This post may well make heads spin. It sure did mine.
A common claim in LC circles is that we "waste" excess fats through futile cycling. Although this has not been demonstrated in any significant amount in humans except in massive fat overfeeding, it is still incorporated into books and blog posts by the likes of Dr. Mike Eades (futile cycling to "blow off" low carb excesses is stated as if fact in The 6 Week Cure).
Inherent in these statements is the implication that this only happens for excess dietary fat when carbs are low ... insulin would be trapping the fats in the cells as the theories go. Well ...
Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a ‘glucose–fatty acid cycle’ in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:
(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),
(ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently
(iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).
This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a ‘fine-tuning’ mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.
The figure below describes the mechanisms by -- as the figure caption states -- nutrient OVERSUPPLY can lead to insulin resistance.
I like schematics like this because even though I'm scientifically-minded, sometimes reading about various reactions gets really confusing. It helps to just see it. The possible ways all three macronutrients can lead to IR in excess are described:
- The fatty acids are shown in the upper left, with the fats that are "burned" proceeding down the left arrow through ß-oxidation (this metabolic process is often referred to as the fatty-acid spiral). An excess of FA's leads to accumulation of "lipid pools" in the cell: that little cycle in the upper left including DG = diacylglycerol (2 FA's on a glycerol) and FA-CoA. In my posts on lipotoxicity and intramyocellular lipids (IMTG or IMCL), I've discussed the implications of this previously. The metabolites DG and FA-CoA activate various enzymes that inhibit glucose uptake. They also lead to cell dysfunction and/or death when they undergo conversion to ceramides and/or peroxidation (formation of ROS).
- Amino acids, surprisingly, can inhibit insulin mediated glucose uptake through the mTOR pathway.
- Glucose can inhibit its own uptake by glucosamine synthesis and its action.
There are two central molecules in the metabolic engines of the cells: Pyruvate and Acetyl CoA. Pyruvate is an intermediary coming from glycolysis (glucose breakdown) and some amino acids, whereas Acetyl CoA is the ultimate "end product" of the preliminary breakdown of many amino acids, glucose and lipids. From Ac-CoA on, the rest of the "metabolic engine" is the same regardless of the source of this molecule.
- The authors describe a state of gluco-lipotoxicity and/or proteo-lipotoxicity that could develop when excesses in either glucose or AA's or both stimulate the conversion of Acetyl CoA to Malonyl CoA that can suppress fatty acid oxidation leading to a vicious cycle of lipid accumulation in the cellular pools.
Malonyl CoA is usually considered a "commitment step" in de novo lipogenesis - fatty acid synthesis - but has previously been ignored in skeletal muscle as DNL wasn't thought to occur at any significant rate in these cells. This is the groundbreaking revelation of this paper ... it DOES occur! The discussion describes how there are two different enzymes, Acetyl CoA Carboxylases (ACC's) that convert Acetyl to Malonyl CoA. ACC-1 expressed primarily in liver and adipose tissue, and ACC-2 in skeletal muscle and other "non-lipogenic" tissues. The two ACC's are compartmentalized in cells so that:
- ACC-1: Generates the cytoplasmic (cellular) pool of Malonyl CoA used for DNL
- ACC-2: Associated with mitochondria and governs this pool of Malonyl CoA to control ß-oxidation
Excerpt:
In skeletal muscle, the suppressive effect of an elevated concentration of glucose on fatty acid oxidation is now recognized to occur ... but the question of whether a cytoplasmic pool of malonyl-CoA might be utilized for fatty acid synthesis has rarely been invoked most probably because of the long-held assumption that skeletal muscle is not an organ where de novo lipogenesis occurs. ... Consequently, the importance of skeletal muscle substrate metabolism in the homeostatic control of blood glucose has been viewed entirely from the reciprocal nature of interactions between glucose and lipid metabolism. Recent evidence, however, suggests otherwise. As discussed below, de novo lipogenesis can indeed be shown to occur in muscle cells and to be modulated by factors influencing nutritional status, thereby revealing another facet of interactions between glucose and lipid metabolism that shows dependency between these two fuel substrates in skeletal muscle.
Here's where this gets really interesting. The discussion continues:
The recent recognition that de novo lipogenesis might have relevance for lipid homeostasis in skeletal muscle stems from the realization that Sterol regulatory element binding protein-1c (SREBP-1c), a member of the family of transcription factors that regulate the expression of genes involved in lipid storage in liver and adipose tissue, is also present in skeletal muscle at a level close to that observed in the liver,41,42 and that its dysregulation might lead to increased lipid storage, and hence contribute to the pathogenesis of insulin resistance. There is now evidence both in humans and in rodents that SREBP-1c mediates insulin upregulation of genes encoding glycolytic and lipogenic enzymes in skeletal muscle,42–46 but most fascinating are the very recent demonstrations that glucose alone (in the absence of insulin) can stimulate de novo lipogenesis in skeletal muscle cells.
