for a cyclic style of dieting?

The questions now become, where do we go from here----------

make a search on this board.
I discussed LPL with nandi when I hadn't a clear pictire of LPL.
nandi gave a great biochemistry lesson about this statment.

Of course, our discussion can not leave out the adipokine ASP and perhaps this is a more formidable target than LPL.

Duchaine--thanks for the reference---a good read

I think DGAT 1&2 are far more interesting targets than LPL. Reduced LPL just means elevated plasma TAG for the most part. proper fat trapping post meal is quite important.

In the absence of LPL or the antagonism of it, is there a way to break down the TAG into FFA for oxidation?

I don't think is correct what u say about ASP, that u suppose is a more formidable target than LPL.
LPL is a rate limting factor, they do not "make"directly TGL.
but consider how the rate limting factor can effect body fat distribution.

vain, u wrote: "In the 1) absence of LPL or 2)the antagonism of it, is there a way to break down the TAG into FFA for oxidation? "
2)about the antagonism: are u talking about the increase of HSLs' activity?
1)about the absence: are u talking about the absence of LPL in musclar tissue?

if I undertand what u mean about 2), consider that what u describe is a "futile cycle", and this process increases FFA oxidation because it requires energie.

Duchaine--yeah, I know LPL doesn't make TGL--I think the key here, as you mentioned, is that LPL is expressed at different rates on various tissues, including that of adipose tissue regions specifically---this will certainly effect fat partitioning.


As far as absence and antagonism of LPL, what I meant here was in the compelte absence of antagonism of it, is there another way to liberate FFA's for oxidative use by muscle and other tissues. That is, is there another enzyme besides LPL that would pick up its duty and effect the breakdown of LDL, VLDL, and chromy (haha) bound fatty acids.

Not to any apricable means anyway. yes it happens but a marginal rate at best. Plus its teribly unhealthy. HL(aka LHL/Liver Lipease has very weak affinity for TAG which is one reason for the extremely reduced speed of clearence.) Mice that are -/- for both variants are terminal if I recall corectly.

see this study for details:



full text here: http://atvb.ahajournals.org/cgi/content/fu...full/17/11/2532



I could not follow this. could you please restate.



Yes but in a positive way unless for the most part. Allow me to digress for the moment and offer a short synopsys to 1) organize my thoughts and 2) bring anyone who might be confused about the discussion up to speed (i.e. not the people allready contrubuting to the thread).

fats are generally ingested as TAG. they are broken down to FFA in the stomach. absorbed in the intestine where they are resynthed in to TAG by the esterification pathway (MAG + MGAT -> DAG + DGAT -> TAG). then they are packed in chylomicron remnants and absorbed by the lympthatic system. Some fats are not reestefied and are absorbed via the portal vein. Though contribution of portal vein absorbton is minimal and for good reason keeping in mind the portal vein glucose sensor.

said chylomicron coated TAG then travel the blood stream in search of LPL to break them down. Mostly in adipose tissue. Now adipose tissue is favored as prevously stated in this thread adipose tissue has lots of LPL compared to other tissue. Now much of fat tissue fat trapping ablity has as much or more to do with the limited blood flow to adipose tissue. LPL breaks down the chylomicron remnants and deposits the FFA in the extra cellular space (though some LPL apears to be bound on the intra cellular surface of the reticular matrix. What signigigance this plays for fat partitioning is anyones guess at this point). fats are then absorbed passively for the most part but they can be actively transported inside the cell. This is why blood flow is so important in my opinion. Look at VAT tissue with its rich blood flow. its terible at trapping fats because 1) LPL is not upregulated by insulin (post meal) compared to SAT tissue and two it has rich blood flow. Rich blood flow reduces the time allowed for passive diffusion to take place.

The chylomicron remnants (broken down peices of the coating of the TAG) then wander the blood stream. They activate ASP. ASP turns on the esterification pathway. The chylomicron remnants are then eliminated or broken down furhter primarly by HL.

This is where I think people get messed up in understanding fat partitioning. Please debate me on this if you think other wise. LPL is rate limiting for fat trapping post meal but not that important in terms of fat partittioning. Without said blood flow restriction it dosent ensure proper distrobution. More imporantly I think is that DGAT determines fatty acid partitioning. DGAT is the final step in the synthesis of a molecule of TAG and is jacked up by ASP. Most importantly however is that DGAT is the only commited step in the pathway. In other words all the other reactions in the pathway are reversable reactions. But once DGAT transforms DAG in to TAG it requires HSL to hydrolize it (via a different enzymatic pathway).

