The Physiology Of Fat Loss Part Four!

Ok, we are nearing the end of our theoretical ordeal. Today we are going to be covering, briefly, Growth Hormone, appetite regulation, cortisol and TNF-alpha and how they may relate to our fat loss efforts.
Note: This is part four, click here for part three.

Ok, we are nearing the end of our theoretical ordeal. Today we are going to be covering, briefly, Growth Hormone, appetite regulation, cortisol and TNF-alpha and how they may relate to our fat loss efforts.

This article is considerably easier than the previous three (part one, part two, part three), because it doesn't go quite as in-depth as the other three.

This wasn't necessary, since a cursory explanation of their actions is more than sufficient to understand their role in the physiology of fat loss. There are however, yet again, references to the previous installments, so those who have read up again have a plus, and will be able to follow better when we reach the less theoretical and more practical part of this series.


Growth Hormone

Growth Hormone is not exactly a major player in fat loss, but it can make a noticeable difference. In obesity we see that GH secretion is largely impaired, conditions where fat loss is enhanced, like starvation, usually display a significant increase in Growth Hormone. There is more than one reason to believe growth hormone may at the very least be a significant player in adipose tissue regulation, and vice versa, how adipose tissue is a regulator of Growth Hormone.

The most obvious way in which growth hormone would aid in fat loss is of course its well-known effect on reducing insulin sensitivity. Growth Hormone has long been a popular product among pro's and amateurs alike, injecting it in the hopes of increasing IGF-1 levels and activity, and so increasing muscle mass. A very costly and largely ineffective waste of time, since the GH/IGF-1 axis is very tightly regulated.

But many have noticed the positive benefits of GH on body-fat reduction. Its mainly from this use however that we know GH increases insulin resistance. To such a degree that bodybuilders originally started supplementing with insulin to overcome this issue. The reduction in insulin sensitivity (cfr part 2) concurrently decreases adipogenic markers in fat cells, like PPARgamma and c/EBPalpha, creating a more suitable environment for fat loss.

But GH also acts directly on the fat cells to stimulate lipolysis. It does this both by inhibiting uptake of fat by fat cells, and increasing the release of fatty acids by those same cells. The primary regulator of uptake in the cells is Lipoprotein Lipase (LPL). LPL is secreted by the cell, removes fatty acids from tricglyceride portions and transports them inside the cell, where they are re-esterified.

GH has been shown to reduce LPL (1), possibly this is mediated by its effect on insulin sensitivity since insulin is primarily responsible for the translocation of LPL. The reduction may be greater in visceral fat (2), which may be the true benefit of Growth Hormone, since another lipolytic hormone, cortisol (discussed later) is extremely effective at reducing fat, but it increases visceral fat, something that could be inhibited by Growth Hormone manipulation.

Likewise it also stimulates the release of fatty acids from the adipocyte via methods discussed previously in articles 1 and 3 respectively. The first means by which Growth Hormone stimulates fatty acid release is by increasing the density of beta2 adrenoreceptors (B2AR) (for functioning of B2AR see part 1) much like thyroid hormone dose (cfr part 3) (3).

More B2AR means more effect of epinephrine and norepinephrine, stimulating amongst other things, lipolysis (release of fatty acids from white adipose tissue). A second manner in which Growth Hormone increases fat loss is also similar to Thyroid Hormone, namely by inhibiting Phosphodiesterase's (3).

As we saw in the functioning of the A1AR, norepinephrine also stimulates calcium signalling which results in enhanced PDE's. These increase the release of adenosine, and inhibitory factor for lipolysis.

An often confusing factor in using Growth Hormone for weight loss, is the fact that GH stimulates the release of IGF-1 under the right conditions. As the name suggests, Insulin-Like Growth Factor exerts insulin-like effects, increasing adipogenic markers (using the same pathways as insulin but a different receptor) and thereby promoting adipose tissue proliferation and differentiation.