Translation: Lipid storage pathways thought previously to only be active in significant levels in liver/adipose tissues have now been shown to be active in muscle cells. What they are seeing is that the DNL stimulated by glucose in this manner is NOT accompanied by the expected suppression of ß-oxidation. They speculate on possible explanations for this, but the bottom line is summarized:
Whatever the explanation, it is clear that de novo lipogenesis, although low in skeletal muscle, can be markedly stimulated in muscle cells, particularly under conditions of high glucose (and/or high insulin) concentrations.
Hmmmmmm..... The discussion goes on to speculate on the physiological significance for DNL in muscles, and that it may contribute yet another "sink" for temporary glucose excesses (e.g. after a carby meal), particularly when glycogen depots are full. However there's a "glitch" because lipid accumulation is associated with insulin resistance. IOW, synthesizing more would seem counter-productive to glucose clearance/disposal unless the synthesized lipids were also "disposed of". Well here's where the observation that ß-oxidation is not suppressed comes into play.
... recent work from our laboratory investigating the mechanisms by which leptin ... may interact with insulin to stimulate thermogenesis in skeletal muscle, suggests the possible existence of a thermogenic pathway of substrate cycling in which lipids derived from glucose... are subsequently oxidized.
So the carbs are thermogenic, not the fats? Looks like it! The discussion gets a bit complicated because it names enzymes and pathways, etc. I'll let the more scientifically inclined amongst you read that part for yourselves.
My summary of "Substrate cycling between de novo lipogenesis and lipid oxidation"One role of leptin has been demontrated to be it's regulation of thermogenesis. This hormone is recognized as being involved, in conjunction with insulin, in glycemic control and in preventing excessive IMCL accumulation. Leptin has been shown to stimulate both glucose utilization and lipid oxidation. This research group demonstrated that leptin can stimulate thermogenesis by a pathway requiring an enzyme known as P13K, and P13K is stimulated by insulin (insulin is described as a "potent activator" of P13K). Leptin apparently also stimulates AMPK, an enzyme involved in lipid oxidation. Therefore, these researchers have demonstrated a concurrent stimulation of glucose and fatty acid oxidation resulting in thermogenesis, and that evidence is consistent with DNL involved in the thermogenesis - experiments with DNL suppressing agents and leptin demonstrate this as w/o DNL, thermogenesis was not observed. As the authors summarize:
Taken together, these studies suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle could be mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that the orchestration of this substrate cycling requires both PI3K and AMPK signaling.
The discussion continues on the possible control mechanisms for this proposed futile cycle of DNL/ß-oxidation that are likely initiated with Acetyl CoA produced by both glycolysis and fatty acid oxidation "backing up" as it overwhelms the Krebs Cycle. This futile cycle is established in brown adipose tissue. I was surprised to learn that this thermogenesis has pretty much been established to involve DNL from glucose:
... analogous to the relation between substrate metabolism and thermogenesis in brown adipose tissue. In this tissue, whose primary function is to produce heat for thermoregulation ... it has long been known that much of the fuel for thermogenesis also derives from glucose being first converted to lipids before being oxidized.70–73 {They go on to describe mouse studies demonstrating that suppressing DNL in BAT leads to hypothermia.}
Furthermore, this ‘dependency’ interaction between these two substrates and thermogenesis is well recognized at the whole-body level, and is attributed to activation of a neuroendocrine network (comprising insulin, leptin and the sympathoadrenal system), which plays a pivotal role in several overlapping regulatory systems: that of blood glucose, body temperature, body weight and more recently intramyocellular lipids.56–58
... The energy-dissipating substrate cycle that links glucose and lipid metabolism to thermogenesis in skeletal muscle (depicted in Figure 3) provides a novel molecular mechanism of thermogenesis through which this abovementioned neuroendocrine network operating through insulin, leptin and catecholamines overlaps in the regulation of body weight, blood glucose and intramyocellular lipids, and hence in the protection against obesity, hyperglycemia and lipotoxicity.
Take away message here? Well, the futile cycle is lipids. But what stimulates and/or is required for this futile cycle to "waste" energy? Who'da thunk it. CARBS!!!