Research is in agreement with me in thining that DGAT is primarily responsible for fat patitioning. For exampple both fish oils and fibrates show an ability to reduced plasma TAG and FFA values far below what is burned off by there inducing of fatty acid oxidation. This puzzled researchers tell the DGAT connection was estrablished. Since PPAR-alpha ligands are able to decrease plasma TAG and FFA beyond what is being burned they must be causing it to be stored in some tissue. Studies show this is not fat tissue but instead liver and muscle tissue (liver mostly). PPAR-alpha ligands manipulate DGAT in such a way as to cause FAT retention in the liver (and to a small degree in muscle tissue) instead of fat tissue. For the full low down you will have to wait for my fat-furner write up.

From my research I would sumerize the following. The most important factors governing fatty acid partitioning in to a given tissue are:
fat tissue : LPL, blood flow, DGAT1.
liver: DGAT 1&2, PPAR-alpha
Muscle: CD36, DGAT1, FFA availability (limited by adipose tissue release).

So if we want enhanced fatty acid partitioning we should:
1. Exercise:
Exercise hits all of these for the most part except LPL though it even gets that indirectly by lowering insulin. exercise increases skeletal muscle blood flow via RAS inhibition. at the same time it does not increase fat blood flow to the same degree. AMPK activation( cuased by exercise or artifical means) in fatty tissue inhibits DGAT1. In skeletal muscle it increases CD36(FAT). CD36 is actually the first cellular alteration of exercise showing upregulaton after just 30 seconds. Exercise increases lipolysis via NE release increasing plasma FFA avialability (effecting muscle). Indirectly this effects the concentration of PPAR-alpha ligands making more of them available for muscle and liver (effcting DGAT1&2 in both tissues).

2. Use fish oil/sesamin/fibrates. for the benifical effects at liver and to a small degree muscle tissue. though I think the benefits in muscle will only show up when exercise is added as PPAR-alpha binding there will do little unless CD36 is upregulated (by exercise or NE) and plasma FFA are available (via reduced adipose storage/DGAT inhibition and/or increased lipolysis).

3. weight training and/or preform HIIT as when blood sugar is reduced to some degree as AMPK activation in fat tissue is about the only thing that naturally lowers DGAT activity in fat tissue. I say reduced blood sugar because AMPK activation in fat tissue will not occur to an apricable degree unless blood sugar is low to normal range. So pre worrk out carbs may enhance performance but they may reduce the FFA partitioning aspects of the training.

Anway you can get my full treatment when my fat burner is released.



Like I said above HL can do this but at a much reduced rate as it has very poor afinity for cyhlomicrn bound TAG compared ot LPL.

This would suggest that something along the lines of fibrate + EC would use useful for accute fat partitioning towards muscle/liver, correct?

Would beza-fibrate have a different effect than sesamin/fish oil due to its PPAR-beta activity?

Spook, could you clarify your above comment, I just didn't follow it coherently from my above-quoted piece.

Also, and this has bothered me for some time. Anatomically speaking, do adipocytes connect to cappilaries? If this is not the case, how does blood flow flux to the adipocyte (or is it completely extracelluarly mediated)? I was under the impression that if LPL is contained on the luminary surface of endothelial cells of the cappilaries that TG would flow through the capillaries into the adipocyte. However, research suggests other modes of TG transport to the intracelluar space for esterfication.

If LPL is overexpressed in certain adipocyte regions (i.e., on those capillaries that service particular fat depot regions) would this not contribute (at least peripherally speaking) to greater accumulation of adipose in these areas? As noted in the intial commentary, females express a greater degree of LPL in the gluteofemoral region. Does this work in concert with A2 andrenoceptorys to create a synergy of both making it harder to liberate fatty acids as well as making it easer to re-esterfy them (given that there is typically an overabundance of fatty acids during any period of excersise necessitating their usage). Of course, other factors, including ASP and other hormones may co-express as a function of LPL level, such that, for women, in the glueteofemoral region, not only is LPL expressed to a greater degree, but so are the related homrones and enzymes further down the lipogenic cascade?