GH itself has the opposite effect. Make no mistake, under caloric restriction IGF-1 is not increased. Its not exactly reduced either, but we do see distinct changes in regulators of IGF-1 activity, the IGF-binding proteins such as reductions in IGF-BP5 and increases in the negative regulator IGF-BP4. So the adipogenic effect of GH is pretty much completely reduced, allowing full expression of its lipolytic qualities.

GH manipulation makes a lot of sense during a diet as well. Increased serum fatty acids inhibit GH release, especially in the beginning of a diet that can be a problem. So increased GH release would be a definite addition. The effect on insulin resistance is also practical in the beginning, when calories are only reduced slightly.

Of course one can question the effect of whole-body insulin resistance in terms of muscle retention long term. In any case, practical application of GH therapy for obesity has demonstrated minor successes, so while it may not be the primary target for most of us, it is something worth considering.


Reduction Of Appetite

For a long time, the most important target for weight loss from a medical perspective, was a reduction in appetite. Makes sense, in animals weight was largely predicted by feeding behaviour. But then we seem to forget that animals don't eat refined foods like we do. Our foods are highly addictive and we don't just stop eating.

And a reduction in appetite does not correlate with a reduction in weight for most either. On top of that, cessation of treatment often resulted in a massive relapse. That's why weight loss from a research perspective, like we in the bodybuilding community do, focuses largely on promoting the actual release and burning of fatty acids, rather than addressing appetite.

Appetite is important, but long term efficient weight loss needs to be paced. A severe decrease in appetite makes it hard to keep eating frequently, and if you don't eat frequently enough, your metabolism slows down and you hit a wall. Likewise too much appetite makes it hard to stay on a hypocaloric diet. So a reduction is highly beneficial, but not too much.

Most wintered dieters will also tell you that some sensation of hunger is necessary to keep yourself convinced you are still on the right course and to prevent any problems associated with dieting before they become too grave.

As a rule anything that aids in fat loss and helps a little along the way in terms of reducing appetite is a nice addition, but we rarely if ever employ products specifically designed for appetite reduction. That's definitely a positive thing, health wise.

Most beta-adrenergic drugs stimulate a reduction in the appetite, especially those that result in stimulation of the alpha receptors (5) (A1AR and A2AR) because these will lead to a decrease in orexigenic peptides, those peptides that usually make us hungry. The A1AR is obviously a more likely target, since it works somewhat pro-lipolytic at a local level as well, whereas the A2AR works anti-lipolytic at a local level.

Sufficient use of A1AR stimulators could allow you to more successfully employ A2AR blockers, although this may still result in a reduction of B3AR density (4) when used systemically. Drugs like ephedrine and methylphenidate are very potent reducers of appetite.


Cortisol

Cortisol is that one hormone we all love to hate, because its one of the most important inducers of proteolysis, resulting in muscle loss. Like most hormones we want some of it, but too much becomes detrimental. When we diet especially, cortisol levels tend to rise drastically. This is not entirely negative though, cortisol is probably the most powerful lipolytic drug there is.

With a few downsides of course. Whereas it reduces fat in most areas, it increases visceral fat mass (beer belly like). This is an evolutionary safe-guard. Visceral fat can be easily mobilized, so relocating fat there may be to our advantage in surviving long spells of caloric restriction.

This is generally not a problem on a diet, visceral fat mass is reduced pretty much as fast as cortisol can relocate the fat there, especially as your diet progresses. The main negative is that if you fall off the wagon, and start binging, chances are you will gain fat in your gut first. The other major downside of course is the muscle loss.

Cortisol is the one hormone everyone would like to be able to control selectively. Turning it off in muscle and visceral fat, and turning it up in subcutaneous fat. This is why most steroid users will opt for an androgen with anti-cortisol properties to aid in retention of muscle mass.

Testosterone and trenbolone are the two most potent drugs in this regard, and they are highly synergistic in this regard as well. Testosterone blocks the cortisol receptor, whereas trenbolone may reduce receptor number and may reduce size of the adrenal gland long term.

Usually in a diet we try to make use of cortisol without letting it get out of hand.


