The Physiology Of Fat Loss Part 2!

I hope you have had the time to reread the first article and comprehend it fully before starting here. This time around we will discuss insulin resistance and how it works to our advantage.
Note: This is part two, click here for part one.

I hope you have had the time to reread the first article and comprehend it fully before starting here. This article will be considerably simpler to understand than the previous one, but only truly so if you fully comprehend the first article. This time around we will discuss insulin resistance and how it works to our advantage in various ways, as well as the manipulation of the first of the PPAR's, PPARgamma, which I consider to be a vital part in proper fat loss.

Understanding The Relevance Of Insulin Resistance In Fat Cells

There are a lot of misconceptions about the relevance of insulin resistance. Some people believe that increased insulin sensitivity is a valid approach to fat loss. This originates largely from the idea that obesity is often the cause of extreme insulin insensitivity. Therefore in these people, and increase in insulin sensitivity will lead to repartitioning of nutrients and may actually cause a reduction in body-fat.

Most who read this however, I take it, are not exactly obese. In normal people insulin is the primary adipogenic (fat building) hormone. Therefor a reduction in insulin, and sensitivity of cells to insulin, is a positive thing for fat loss. Any fat loss preparation that contains insulin sensitizing agents is therefore not suited if your goal is to get really ripped. Products like ALA and r-ALA, free form L-taurine, D-Pinitol and the like are therefore absolute scams if they are being sold for fat loss purposes.

Insulin activates several enzymes needed for fat gain, such as Fatty acid synthase (FAS) etc. It also increases glycogen stores. While this is a good thing for performance, it is a negative aspect for fat loss. When norepinephrine (NE, cfr part1) is released it will begin by acting as a glycolytic agent, that means it turns glycogen back to glucose. At this point that means the metabolically active cells are still using glucose since it is readily available, instead of burning fat.

I won't discuss this in detail, as we will revisit this aspect in the third instalment, but when glucose becomes low, ATP:AMP ratio (energy balance) drops and that activates AMPK, a Kinase that tells the mitochondria to burn fat for energy instead of glucose. At this point the FFA's produced by WAT (cfr part 1) can be burned).

Most bodybuilders are already aware of this, since they will not only lower calories during a diet, but lower mainly carbohydrates from the diet. This is because carbohydrates increase blood glucose and blood glucose elevates insulin. So in essence you already know that less insulin equals more fat loss.

What is however important to understand is that a reduction in insulin signalling means a reduction in protein synthesis, and thus, later in the diet, a greater chance of muscle loss as body-fat gets lower. We must therefore distinguish between insulin resistance in the fat cell and insulin resistance in the muscle cell. Both will promote fat loss.

But if we can promote insulin resistance in the fat cell without promoting it in the muscle cell, we may take a little longer to lose body-fat, but we might spare more muscle. The reason insulin insensitivity in muscle helps fat loss is the storage of glycogen. This would however not be a major factor when dieting with low calories and low carbs. First of all there wouldn't be much glucose to store as glycogen, and secondly the low glucose level would keep insulin levels down as well.

Norepinephrine Inhibits Insulin Release

From part 1 of this article series, it should already become clear that increasing the release of NE will be crucial in stimulating maximal fat loss. And we haven't even discussed its effects on muscle retention yet.

Well, NE may play multiple roles in this process via its inhibition of insulin. When NE release is increased, NE is also released near the beta cells in the pancreas, responsible for secretion of insulin, and inhibits the release of insulin. So again, insulin becomes less of a factor in fat loss.

Interleukin-6 Is Perhaps The Best Target

Another way in which NE aids in this aspect is by stimulating the release of Interleukin-6 (IL6). The release occurs through both PKA and Ca2+ (2) and is thus likely mediated by Src, possibly through its activation of one or more Mitogen activated protein Kinases (MAPK). IL6 is a particularly interesting target as well, because it seems to increase insulin sensitivity in muscle tissue, while it inhibits insulin sensitivity in adipose tissue (1).

In the fat cell an increase in IL6 will primarily result in a reduction of the cytokine adiponectin(4). Adiponectin is known to improve insulin sensitivity. So by inhibiting its release, IL6 makes the fat cell less sensitive to insulin.