A" adrenoreceptors regulate lypolisis as well as lypogenesis(A2 stimulation increases LPL activity). so I think: yes, they will create a synrgy for fat-gain

Sorry As I am sure you are aware I am hardly the most elequent person around.

The meaning was that yes it effects fat partitioning but in a postive way as it allows proper post meal fat trapping to take place thus keeping plsam TAG levels in check.

In other words the fat must go somewhere. If you had less LPL near your fat cells then it would jsut float in the blood stream.



Not completely sure but I am about 90% certain that its completely extracellularly mediated. And yes I think its other means of transportaton in to the intra cellular space. Namely passive diffusion and active transporters. I do distinctly recal a study on this though I am to lazy to go look it up now. What they did was take pre-adipocytes in a dish and drop in a explanted capliary network then injected said capilary network with VEGF. what they found was that the baby fat cells differentiated in to a supporting lattice matrix fixing the capilaries in place but leavin large extra cellular pools. The fat cells that directly connected to the blood vessels were not normal fat cells as we think of them. They only had half of there cellular machinary functioning and were very rigid. The thinking was that there role was to develop extra cellular fluid pokets around adipose depots. Quite an interesting study but all in-vitro of course.



Yes I think this would be the case. With once necessary condition also supplied. That being restricted blood flow to said area. That said one can make a valid argument against this being important for fat distrobution. Studies on rats show that when fat is ingested roughly half of it is imediately stored and the other half release (whole body studies). Thus since such a signifigant portion is imediately released in to the blood stream it may mean that LPL density has little to do with fat distrobution patterns as LPL is only really important for fat traficking after a meal and not so much in determining where plasma fats get stored. So the enhanced glutofemoral LPL levels may just be important for proper post meal fat traficking and then its the adreno receptors and other hormondal factors (T3 receptos, PPAR-gamma, angiotensin) that determine whole body distrobution. I have not specifically made up my mind as to which is the most probobable. Though I lean toward that latter. That meaning that LPL is only signifigantly important for post meal fat trapping and that distrobution is determined by endocrine hormones.

So Spook, what you are articulating here is that there may be set, discrete blood flow patterns that allow blood borne TG to travel to certain adipocyte depots but not others? Thus, perhaps greater amounts of Chromy bound TG (or lipoprotein bound) are shunted to certain adipose tissue depots which as a result, need more expression of LPL? This is intriguing. However, why then would we phenotypically see that the areas which are hardest to rid of fat due to A2 status and restricted blood flow the ones that we see typically accumulating fat at a faster rate than other areas/depot regions? Here I would be talking about lower abdominals at the T-4 level and blow, as well as posterior super-illiac adipose tissue?



This of course assumes that the TG would not be hydrolized by LPL on muscles cells and therefore oxidized? Hypothetically, if we went in and destroyed LPL mRNA/genes in ONLY adipose tissue, would the resultant increase in blood-borne protein bound fat overwhelm other tissues that express LPL for storage (and eventual oxidation in muscle tissue)?

No. Seeing as how fat uptake is mostly pasive difusion (unless exercise or some other substance upregulates CD36) then LPL the FFA freed from TAG will simply be washed away from said muscle tissue as blood flow is increased there. Passive difusion works acros a concentration gradient. If a given region of muscle is full then said fats freed by LPL will just get moved out to the blood stream. Fat cells are specifically designed for this reason as insulin and or ASP activates DGAT which allows for esterificaiton of intra-cellular fat in an adipocyte thus relieving pressure on the concentration gradient by storing said tag in the perilipin droplet. Muscle tissue also posses DGAT but it is not upregulated by insulin to the extent that adipose tisue DGAT is. In muscle tissue its hypoxia and/or AMPK activation that upregulates DGAT .



the problem with this idea is rate of storage not overwhelming LPL. say there is adequate LPL to hydrolize all the TAG even without adipose LPL. Who is going to store it? clearence rate for FFA would go way down as would plasma levels which would negatively effect insulin sensitivity and show symptoms like lipotoxicity.