TNFalpha

TNFalpha (Tumour necrosis factor alpha) is a cytokine that is not that different from cortisol in the way it acts. It also initiates catabolism in most tissues and has definitely been established as a factor that increases fat loss (6), but here too it's largely a choice between the positive and negative effects, because TNFalpha also reduces calorie expenditure.

It has been shown to reduced UCP1 (7) and UCP2 (8) activity, and with that, logically, a reduction in the amount of calories burned and in thermogenic activity. This may be, at least partially, due to its effects on catabolism in tissues rich in UCP1 (9) and UCP2.

PPARgamma negatively regulates TNF-alpha, so odds are when we interfere with PPARgamma we may be increasing TNF-alpha. Since PPARgamma increases the number of cells, and TNF-alpha reduces them, that makes perfect sense.

TNF-alpha closely relates to cortisol. For example it does make more cortisol available in cells. When glucocorticoids are excreted they are usually inactive. They need dehydrogenase enzymes to activate them. The 11-beta HSD enzyme family has been shown to modulate cortisone to create active cortisol. TNFalpha seems to increase intracellular activity of at least one of the 11-beta HSD enzymes (10). This is, in part, how it regulates its proteolytic and apoptotic effects.

Norepinephrine induced fat loss seems to protect against the apoptotic effects of TNF-alpha (11) however. TNFalpha represents a different means of non HSL-dependent fat loss, that results in permanent destruction of fat cells. This may be beneficial in extremely obese subjects, but the predominantly negative effects of TNF on muscle tissue make it a less likely candidate for dieting athletes.

TNF will be pretty much a non-factor when discussing dieting aids. It can be perceived as positive (increased fat loss) or negative (increased muscle loss) when a fat loss aid also increases TNF levels.

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


Conclusions

Ok, we are nearly there. The last theoretical instalment will discuss sex hormones (testosterone and estrogen) and the much discussed leptin. The latter will be highly controversial, since my view, both theoretically and practically, is quite different from the hype you may have been forced to swallow in the past.

It's up to each individual reader to decide what they come away with from this article series of course.

References

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  2. Flint DJ, Gardner MJ. Influence of growth hormone deficiency on growth and body composition in rats: site-specific effects upon adipose tissue development. J Endocrinol. 1993 May;137(2):203-11.
  3. Nam SY, Marcus C. Growth hormone and adipocyte function in obesity. Horm Res. 2000;53 Suppl 1:87-97.
  4. Gomez-Ambrosi J, Fruhbeck G, Martinez JA. Interactions between an alpha2-adrenergic antagonist and a beta3-adrenergic agonist on the expression of UCP2 and UCP3 in rats. J Physiol Biochem. 2002 Mar;58(1):17-23.
  5. Rasmusson AM, Southwick SM, Hauger RL, Charney DS. Plasma neuropeptide Y (NPY) increases in humans in response to the alpha 2 antagonist yohimbine. Neuropsychopharmacology. 1998 Jul;19(1):95-8.
  6. Warne JP. Tumour necrosis factor alpha : a key regulator of adipose tissue mass. Journal of endocrinology (2003) 177; 351-355
  7. Valladares A, Roncero C, Benito M, Porras A. TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK. FEBS Lett. 2001 Mar 23;493(1):6-11.
  8. Merial C, Bouloumie A, Trocheris V, Lafontan M, Galitzky J. Nitric oxide-dependent downregulation of adipocyte UCP-2 expression by tumor necrosis factor-alpha. Am J Physiol Cell Physiol. 2000 Oct;279(4):C1100-6.
  9. Porras A, Alvarez AM, Valladares A,Benito M. TNF-alpha induces apoptosis in rat fetal brown adipocytes in primary culture. FEBS Lett 1997; 416 : 324-328
  10. Heiniger CD, Rochat MK, Frey FJ, Frey BM. TNF-alpha enhances intracellular glucocorticoid availability. FEBS Lett. 2001 Nov 2;507(3):351-6.
  11. Briscini L, Tonello C, Dioni L, Carruba M, Nisoli E. Bcl-2 and Bax are involved in the sympathetic protection of brown adipocytes from obesity linked apoptosis.FEBS Lett (1998) 431 ; 80-84