The Physiology Of Fat Loss Part Three!

In part three of this article I will try to tackle fatty acid oxidation, the whole body beneficial effects of alpha2 adrenoreceptor stimulation and the effects of thyroid hormone.
Note: This is part three, click here for part two.

The bad new is, if you don't understand or haven't read the first two parts (part one and part two), you may be a little lost reading this article, since I make a few references. The good news is, however complicated this stuff may be at first glance, if you have read and comprehend the first two articles, then this one should be an absolute breeze.

In this one I will try to tackle fatty acid oxidation, the whole body beneficial effects of alpha2 adrenoreceptor stimulation and the effects of thyroid hormone.

Fatty Acid Oxidation Is The Final Step In Optimizing Fat Burning

Fat loss has forever centered around lipolysis and reduction in appetite. However, reducing food intake and increasing the release of fatty acids is just one step, now you have to also make sure the released fatty acids actually get burned. In caloric deficit, on a low carb diet this will occur regardless. But that doesn't mean we can't help the process along a bit. In order to do this, we are going to discuss the mechanisms by which fatty acid oxidation increases.

Food stuffs get burned in metabolically active cells. These cells possess mitochondria, which you could portray as little factories that take your macronutrients and turn them into ATP for energy. Under normal circumstances, these little factories work on glucose. However there are organs in the body that rely on glucose more, such as for instance the brain.

ATP Molecule

When a glucose shortage occurs, the glucose will be spared for the brain, and the other metabolic active tissues will have to function on something else. This is why we actually have fat. Fat is easily stored in the body and contains twice as many calories as glucose.

When we require energy but don't get enough from our food we initiate lipolysis to acquire fat as a substrate for energy production. This means the mitochondria must adapt to burning fat instead.

The main users of energy are the liver and the muscles. This also clarifies why bodybuilders have considerably less trouble losing fat than your average person, because we simply have a higher amount of metabolically active cells. The change in these cells occurs largely through processes we previously discussed in fat cells (cfr part2) regarding insulin resistance, namely through AMPK activation (as a result of low energy balance) or stimulation of Interleukin-6 (IL6).

Both these occurances have been shown to reduce the adipogenic (fat gaining) market acetyl-CoA carboxylase (ACC). To oxidize a fatty acid, you need to get it into the mitochondria, this occurs via carrier molecules, in this case Carnitine Palmitoyl tranferase (CPT) . What ACC does is create a product called malonyl CoA that basically inhibits CPT from actively carrying out its duty.

So when AMPK reduces ACC we are in fact freeing up more CPT that can transport fatty acids to the mitochondria. Again we are staying in the same line of manipulation.

PPARalpha And Beta

In the last article we also discussed a nuclear receptor called PPARgamma, and said it had two other brothers, namely the alpha and the beta receptor. These two exert positive effects by increasing fatty acid oxidation. PPARalpha agonists are widely used in the reduction of cholesterol. This is because they induce fatty acid oxidation in the mitochondria of the liver.

In the liver the beta receptor, however, is nothing more than a failsafe. In muscle tissue, the situation is the opposite. This tissue is quite poor in the alpha receptor and quite rich in the beta receptor. Here the beta receptor will play the crucial role (1).

The use of common PPARalpha agonists, such as fibrates, is sometimes recommended to increase fatty acid oxidation. But in the real world such a thing has failed miserably. A true explanation I couldn't give you, maybe because the induction of the alpha receptor already occurs readily in a starvation state. There is however one fibrate that seems to elicit minor successes, namely bezafibrate.

This is possibly because bezafibrate is also a PPARbeta stimulator (2). In bodybuilders it makes more sense to target the PPARbeta receptor anyway, since our bodies comprise of over (sometimes well over) 50% muscle mass. With that much metabolically active tissue, tuned to oxidize fatty acids, must evoke some type of increased reaction in fat loss.

When we get down to discussing various fat loss products, we will encounter more ligands for these receptors. But it is important to know that the body too makes an endogenous ligand for the PPARbeta receptor, namely prostacyclin (3,5) (Prostaglandin I2 or PGI2). Stimulation of BAR's by, for example, NE to stay in the same line, does lead to a modest increase in PGI2 production (4).

Whole Body Effect Of A2AR Stimulation

We first discussed the alpha2 adrenoreceptor (A2AR) in part one of this article series. We said it was an anti-lipolytic receptor, at least locally in the fat cells. Which implied that systemically it may produce some form of positive effect. This is most certainly the case. When stimulating the alpha2 receptor in the brain, part of its effects are a reduction in the orexigenic peptide Neuropeptide Y (NPY) (6).

Orixigenic implies that it stimulates appetite. Which means a reduction in NPY will reduce appetite. This will be important to remember, as in the next article we will discuss appetite suppression, and in the article after that why systemic blockade of the A2AR has proven a poor choice in fat loss.

But NPY apparently does more than just regulate appetite, it exerts a profoundly negative effect on thyrotropin Releasing hormone(7) (TRH). It reduces the amount of TRH secreted from the hypothalamus. TRH in turn stimulates the pituitary to produce thyroid stimulating hormone (TSH or Thyrotropin) and TSH stimulates the thyroid to produce the hormone T4.

