The Physiology Of Fat Loss Part Five!

We have arrived at part 5, the last of the purely theoretical parts. This time around we are discussing the various sex hormones like DHEA, testosterone and estrogen.

Note: This is part five, click here for part four.

We have arrived at part 5, the last of the purely theoretical parts. After this we will be discussing more directly relevant topics such as actual ingredients and supplements that can aid fat loss. Of course a lot will depending on your understanding of these first 5 articles. This time around we are discussing the various sex hormones like DHEA, testosterone and estrogen.

Although not the main contributors to fat loss, they do play a crucial role in where fat is stored and how much fat is gained under anabolic conditions. Not to mention they play a pivotal role in the retention of muscle mass while dieting, which is still a major concern for most of us.

Apart from that we will also be discussing a little known factor, called adipsin, and leptin. The discussion of leptin is kept to a minimum however, since it will not be a major factor at all. It is only addressed here since it is often raised in discussion, and I do want to make this series a complete one.


Testosterone is a hormone with a dual effect. Partially lipolytic and partially adipogenic, or at least anti-lipolytic. This is clearly evident in the fact that it tends to decrease fat in older men, with low testosterone levels, but is largely seen as a steroid more likely to cause fat gain among athletes.

That testosterone is anti-lipolytic is somewhat logical. Androgens tend to increase IGF-1 release (2), which results in lower Growth Hormone and more activation of adipogenic markers. But it also exerts more direct effects. High levels of testosterone lead to higher levels of adrenoreceptors (3) in fat cells, and while testosterone does increase beta receptor density, it seems to have a predominantly pro-alpha anti-lipolytic effect (4).

On the other hand testosterone may exert a positive central effect, where it reduces appetite by lowering Neuropeptide Y, and increase Cocaine and Amphetamine related transcript (CART) (5) and has been shown to lower Lipoprotein Lipase (LPL) (6) which would in turn reduce the uptake of fatty acids into the fat cells.

Testosterone's main contribution with regards to body-fat is not so much its reduction, as it is the prevention of gaining additional fat mass in a pre-dominantly adipogenic (anabolic) environment. In the body we have pluripotent stem cells, that could develop into either pre-adipocytes or muscle satellite cells. Under the influence of testosterone, these stem cells are more likely to evolve into muscle satellite cells (23). This not only decreases the capacity to form fat cells in the body, it also increases our capacity for muscular repair, regeneration and hypertrophy.

Addition or manipulation of testosterone during a diet is usually considered with the retention of muscle mass in mind. Greater levels of protein synthesis, as well as a reduction in the activity of cortisol leads to more muscle being retained in a more catabolic condition, such as exists on a hypocaloric diet.

Knowing what to expect is therefore important, in that sense that testosterone may initially and dose-dependent, decrease fat tissue, but may end up slowing it down in the end. It may also be worth considering that testosterone seems to burn fat more efficiently in intramuscular and deep adipose stores, rather than subcutaneously, where the most visible fat pockets are located (7).


Estrogen is the second factor people often consider. Especially steroid and prohormone users are often plagues with a serious misunderstanding of estrogen and its effects on adiposity. Most are convinced that estrogen increases fat gain or retards fat loss, when in effect the opposite is true. Estrogens, and especially estradiol (E2), is probably a more effective fat loss aid than is testosterone. Although like testosterone, it may have certain anti-lipolytic effects by increasing a2 adrenoreceptors in specific female patterning (harder to lose fat in thighs and butt).

First of all, estradiol also reduces LPL (6), just like testosterone does, so uptake of fatty acids in adipocytes is reduced. Apart from that, its effects can be divided in three categories. Its effect on insulin-related events, its effects on Growth Hormone and its effects on reducing appetite.

Estradiol can cause a reduction in weight, with only a minimal effect in insulin itself (8), but that does not mean it does not alter the body's reaction to insulin. Estradiol lowers insulin receptor number (9), and in very high doses even actual insulin sensitivity (10). It does so in various ways, not in the least by reducing GLUT4 recruitment and translocation in adipocytes (11), which results in less glucose uptake in fat cells.