No what I am trying to articulate is that LPL density is mostly involed with post meal fat trapping ability and not body fat distrobution patterns. For example femoral obesity is more healthy than central obesity because the femoral tissue is able to trap fat more effectively post meal thus reducing plasma FFA, where as central obesity can't.



hormones. For example glutofemoral obesity is associated with drastically reduced angiotensin levels in said tissue. angiotensin blocks insulins upregulation of DGAT as well as insulins ability to induce pre-adipocyte differentiation. So in said tissue the threshold for insulin's negative effects on that specific tissue are lowered. Also because angiotensinogen is so low ACE activity is upregulated (10 fold in one study) which dramatically reduces blood flow to said area thus allowing for more fat trapping to take place.

For the record what I am stating is that LPL distrobution only plays a minor part at best in fat distrobution patterns. fat distrobution patterns are determined predominantly by sex hormone rations at the high level. Downstream of sex hormones is the RAS-aldosterone system that determines much of ones body fat distrobution patterns.

As for specific regions given all other things being equal. (i.e. why don't we gain all our fat in our face or something like that). Then I think it is largely blood flow mediated as well as genetic components that program where pre-adipocytes are pooled.

Spook--I would be very interested to hear in what manner the RAS-alodosterone system plays in the phenotypic expression of the body-fat genotype--as for sex hormones, I have found an exhuastive search of the literature revealing only mediocre evidence that is never seemingly concrete or coherent in that specific pathways in which certain hormones effect certain patterns are often only mildly elucidated with many gaps in the pathways.....

well I am currently working on an article on the RAAS-aldosterone system as it pertains to body compositon. I agree about direct evidence about set hormones as you stated it. But the thing is sex hormones control activity of the RAS-aldosterone system (after acounting for ones ACE genotype). And its the RAS-aldosterone system that I think determines much of ones bodyfat distrobution patterns. You can read all about it in my article but the gist is as follows:

for the uninitiatedd a brieg summary of RAS-A is provided. the starting compund is antiogensinogen and its produced mainly by the liver and adipose tissue. Adipose tissue becomes a signifigant source particularly in the over weight. Angiotensinogen is acted on by renin wich is produced local in tissue as well as available in the blood stream. renin acts on angiotensinogen to produce antiogensin I. angiotensin I is acted on by ACE to form antiogensin II (angII) and angII binds to AT1 and AT2 receptors to do its thing. When AngII binds at the adrenals it causes aldosterone to be released.

So the key points in this pathway are angiotensinogen producton and ACE activity. renin is not rate limiting in normal people.
Its also important to remeber that ACE maybe named for its relationship to the RAS-A patwya but it also serves two other purposes. Both of which it has higher afinity for than AngI. First is the degradation of Bradykinin. Bradykinin is whats upregulated by exercise and insulin in skeletal muscle. It causes arginine to be convereted to NO which caues vasodilaton and increased blood flow to local tissue.

So more ACE activity in a given tissue region means less blood flow to that region. Exercise induces muscle pumps largely by increasing bradykinin production while simultaneously decreasing ACE activity.

ACE's other role is degredation of Substance P in neural tissue. slightly low substance P levels have been linked to major depression but super high levels seem causative in bi-polar disorder. So more ACE activity means less substance P means propensity for MD. Also more ACE activity means more aldosterone and hyperaldosteroneism is also linked to the severity of symptoms in major depression as well as the severity of withdrawl in addiction. For example the ACE D/D genotype (lots of ACE activity) was corelated with suicide atempts in instatutionalized MD patients.

Now we also need to talk about cortisol to see how ACE plays its part. Cortisol is released from the adrenals in response to ACTH with is released from the pituitary in response to CRH. plasma values of cortisol are determined largely by the activity of 11-Beta-HSD 1/2 in the liver. plasma levels are important as its plasma levels that determine cortisol levels in neural tissue. There cortisol or metabolites bind to the GR and the McR. both of which shut off further CRH secretions. CRH secretions are of course determined by stress, GR & McR sensiity, and NPY levels (see Letin VI). So at the liver we are primarily concerned with low 11B-HSD1 and hgh 11B-HSD2 levels as that lowers plasma cortisol and metabolites thus the negative feedback never reaches the brain promoting a hyper-active CRH system.

Local upregulation of cortisol activity is also a problem as this is shown to be a problem in obesity and particularly abdominal obesity. So here we are worried about elevated 11BHSD1 activity in local tissue.