T4 is an inactive metabolite that is reduced to T3 in peripheral tissues. T3, the active thyroid hormone is what you call a metabolic regulator. It is known to increase metabolism, thus burning more calories. Use of ephedrine, a stimulator of NE release has shown elevated levels of T3 for up to 12 weeks (8). This is most likely mediated via the reduction in NPY.

So in essence, all the adrenoreceptor exert some type of positive influence on fat loss. Only the BAR's however are uniquely pro-fat loss. The AAR's also exert negative effects. The reduction of these negative effects without compromising the positive effects will be an important part of fat loss supplementation.

Thyroid Hormone

Thyroid Hormone or T3, may also aid in fat loss, eventhough long term caloric restriction lowers T3 levels. So obviously, this is one target for supplementation that will prove a highly synergistic target.

The primary way in which T3 promotes fat loss, is by raising metabolism. That means using more calories to achieve the same. If you recall we discussed something similar in part 1 when we discussed BAT thermogenesis. Well, then it should be of no surprise that T3 predominantly works by increasing levels of uncoupling proteins (UCP's) that uncouple ATP synthesis from mitochondrial oxidation.

The first site of action is obviously UCP1, which is uniquely expressed in BAT and leads to an increase in thermogenesis. There are however two other UCP's, namely UCP2 and UCP3. UCP2 is most widely expressed, and UCP3 is only expressed in BAT and muscle tissue (10). The role of UCP3 is however not quite clear, as it plays no role in thermogenesis (9), bringing into question whether or not it is really an uncoupling protein.

Another method in which T3 increases fat loss is via its metabolite T2. T2 acts directly on the mitochondria to increase their productive ability and thus producing extra ATP, only to end up wasting it. An increase in ATPase activity ensues, thus breaking down the ATP again. A lot of it is wasted on something called 'substrate cycling' as well, which is the process of lipolysis, followed by lipogenesis.

Thus releasing and re-esterifying fatty acids. This creates a futile cycle that wastes ATP. This can be partially useful if the re-esterification can be inhibited. Most of the extra ATP however is wasted by increased heart rate. T2 increases the need for oxygen, so you take up more oxygen which leads to increased cardiovascular pressure to transport all that oxygen to where it is needed (11). BAT, coincidentally, is one of the largest consumers of extra oxygen (12).

T3 Molecule

Closely related to the substrate cycling is the effect T3 has on BAR's. During long term stimulation by ligands, such as NE, phosphorylation and deactivation of the B1AR and B2AR can occur, leading to reduced lipolysis in WAT. T3 can increase the expression of BAR's (13) and increase your beta-adrenergic capacity.

Presumably this has something to do with substrate cycling, since increased BAR's stimulation would lead to more Adenylate Cyclase activity, which is also sort of an ATPase and can waste extra ATP. In this case much to our benefit, as we would be releasing fat.

It may also have to do with increasing thermogenic capacity, since T3 promotes the half-life time of the B3AR, which would further increase UCP1 expression and mitochondrial uncoupling (16)

Somewhat contradictory are T3's effects on insulin and insulin sensitivity. It seems to promote adipogenisis, not only via re-esterification of fatty acids, but also through increased sensitivity to insulin (14,15) . It is therefore wise to couple the manipulation of T3 to the manipulation of insulin sensitivity (cfr part 2).

However, hyperthyroid states generally lead to a reduction of insulin release (17), possibly due to increased apoptosis of the pancreatic beta-cells (18). This would make the effects on insulin roughly status quo I imagine.

T3 is also a Phosphodiesterase inhibitor (21). If you recall from article one, the A1AR stimulation lead to a Ca2+ dependent increase in PDE expression and PDE increased the breakdown of cAMP and the release of the inhibitory factor adenosine. Since T3 can reduce PDE somewhat, NE downregulates its own negative feedback by increasing T3 levels initially.

This same study showed that T3 can prevent Ca2+ dependent proteolysis and possibly spare muscle mass on a diet. This is however highly conflicting information, since T3 is only upregulated at the beginning of a diet, when you are less likely to lose muscle and of course the fact that T3 itself can exert a negative influence on muscle mass retention, since it initiates ubiquitin-proteasome related catabolism (13).

T3 also seems to increase Growth Hormone levels (22). But we will discuss the role of growth hormone in a future article

And then there is of course the question of whether or not T3 reduces A2AR (19,20) density. I'm inclined to believe it does, since increase in thyroid hormone usually leads to an increase in appetite, and it makes sense that T3 has several negative feedback channels, one of them possibly being an increase in NPY through negative regulation of A2AR. This would imply a dual action of T3, both negative and positive to fat loss.

The downside to T3 is that it severely stresses the heart, is catabolic to muscle, increases insulin sensitivity and appetite. These are some things that must be taken into account when trying to manipulate T3 levels in a diet. You want to prevent a drop in T3, but not necessarily increase T3 a whole lot.

Note: This is part three, click here for part two.