This will result in a negative energy balance and a greater activation of lipolysis, right where we want it, in the fat tissue. The effect of estradiol on insulin is quite acute, and clearly evident in the fact that short-term modulation drastically reduces glucose appearance (release) and disappearance (uptake) (12), suggesting a dysfunctional glucose transport system.

The second way in which estradiol may increase fat loss, is its effect on growth hormone (13,14). Unlike testosterone, which stimulates the GH/IGF-1 axis, the effect of estrogen may actually be in reducing systemic (liver-derived) IGF-1 (13), which lowers inhibition of Growth Hormone.

In doing so it obviously reduces the anabolic capacity of the body (which is why we don't use estrogen to build muscle) but increases the fat burning capacity since whole-body IGF-1 is reduced, leading to a reduction in adipogenic markers (since IGF-1 and insulin activate the same cascades) and a concurrent increase in Growth Hormone, leading to further decreases in LPL and upregulation of beta-adrenoreceptors (cfr. Part 4). Estradiol may even reduce IGF-1, while increasing IGFBP-3 (15).

This may in effect be the reason why estradiol does not promote growth, since unbound IGFBP-3, which is under normal circumstances the main carrier or IGF-1 in circulation, has been attributed charachteristics that inhibit growth (16). It acts as a pro-apoptotic agent to activate cysteine proteases, much in the same manner that cortisol or TNFalpha would (cfr. Part 4).

This implies that as long as we are seeing an increase in estradiol accompanied by an equal or larger increase in testosterone, we are reaping positive effects, on both fat loss and muscle retention since testerone increases IGF-1, while estradiol prolongs the half-life and effect of the hormone by increasing IGFBP-3 and IGF1-receptor density (20). Without the testosterone increase, it may however increase muscle loss (and potentially increase fat loss further by enhancing apoptosis of fat cells ?).

A third way in which estradiol helps as a fat loss agent is by reducing appetite. It reduces sensations of hunger via modulation of melanin-concentrating hormone. We have discussed the role of orexigenic (hunger inducing) peptides once or twice previously, specifically NPY.

Obviously NPY isn't the only peptide involved. For instance Agouti-related peptide is also involved, as is melanin-concentrating hormone (MCH). When energy intake is restricted, MCH levels sky-rocket, leading to an increased sense of hunger. Estradiol was able to completely abolish this increase in MCH (17), making it a very potent appetite suppressor during low-calorie diets.

Lastly, estradiol increases both the release of arachiconic acid (18) and the actions of cyclo-oxygenase (19) in certain cell types. This results in a quick and effective increase in several prostaglandins, including PGF2 and PGI2, that are related to lower body-fat levels. Because these effects can be highly varying in different cell types it should not automatically assumed that these events do occur, or that they necessarily contribute to fat loss however.

Estradiol can also prevent muscle loss, once again only in the presence of testosterone, by blocking the low affinity glucocorticoid receptors (22), protecting against the effects of cortisol. Testosterone, or another blocker of the high affinity receptors must be present however, otherwise the blocking of the low affinity receptor would not yield very good results.

On a closing note, as with testosterone, the effects of estradiol are not uniformly positive. It has been shown to enhance PPARgamma (20), so modulation of testosterone/estradiol levels should occur in the presence of a PPARgamma blocker for maximal effects on fat loss. And lastly, estrogen increasing products are often omitted during diets for the simple reason that estradiol increases aldosterone (21), a hormone that increases sodium retention, and as a result water retention.

Excess levels of estrogen often lead to water retention and a puffed up look. While this does not affect fat loss one iota, and can be addressed quickly, in only 1 or 2 days, it does make it difficult for the dieter to judge his progress accurately.


Once, when discussing the relevance of insulin resistance I commented that this would also reduce the esterification of fatty acids into fat cells. Someone then remarked to me that fatty acids stimulate their own esterification by increasing release of Acylating stimulating protein (ASP). But a lower insulin environment is conducive of more norepinephrine release and effect. When fat cells are stimulated by norepinephrine, they reduce their production of adipsin (1).