Now recall a few specific facts from my leptin articles.
1. VAT secretes way more angiotensinogen than SAT tissue.
2. VAT tissue has tons of blood flow right in to the portal vein.
3. In the study on hypertrophied adipose cells the single largest upregulation in gene transcription was for angtiontensinogen (a 700% increase).

So what regulates angiotensinogen production? Three things mainly. Cortisol, androgens (hences the sex hormone link), and elevated blood sugar (though its not insulin mediated but it seems its directly related to blood sugar levels. It maybe low glucagon that controls it but I have not seen direct evidence, though I did see studies that ruled out direct inuslin upregulation. this makes sense as HAT cells are insulin resistant so it should not be insulin mediated).

Androgens or elevatd blood sugar seem to exert the most control. The othe key point in the pathway is ACE. It's activity is largely determined by by ones ACE genotype.

recall that is requires a base level of androgens to develop VAT tissue. Androgens upregulate angiotensinogen production in fat cells. particularly VAT cells. we know VAT tissue growth is mediated directly by cortisol so how are the two connected. Well first things first 11BHSD1 upregulation in the VAT cell upregulates both angiotensinogen production and it also upregulates the AngII receptors. This is what makes VAT insulin resistant as AngII blocks insulins ability to elict a downstream signal in adipose tissue. Specifically it blocks glucose uptake, insulins ability to induce preadipocyte recrutment.

Now right next to the VAT tissue is the liver and the two are connected via he portal vein. So because of andogens raising local cortisol (by ocupying reducing enzymes) and its direct effect on the VAT tissue it upregulates AngII levels and the cells jsut get bigger and bigger and release more and more angiotensinogen. now at the liver AngII is creates a super vicious cycle. It just so happens that AngII regulates 11BHSD1 and 2 in the liver via post transcriptional means. Specifically it upregulates 2 and down regulates 1. So this creates a kind of cortisol sink at your liver. As I said above this lowers plsma levels preventing negative feedback thus producing a hyper-active CRH system.

Secondly deactivation by 11B-HSD2 just provides more substrate for subsuquent reactivation in the nearby adipose tissue. So the whole thing is jsut one super vicious cycle that is nearly impossible to break out of.

Androgens kick off the party and then the interaction of cortisol at the adipose cell and AngII at the liver results in a self sustaining cycle that jsut keeps increasing both total (cortisol + metabolites) levels and total AngII and angitensinogen levels. This is all backed by quite abit of reasearch. by explanation is theoretical as I myself have peiced this together. In other words I did not read in is a review paper. That said there is higher level evidence. For example there was a study conducted on 1000 italian males that tracked them over 20 years. What they found was that the ACE D/D genotype (Lots of ACE = lots of AngII) was corelated with abdominal obesity as the men aged as well as heart disease and pre-mature mortality.

This is not event getting in to the neurlogical aspects of AngII or aldosterone. That would take far to long so youl jsut have to wait for my article. But sufice it to say the main thing that control PVN activaton is AngII. remember from my leptin articles that the VMH delivers GABA to the PVN to keep it inactive. So its not surprising that if you inject the PVN with a GABA-A receptor antagonist the PVN activates. however if you also inject the PVN with a AT2 (or was it AT1 I can't remember off the top of my head) the PVN will not activate. So in my leptin article when I said that the PVN wants to run non stop. What is making it wan't to run is AngII.

There are even more neurological connections to this. recall from my leptin articles that much of the regulation at the PVN by catcholamines is via the A2-AR. In one incredibly iteresting study they examined both normal, abdominally obese, and peripherally obese women. They ran three trials in the test subjects. In the control trial they injected the women with CRH and AVP (both stress response hormones). What they found is that in the control trial the women with abdominal obesity showed higher cortisol response compared to peripheral obese or the normal women. They then repeated this but added a A2-AR agonist. In that trial all groups showed an identical drop in NE and E levels but no signifigant difference. Then finally they added yohimbine to the CRH+AVP mixute. In this trial is where things get really interesting. all three groups showed a similar upregulation of NE and E. However in the peripherally obese group and the normal women ACTH levels decreased. However in the abdominally obese group they went up two fold.


Now in the other extreme of fat distrobution we have glutofemoral obesity.

