The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner

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!e Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a
Fat Burner
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The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a “Fat
Burner”
Introduction
Low carbohydrate dieting (low carb) is popular in the paleo and ancestral diet
communities. The scientific literature on the merits of this diet, however, remains
contested. Examples of clinical studies showing benefits for weight loss [1] and
metabolic syndrome [2] are easy to find. Likewise, studies showing negative effects,
such as on exercise performance [3], also continue to be published as valid
criticisms of claims made by the diet’s adherents. A meta-analysis of weight loss
trials suggests that low carb dieting is as or more effective than low-fat for up to one
year, at which point results converge [4]. Most clinical studies do not extend to one
year, let alone the decade or more that would constitute evidence of long term
effects. Furthermore, even if a low carb diet does produce more rapid weight loss
than other dieting regimens, it does not necessarily follow that it is healthy; several
unhealthy states can cause weight loss.
These points underpin the faulty approach of using clinical studies to answer the
question of whether low carb is “good” or “bad.” This reduces the debate to a back
and forth of dueling studies. Rather than argue a side with macro-level data, I will
present a discussion on the physiology of the metabolic state achieved from a low
carb diet. The discussion is in three parts, 1) acquisition of a fat-burning
metabolism, 2) the long-term physiology associated with this state and 3) health
implications specific to the polyunsaturated fatty acids (PUFA).
1) Entering the fat-burning state
The biochemical processes that mobilize stored and dietary fat for use as energy
substrate are initiated due to a depletion of blood glucose. The key hormonal
switches involved, adrenal glucocorticoids [5] and catecholamines [6], are secreted
as a hypoglycemic response. These hormones are also secreted in response to
fasting [7]. Unlike the reciprocity seen in the control of glucose usage by insulin [8],
which is secreted as a reaction to glucose, the hormones that control fatty acid
utilization are regulated by glucose, not fatty acids. This, in addition to the similarity
of the hormone profile between starvation/fasting and consuming a ketogenic, very
low carb diet, suggests that glucose sparing and reliance on fat as a primary energy
source is the emergency, not the homeostatic, program for humans.
Another point of evidence for this view is that protein, both dietary [9] and tissue
[10], is catabolized for production of glucose during hypoglycemia. This source of
glucose is sufficient to prevent ketosis during carbohydrate restriction, provided a
high enough protein intake [11]. For non-ketotic low carb dieting, this energy
substrate production may account for much of the observed weight loss; the process
of gluconeogenesis from amino acids costs approximately 33% of the energy
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Mamounis: The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner
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obtained in the oxidation of the resulting glucose [12]. Additionally,if the saturable
urea system [13] is overwhelmed by amino acid derived ammonia, symptoms of
hyperammonemia, or “rabbit starvation,” follow [14]. Even at a subclinical level,
greater ammonia is a burden on kidney nephrons [15,16].
2) The long-term physiology associated with fat burning
Once a fat burning state is achieved, loosely defined hormonally as lower insulin and
higher glucagon, cortisol and catecholamines, other changes begin to assert
themselves that integrate into the overall low-level stress state. One of these
changes is a depression of the respiratory quotient, as less carbon dioxide (CO2) is
produced from using fat for fuel relative to using carbohydrate. Hormones of
metabolic control are affected at the level of production and action.
CO2
It is often taught that CO2 is a by-product, or even a waste product, of cellular
respiration. Although it is true that CO2 is largely exhaled in the breath, and that
inhaling pure CO2 is lethal, it does not follow that CO2 is physiologically
unnecessary or without benefit. At the molecular level, CO2 is necessary for
respiration through its displacement of O2 on hemoglobin [17]. At the tissue level,
CO2 relaxes the smooth muscle around vessels, allowing for dilation [18]. In
hypocapnic (low blood CO2) conditions, the nitric oxide system, which inhibits
respiratory enzymes [19], is mobilized to ensure dilation [20].
These effects are characteristic of acute clinical hypocapnia, but subclinical capnic
differences have physiological effects as well. During sleep, for example,
hypercapnia increases neuronal oxygenation [21]. Additionally, the rate of Vitamin
K dependent carboxylation reactions is determined by CO2 concentration [22].