Adipsin (aka complement factor D) is a serine protease secreted by adipose cells (1). Adipsin can cleave complement protein C3 into C3a and C3b. C3a can be inactivated to C3adesArg, and C3adesArg is simply another name for ASP. So sympathetic activation of fat cells reduces their adipsin release, which reduces expression of ASP and consequently inhibits uptake of glucose and esterification of fatty acids.

This too makes perfect sense, when insulin is low, glucose uptake is low and that means a greater need for free fatty acids. It makes no sense to esterify them if they will be needed again shortly. Because they are not being esterified they can be transported out of the cell again and be burned.


Another hormone that should be well known to most is Dehydroepiandrosterone, or DHEA. It emerged as a supplement a while ago now, and was at that time hyped as another holy grail. It has since somewhat disappointed as a supplement, rarely being worth the money for most. Nonetheless new things are being uncovered about DHEA on an almost daily basis that do really prove it plays a key role in many bodily functions.

As an intermediate step to the production of testosterone and estrogen, as a neuroactive steroid and behavioural regulator and … as a lipolytic substance. Surprisingly DHEA was never marketed as a fat loss drug. In contrast, an analog called 7-oxo-DHEA WAS marketed as a fat loss drug.

In direct comparison however, the use of DHEA resulted in a much lower fatty acid content in fat cells, while 7-oxo-DHEA actually INCREASED fatty acid content in the fat cells (24). The difference correlated highly with the difference in stearoyl-CoA desaturase (SCD1).

Most likely part of the difference is mediated by DHEA's effect on SCD1. Another possible contributor is the fact that 7-Oxo-DHEA reduces the formation of active cortisol. While this may be somewhat effective in regards to minimizing loss of muscle, it is a huge negative with regards to fat loss, where cortisol is highly lipolytic in all tissues safe for visceral fat. Athletes rarely if ever have a high visceral fat depot, and if so, with training it is the first fat depot likely to get reduced since it is in a position to be readily used by the liver. Making visceral fat the least of the concerns of the exercising individual.

Furthermore it was concluded that DHEA, but not 7-oxo-DHEA, reduced the differentiation of pre-adipocytes to full adipocytes. Preventing actual fat gain, under the influence of hormones that increase differentiation, such as leptin, IGF-I and insulin.

Most likely this occurs through the reduction of expression of PPARgamma (25). And on a final note, that same study also proved that in differentiating pre-adipocytes, DHEA promoted thermogenisis (formation of brown fat cells) while 7-oxo-DHEA had no effect on thermogenisis at all. This is corroborated by a study (26) showing that DHEA increases expression of UCP1 and UCP3 in brown fat cells. Since the expression of UCP1 technically makes a fat cell a brown fat cell, this means DHEA promotes the formation of BAT over WAT.

As if this were not enough, DHEA also increase beta-adrenergic fat loss (27) through a mechanism that does not involve the reduction of adenosine activity. That means it will again support any and all drugs that use the c-AMP dependent cascade to releasing fatty acids.

Meaning that DHEA increases fat burning, decreases fat storage, fat cell formation and of the fat cells that do get formed, it promotes the formation of those that can contribute to fat burning. That makes DHEA probably one of the most versatile hormones in the body with regards to fat loss. Products that affect DHEA positively, would also affect fat loss positively therefore.


Leptin is a hormone that is primarily secreted from the fat cells themselves, in response to the amount of triglycerides they stock. On a paracrine level they serve to signal neighbouring pre-adipocytes that the existing fat cells are full and that the pre-adipocytes need to proliferate and differentiate.

It does so via a specific leptin receptor that uses the same downstream signalling cascades as insulin, and results mostly in similar effects, namely the activation of cEBP alpha and PPARgamma, factors of proliferation and differentiation, causing an increase in the amount of fat cells.

Because leptin serves as a signal of excess, it fulfils many functions on an endocrine level that may be perceived as positive to fat loss, such as a reduction in appetite, diminished response to appetite inducing signals, and so forth. Mainly because of its many roles in this regard, it has been hyped as the next big factor in weight loss. Of course, anything is a big factor if you represent it on a very simplistic level.