At the same time it seems to activate the Supressor of Cytokine Signalling (SOCS3), also activated by insulin itself, which would reduce insulin sensitivity. This is one of the negative feedback signals for insulin signalling as well. Combined a fat cell would experience an immense reduction in sensitivity to insulin.

This becomes evident in the reduced expression of mediators of insulin-related fat gain, such as Fatty Acid Synthase (FAS) and acetyl-CoA carboxylase, and of the transcription factors C/EPBalpha and PPARgamma (which will be discussed at length later on). IL6 is therefore one of the most promising targets in both fat loss and muscle gain. This is also supported by the fact that IL6 is upregulated by physical activity, improving muscle gain and glucose disposal in muscle, while reducing fat gain in fat cells by opposite mechanisms.

Norepinephrine May Reduce Insulin Sensitivity Via AMPK

As we saw in part one, and earlier in part 2, a negative energy balance leads to activation of AMPK. Increase NE will definitely lead to increase in AMPK activation. First of all the activation of Adenylate Cyclase (AC) via the BAR's will lead to ATP being broken down to make cAMP.

Secondly, via the A1AR and its second messenger, Ca2+, we experience an increase in PDE's that breakdown cAMP to AMP, further lowering the ATP:AMP balance. Whether or not activation of AMPK leads to insulin resistance is not entirely sure, but a number of insulin's adipogenic markers are definitely reduced during AMPK activation (5).

There is no established link between AMPK and IL6 (6), so they regulate their effects independently of each other and may be additive in their effects.

What Is PPARgamma?

PPARgamma stands for peroxisome proliferator activated receptor gamma. There are three PPAR's, nuclear receptors, that all modulate fat homeostasis. However the other two, the alpha and beta receptor, have a positive effect on fat loss, predominantly via effects on liver and muscle respectively, improving the oxidation of fatty acids. PPARgamma on the other hand is a negative regulator of fat loss (7).

It is a key factor in adipocyte (fat cell) differentiation, or if you will, the recruitment of more adipocytes. It also increases the synthesis of fatty acids and the uptake and storage of glucose (9) and downregulates the B3AR (8). And if you remember the inhibitory role of perilipin on lipolysis from the previous article, well PPARgamma increases perilipin (3). Inhibiting PPARgamma is therefore a valid, and not often enough explored, pathway for increasing fat loss.

In fat cells, a reduction in PPARgamma would reduce adipogenesis drastically, thus allowing for more fat loss and less fat gain. The role of PPARgamma in fat gain is easily demonstrated, as bodybuilders have in the past (and still do) used PPARgamma agonists like metformin, with as a result an enormous amount of fat gain over a short period of time.

Because PPARgamma plays a role in increasing insulin sensitivity, they assumed it would mimic the effects of insulin. As we saw at the beginning of part 2 however, for a non-obese, non-diabetic person, such methods are not well suited for fat loss and may have, obviously, the opposite effects.

In fat cells there are multiple mechanisms to reduce PPARgamma. Most of them likely related to a reduction in insulin sensitivity. IL6 for instance, lowers PPARgamma expression, and it has even been postulated that this is the manner in which it lowers adiponectin. Likewise, AMPK will reduce PPARgamma as well, independent of IL6. Manipulation of IL6 and AMPK is however not the end all of PPARgamma downregulation. We can also supplement with specific antagonists of the receptor. Which is something we will definitely discuss in later instalments of this series.

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


I hope you are able to keep up so far. I know I'm not making it easy on you, asking you to take in this much, but admit, it was easier to comprehend than the previous article. Especially if you digested the previous article correctly. But don't let that fool you, its going to get a lot tougher next time, as we discuss the oxidation of fats, the other two PPAR's and thyroid hormone.


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  2. Neal JW, Clipstone NA. Calcineurin mediates the calcium-dependent inhibition of adipocyte differentiation in 3T3-L1 cells. J Biol Chem. 2002 Dec 20;277(51):49776-81. Epub 2002 Sep 25.
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