Furthermore, abundant intra and extracellular CO2 is protective for proteins and
lipids susceptible to oxidation. The relatively unreactive oxygen in CO2 transiently
associates with amide bonds in proteins, which in sufficient concentrations crowds
out reactive oxygen and lowers peroxidation [23,24]. Lastly, CO2 exiting the cell
takes with it H2O through a dynamic equilibrium with H2CO3 in aqueous solution
[25], lowering cellular bulk water. By removing bulk water, the stoichiometric
equilibrium of ADP and ATP is pushed towards ATP. This function of CO2
production may play a large part in the insufficiently explained large increase in
ATP synthesis of eukaryotic over prokaryotic enzyme systems, as the motive force
of a mitochondrial proton gradient is untenable [26]. It can be concluded that within
physiological levels, higher CO2 has benefits, and a higher ratio of carbohydrate to
fat being oxidized for fuel yields greater CO2.
Thyroid Hormone
A molecule inextricably related to cellular CO2 production is thyroid hormone
(triiodothyronine, T3). T3 is required to produce, among other things, the sex
steroids [27] and vitamin A from beta-carotene [28]. Metabolic rate and T3 levels
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are nearly synonymous, and exert long-term control of heart rate [29] and heat
production [30]. During metabolic dysregulation, or acute stress, epinephrine and
norepinephrine become more involved in heart rate [31] and body temperature
[32], in a similar phenomenon to energy substrate mobilization during stress
described above. Despite the name of the thyroid gland, most of the body’s T3 is
produced in the liver by converting the prohormone tyrosine to T3. This production
is dependent on liver glucose and glycogen [33] and enhanced through an insulin-
suppressive action on paraventricular neuropeptide y secretion [34]. Additionally,
hypoglycemia-induced glucocorticoids oppose T3 production [35]. Clinically, a
calorie restricted, low carb diet causes a similar depression of T3 as starvation,
which is not seen in calorie restricted carbohydrate feeding [36]. Thus a low
carbohydrate diet appears to be a T3 suppressive diet.
Insulin Resistance
One of the more understood areas of macronutrient physiology is the Randle Cycle,
or substrate competition between glucose and fatty acids. At the cellular level, high
concentrations of malonyl-CoA from glucose metabolism inhibit the carnitine
palmitoyl transferase (CPT) system that shuttles fatty acids towards beta-oxidation.
Alternately, high concentrations of acetyl-CoA and citrate from beta-oxidation
inhibit the pyruvate dehydrogenase complex (PDHC) that shuttles glucose
metabolites towards the Citric Acid Cycle [37]. Thus, there is a tendency to continue
using the fuel already in use.
This addresses the misunderstood issue of treating hyperglycemia/insulin
resistance/metabolic syndrome by reducing or removing carbohydrate intake.
During high-fat diet, total and oxidative glucose disposal is impaired, and
pharmacological blockade of fatty acid oxidation reverses this [38]. The reduction of
glycemia seen in low carb dieting is not a sign of increased insulin sensitivity, but
simply a removal of the challenge. An analogy is the removal of dairy from the
lactose intolerants diet; the reduction seen in their symptoms does not reflect an
improvement in their ability to handle dairy. A sign of metabolic health is flexibility
of use between glucose and fat [39], but even in healthy subjects a fatty acid infusion
reduces glucose disposal [40]. Fatty acid oxidation is synonymous with some degree
of glucose intolerance.
Not all fatty acids participate in this effect to the same degree. Inhibition of glucose
metabolism increases with chain length and degree of unsaturation of fatty acids
[41]. This effect is therefore strongest with PUFA.
3) Health implications specific to the polyunsaturated fatty acids (PUFA)
Breakdown Products and Metabolites
In addition to the issues of dietary fat discussed above, PUFA carry the danger of
diverse, damaging metabolites. Non-enzymatically, PUFA can be oxidized into
peroxides and aldehydes that are likely a key factor in atherosclerotic plaque
formation [42,43], as well as damage to cellular contents, such as membrane lipids
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like mitochondria [44]. Enzymatically, lipooxygenases and peroxidases produce
eicosanoids from PUFA, many of which have been shown to have inflammatory
effects [45]. The prostaglandins, thromboxanes, and leukotrienes produced from n-3
PUFA are generally considered anti-inflammatory compared to those produced from
n-6 PUFA [46]. This anti-inflammatory categorization based on immune activity
assays is an example of another action unique to PUFA, that of enzymatic inhibition.