When leptin becomes the dominant signal, it pretty much regulates everything. It lowers LH, it lowers TSH and it increases CRH. Normally this would lower testosterone and T3, and increase cortisol, resulting in more muscle loss and a slower metabolism, if it wasn't that leptin itself maintains these functions in the stead of the normal regulatory mechanisms. So far so good. Of course, unless you plan to inject leptin, your leptin levels will eventually drop.

As triglyceride count drops, so does the signalling thereof. Even with supplements proven to increase leptin, increases occur percentagewise, meaning they are much lower in individuals with lower tri-glyceride stores. The leaner you get, even with supplementation, the lower your leptin levels will get.

At a certain point leptin gets too low to exert much of an effect. But since all the time you spent trying to keep leptin elevated lowered your TSH and LH, and increased CRH, you are now left with nothing to regulate testosterone and thyroid hormones, resulting in a lower metabolism more prone to store fat, and at the same time increasing cortisol levels, which results in greater muscle loss.

One study (28) showed that people who experienced a faster and greater DROP in leptin levels, early in the diet, lost weight faster and kept it off longer. This caused me to postulate that lowering leptin faster might be a wiser course of action. I attempted and tested this by lowering all factors that could increase leptin (mainly vitamin E and zinc) without making any other changes. Indeed, progress occurred more rapidly than normal.

However I might have been equally erroneous in my attempt, since I learned that zinc may be adipogenic through its manipulation of IGF's, and that the increase in weight loss may therefore have been due to less IGF-I signalling, rather than a drop in leptin. I was equally foolish to believe that a manipulation in the other direction would pay off. Leptin, as it turns out, is a non-factor in the diet. This is of course my opinion, and many people are less than happy with this opinion. So make up your own mind.

What I can tell you is that leptin uses the same downstream signalling cascades as insulin, and has the same negative effects as insulin as a result, at least in adipose tissue. Since it is released there, it is also safe to assume its autocrine/paracrine effects are greater than its endocrine effects.

Moreover, even if it differentially manipulated these cascades, resulting in a positive effect, it would still be less of an advantage than simply reducing insulin resistance. Since this is a valid way to increase lipolysis, any and all attempts at manipulating leptin would be utterly futile anyway, since the body would lose its sensitivity to leptin. Most likely this has a lot to do with the fact why manipulating leptin negatively was just as nonsensical as manipulating it positively.

In people with Type II diabetes leptin is increased phenomenally, as is insulin. These people keep increasing their bodyweight, despite the homeostatic role of leptin. Again, this is as a result of the cross-signalling between leptin and insulin. An insulin insensitivity will automatically decrease leptin sensitivity, so the lack of effect here is as a result of insensitivity to leptin.

Such people may highly benefit from an increase in leptin sensitivity, as well as insulin sensitivity. Of course, since this targets the same cascades, treating one largely treats the other. If you suffer this type of insensitivity, or fear you may suffer it, it is in your own best interested to get this tested and to receive proper treatment for your condintion by a licensed medical professional, rather than to put your hopes in unregulated supplementation.

For non-obese individuals however, leptin remains largely, a non-factor due to the better results with insulin desensitizing drugs (rendering leptin inert), the difficulty in manipulating leptin naturally and the lower tri-glyceride stores.


That concludes I believe a rudimentary discussion of all the major players in fat loss in the human body. This 5-part review is neither entirely complete nor entirely detailed, but it does comprise roughly everything you'll need to know to understand various supplements and drugs used for fat loss.

Using the first 5 articles as a guide you, will learn to comprehend compounds discussed in future features, why they are used the way they are and how best to incorporate them in your regimen. Hopefully you gave this all some time to sink in and it makes some sort of sense now. Some have written to me that the previous instalments were very easy to comprehend, for which I am thankful, while others wrote me saying it was a hard to digest.

Nonetheless I hope all readers came away with something to take home and will be able to apply this knowledge, be it to future articles on supplements, or in understanding past articles and features.

This was the last of the purely theoretical articles, the next installement should contain more practical information, although I have no idea yet as to how it will evolve or how they will be structured.

Note: This is part five, click here for part four.


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