Glutofemoral fat tissue is of course also mediated by A2 density as this region is known to have elevatd levels in both men and women. Fat explants from peripherally obese women's adipose stores shows a mirror opisite of VAT tissue. Specifically dramatically reduced levels of angiotensinogen secretion. However ACE activity was upregulated localaly by 10 fold to compensate. So this throws a wrench in to the normal antagonistinc balance between NE and insulin to the net lipolytic vs. lipogenic state of the adipocyte. Such reduced levels of AngII means the threshhold for insulins actions at the fat cells us reduced. In other words jsut as VAT is isulin resistance glutofemoral fat from obese women is super insulin sensitive.

this also has an impact on blood flow to this tissue. Because ACE activity is so high it prevents vasodilation for occuring. Thus creating the perfect environment for fat storage. Super low blood flow so fats can't escape and super high insulin sensitivity to promote storage.

So seeing as how androgens mediate angiotensinogen secretions in this case we can say its lack of androgens that conttribute to this phenomenon.

Again this leaves out all the nurological stuff like the fact that ACE genotype is assoicated with addictive behavior patterns like binge eating and alcohal or drug use.

Thre is some further evidence that RAS-aldosterone is intimantly connected t fat distrobution patterns. For example an out of whack sex hormone ratio can cause gyno. We all know that. However an aldosterone antagonist can also induce gyno. So it apears that RAS-Aldosterone system is also related to breast tissue development.

Anyway check out my article when its released.

Spook, how does your thinking on this matter jive with the evidence of lower cortisol response (to stressors) in those with the metabolic syndrome and abodminal obesity. There are some that see hypocortisolism as adaptive and some that see it as maladaptive, and of course there are varying explanations as to the origins of this profile. However, one might imagine, at least from an adaptational standpoint, lowered cortisol responding would be beneficial from a fat topography standpoint, irregardless of other mechanisms in the HPA axis. Furthermore, in the case of elevated cortisol contributing to HPA dysfunction, morphology, and--pertinent to our discussion--fat topography, is the elvated coritisol (in such cases) a cause of current adipose tissue paterns, or merely a consequence? Aside from a synergy with insulin to effect LPL activity (upregulation) are their other direct pathways involving coritsol as a mediating/moderating factor based on the theory you present? (I will wait for your article, I just wanted to continue the discussion at hand).

Also what is your take i\on the usefulness of ACE inhibitors in the quest for the perfect body?

I think it actually jives very well. Studies showing lower cortisol response or shall we sa hypo-HPA need to be subdivided. In studis on women with abdominal obesity it actually seems much more common to find hyper-HPA if you remove the studies on women with PCOS (as mesured by the DEX/CRH supression tests). I have pretty much given up on looking at any data on DEX supresion tests alone as they simply do not provide information in many individuals that have HPA disfunctions. Men generally have a much greater chance of showing hypo-HPA. so its sexually dimorphic.

I think the best explanation is as follows: (especially in light of why PCOS women are outliers in the normal pattern of things.)

1. women without PCOS tend to show hyper-HPA with abdominal obesity.
2. women wich PCOS or men tend to show normal to hypo-HPA in abdominal obesity.

So what do women with PCOS have in common with abdominally obese men? elevated blood sugar and elevated androgens(compared to normal women). Seeing as how those two things are specifically involved in angiotensinogen secretions I think we have a clue as to what direction to look.

Now to explain this I need to get i to the neurological aspects a little. There are of course numerous points in the pathways that can result in hypo-HPA. the two mot common seem to be CRH desnsitization at the pituitary (in cases of hyper-CRH), desensitization of ACTH response at the adrenals( generally causesed by reducion of 11-beta-hydroxylase activity ), or in the mid brain regions by super sensitivity of the GR and/or the McR.

Now a fair amount of studies show that in abdominal obesity when hypo-HPA is present elevated aldosterone is also present. So there is one explanaton right there. aldosterone binding to the McR could shut off further CRH release. Now I think its a little more complicated than that however.

I think that would only be part of the equation. The other parts are that AngII signaling at the adrenals can overwhelm 11-beta-hydroxylase activity if in excess. This generally shows signs of adrenal hypertrophy (like in PCOS women).

finally and I think probobly most important is angiotensin direct effects on neural tissues in the PVN and VMH. angiotensin can drive dopamine levels in said tissue to down to the point that they are undetectable. at the same time it decrease NE metablism in those tissues. So you get a very active PVN. Any or all of these could result in desnsitizaton. Of course I think other factors play a role in this like TNF-alpha or some of the IL family of cytokines. So its not just RAS-A in the case of hypo-HPA.