Proteolytic Inhibition
Most of the endocrine activity ascribed to PUFA centers around metabolites, but
several purported receptors are hypothesized to accept native PUFA as ligands and
alter cell function [47,48]. PUFA alone, for example, can lower circulating LDL [49]
and, in the case of n-3, reduce systemic inflammation [50]. How do they accomplish
these actions? Conceptually, there are two ways to reduce inflammation, one being
to remove the source, as when taking an antibiotic to clear an infection, the second
being to inhibit the action of immune cells, reducing markers of inflammation
absent addressing the cause. Some evidence points to PUFA working via the latter
mechanism.
The LDL lowering effects of PUFA could be caused by inhibition of the proteolytic
cleavage of sterol regulatory element-binding protein-1 (SREBP-1) from the
cytosolic matrix [51], a similar phenomenon to Tuberculosis bacilli-derived PUFA
inhibition of tryptic digestion [52]. The glucuronosyltransferase enzyme, a drug
clearance system in the liver, is similarly inhibited in the presence of PUFA [53]. In
nature, the most abundant source of PUFA, plant seeds, lay dormant until
germination is activated in part by decoupling stored PUFA from their enzymes
through water driven H2O2 production [55]. The other significant natural source of
PUFA is cold-water fish. These fish use PUFA in order to maintain low viscosity in
temperatures approaching the freezing point of water, consequently adapting very
low metabolic rates [56].
Plant seeds and cold-water fish have very different metabolisms and physiological
needs than mammals. The suppressive actions of PUFA may explain why one of the
symptoms of so-called essential fatty acid deficiency is a 25-30% increase in the
basal metabolic rate [57]. Thyroid hormone, discussed above as the master
metabolic regulator, is blocked at the production [58], transport [59], and cellular
action [60] steps by PUFA. If fat, in the context of mammalian systems, is a storage
fuel to be used during emergencies, PUFA is an agent by which that system is slowed
for preservation over the course of the emergency.
Conclusion
Liberated fatty acids in general, and PUFA in specific, slow the cellular processes of
high metabolic rate organisms. Evidence for the effects on thyroid hormone, CO2,
insulin action, etc. is here presented, but ultimately “good“ or “bad” vis a vis low carb
can only be decided through perspective. Many believe that slowing down the
metabolic rate can extend life by reducing wear on the body. This perspective is
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DOI: 10.15310/2334-3591.1048

exemplified in the caloric restriction community. Others believe that the reduction
in metabolic rate during aging is a harbinger of decline to be opposed. This could be
called the metabolic hypothesis. It is also argued that acute stress and even
inflammation is adaptive and beneficial to long-term health. Intermittent fasting
puts those ideas into practice. Again, an opposing school of thought advises to eat
many small meals throughout the day to avoid the stress response of fasting and
support homeostasis.
This article, and the talk it drew from, is an attempt to ground discussion in the first
principles of physiology. It is an interesting aspect of the low carb debate that some
of the very same phenomena, or perhaps the connotative definitions of them, are
seen as good by one side and bad by the other. This shows the futility of the dueling
studies approach to debate, as nearly every diet and health paradigm has literature
to support it. A lens of perspective must be rigorously applied to this literature and
to the claims of its proponents.
Ultimately, health is determined by outcomes rather than inputs, and an agreed-
upon definition is required for discussion. I suggest Dr. Michel Accad’s praxeological
definition of health “as the state that is present when one's physical and mental
conditions allow the pursuit of one's chosen ends,” as opposed to the current
medical one of “body as machine” that either does or does not currently present
defects. Starting from a place of clarity, and moving through evidence with
precision, correct conclusions are more likely to be arrived at than through the back
and forth “gotcha” of the presentation of insufficiently examined information.
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Mamounis: The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner
Published by Journal of Evolution and Health, 2017