We are nearing the end of the theoretical stuff. In the next article I will hopefully manage to wrestle through Growth Hormone, appetite reduction and cortisol. After that we still need to address the effect of the sex hormones (estrogen, testosterone) and go through some data on cytokines and then we have covered, at least in large lines, most of what fat loss is all about, allowing us to move into more practical applications and useful tips after that.

Just a little warning to the lazier readers, none of those things will make much sense to you if you haven't read this article and the previous ones. Like I stated then, reading these may take a little effort, but it will be well worth your while.


  1. Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol. 2003 Dec;17(12):2477-93. Epub 2003 Oct 02.
  2. Peters JM, Aoyama T, Burns AM, Gonzalez FJ. Bezafibrate is a dual ligand for PPARalpha and PPARbeta: studies using null mice. Biochim Biophys Acta. 2003 Jun 10;1632(1-3):80-9.
  3. Kim MJ, Deplewski D, Ciletti N, Michel S, Reichert U, Rosenfield RL. Limited cooperation between peroxisome proliferator-activated receptors and retinoid X receptor agonists in sebocyte growth and development. Mol Genet Metab. 2001 Nov;74(3):362-9.
  4. Axelrod L, Ryan CA, Shaw JL, Kieffer JD, Ausiello DA. Prostacyclin production by isolated rat adipocytes: evidence for cyclic adenosine 3',5'-monophosphate-dependent and independent mechanisms and for a selective effect of insulin. Endocrinology. 1986 Nov;119(5):2233-9.
  5. Hatae T, Wada M, Yokoyama C, Shimonishi M, Tanabe T. Prostacyclin-dependent apoptosis mediated by PPAR delta. J Biol Chem. 2001 Dec 7;276(49):46260-7.
  6. 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.
  7. Sarkar S, Lechan RM. Central administration of neuropeptide Y reduces alpha-melanocyte-stimulating hormone-induced cyclic adenosine 5'-monophosphate response element binding protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology. 2003 Jan;144(1):281-91.
  8. Astrup A, Lundsgaard C, Madsen J, Christensen NJ. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr. 1985 Jul;42(1):83-94.
  9. Teruel T, Hernandez R, Benito M, Lorenzo M. Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38 mitogen-activated protein kinase-dependent manner in fetal primary brown adipocytes. J Biol Chem. 2003 Jan 3;278(1):263-9. Epub 2002 Oct 31.
  10. Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun. 1997 Jun 9;235(1):79-82.
  11. Lanni A, Moreno M, Lombardi A, de Lange P, Goglia F. Control of energy metabolism by iodothyronines. J Endocrinol Invest. 2001 Dec;24(11):897-913.
  12. Ma SW, Foster DO. Redox state of brown adipose tissue as a possible determinant of its blood flow. Can J Physiol Pharmacol 62: 949-956, 1984
  13. Clement K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C, Storey JD, Brown PO, Barsh GS, Langin D. In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res. 2002 Feb;12(2):281-91.
  14. Torrance CJ, Devente JE, Jones JP, Dohm GL. Effects of thyroid hormone on GLUT4 glucose transporter gene expression and NIDDM in rats. Endocrinology. 1997 Mar;138(3):1204-14
  15. Romero R, Casanova B, Pulido N, Suarez AI, Rodriguez E, Rovira A. Stimulation of glucose transport by thyroid hormone in 3T3-L1 adipocytes: increased abundance of GLUT1 and GLUT4 glucose transporter proteins. J Endocrinol. 2000 Feb;164(2):187-95.
  16. el Hadri K, Pairault J, Feve B. Triiodothyronine regulates beta 3-adrenoceptor expression in 3T3-F442A differentiating adipocytes. Eur J Biochem. 1996 Jul 15;239(2):519-25.
  17. Fukuchi M, Shimabukuro M, Shimajiri Y, Oshiro Y, Higa M, Akamine H, Komiya I, Takasu N. Evidence for a deficient pancreatic beta-cell response in a rat model of hyperthyroidism. Life Sci. 2002 Jul 19;71(9):1059-70.
  18. Jorns A, Tiedge M, Lenzen S. Thyroxine induces pancreatic beta cell apoptosis in rats. Diabetologia. 2002 Jun;45(6):851-5. Epub 2002 May 17.
  19. Viguerie N, Millet L, Avizou S, Vidal H, Larrouy D, Langin D. Regulation of human adipocyte gene expression by thyroid hormone. J Clin Endocrinol Metab. 2002 Feb;87(2):630-4.
  20. Richelsen B, Sorensen NS. Alpha 2- and beta-adrenergic receptor binding and action in gluteal adipocytes from patients with hypothyroidism and hyperthyroidism. Metabolism. 1987 Nov;36(11):1031-9.
  21. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Catecholamines inhibit Ca(2+)-dependent proteolysis in rat skeletal muscle through beta(2)-adrenoceptors and cAMP. Am J Physiol Endocrinol Metab. 2001 Sep;281(3):E449-54.
  22. Volpato CB, Nunes MT. Role of thyroid hormone in the control of growth hormone gene expression. Braz J Med Biol Res. 1994 May;27(5):1269-72.