I do think though that its downstream of sex hormones again. especially since obese women seem to favor hyper-HPA as opposed to hypo-HPA. I think one of the reason for this would be that estrogen is directly protective of AVP release in the dorsal region of the PVN. many studies on that. So in such women you get one stress compund saying "release cortisol" namely angiotensin. while estrogen is protecting AVP release. seeing how AVP and CRH work synergistically at the pituitary to cause ACTH release this says to me that such an individuals is going to have to release more CRH to compensate for the lack of AVP. thus resulting in a hyper-CRH system. Now much of the desensitization of CRH actually seems to be caused by AVP and not CRH at the pituitary. So we end up with hyper-responsive HPA and excessive cortisol release.

So I think in men (that often have several fold higher levels of AVP) that AVP is mostly responsible for HPA supression at the level of the pituitary.

Damn I just re-read that and its allmsot incomprehensable. Blah. I wish I was more articulate. Anyway the last paragraph sums up my opnion pretty well. Specifically I think sex homones regulate the dimorphic response though two down stream signals. AVP and angiotensin.



I think both. it has to be both of be a vicious cycle. elevated cortisol by any means seems to promote modifications in fat distrobution but the alterations in distrobution are self sustaining thus it can become a consequence. I think which one is primary will differ on an individual basis.



sure there are many but they are disparate and don't occur in all individuals. The previous argument seems to hold true for just about everyone who is normal. Some of the following can be contributing factors but they do not show up in all populations for various reasons.

first and formost is cortisols involvement in mediating reward pathways. the degree of cortisol release given dopaine surge is predictive of the severity of addiction and withdrawl. such activity can increase caloric intake. they don't call it comfort food for nothing.

11-Beta-HSD1 upregulation increases leptin and TNF-alpha production in obese people. by relation to TNF-alpha cortisol can mae fat tissue insulin resistant which effects fat distrobution.

I know you asked specifically about cortisol but CRH (which is related) has a wealth of informaton on direct pathway mediation in adipose cells.

for example we see that distrobution of CRH 1 & 2 receptors differs dramaticlly betwen VAT and SAT

thats a tricky one. You can make arguments both ways. I think they are benifical especially for the over weight and anyone on the extreme end of either body fat distrobution type as ACE inhibition would seem to have a normalizing effect on either extreme.

Whats not clear is ACE inhibitions effects on muscle tissue in humans. One school of though is that they decrease muscle growth and will there for hurt body composition in the long run. I do not agree with this assesmant. I think if anything in humans they might have the propencity to promote fast to slow twitch conversion. And they probobly do decrease strength gains.

I base this on the some of the research that shows fiber conversion in animals. in animal models angiotensin makes muscles grow. but in geriatrics ACE inhibition or the ACE I/I genotype is associated with reduced atrophy. And in geriatrics its the fast twitch fibers that atrophy first.

So if I had to make a guess it seems that ACE inhibition will result a reduced potential for the development of fast twitch muscle fibers. This is how I think it reduces measured increases in hypertrophy in animal models and the limited data in humans.

Now how bad that is , is debatable. Because at the same time it should also increasing glycogen supercompensation and nutrient delivery to muscle tisue as well as sketal muscle insulin sensitivity.

So which side wins out? any ones guess at this point as data is simply lacking. from my own personal expirience I tend to to think they do decrease strength gains but improve bdy composition at least in a recreational lifter like myself. I think the glycogen supercompensation that they seem to elicit and the improved insulin sensitivity seems to outweigh any possible loss in hypertrophy but again this is just my own personal expirience with my body. It could be and probobly is different in different people.

I still think there use wise in those who are over weight and or older from the standpoint of increased health as well as effects on body fat and insulin sensitivity.

Spook, I will digest your detailed reply this evening, but I wanted to say your point regarding reward pathways is something which I think is commonly overlooked in that one of cortisol's primary influences on fat topography and fat gain may simply be as a mediating variable at the whole system caloric intake level.

I appreciate your breadth and depth of commentary on these posts.

Best thread I've read in a while.

Two thumbs up, and a bump.