An intriguing new study looked at 2 different types of
enteral feeding in 60 critically ill patients for 7 days. The fat-based formula
was 37%E glucose, so this was not a test of a low carb diet, and predictably
the differences in glucose and insulin AUC, though trending in the right
direction, were not significant.[1]
The significant finding was higher resting energy
expenditure (REE) in the higher-fat group.
In my opinion this was not an effect of higher fat feeding
but an effect of a high intake of a particular type of fat – no-one in the real
world would ever eat 45% of energy as fat from rapeseed and sunflower oil exclusively (if nothing else, natural protein foods would supply other fats not found in the protein isolate used here).
“Fat-based EN formulas contain 45% fat, 37% carbohydrates,
18% protein, and 2.3 g of fiber per 100 ml, whereas glucose-based EN formulas
are comprised of 30% fat, 55% carbohydrates, 15% protein, and contain 1.5 g of
fiber per 100 ml. Both formulas have a caloric density of 1 kcal/ml and contain
rape seed oil and sunflower oil. Initial assessment of resting energy expenditure
(REE) was performed for each patient using the technique of indirect
calorimetry. Target energy was 25% above the measured REE [13]. Both study
groups received early EN that was initiated with the target dosage and
continuously administered at a constant rate for 7 days via a nasogastric
tube.”
The diet was very high in monounsaturated and
polyunsaturated fat, and very low in saturated fat.
Unsaturated fats are well-known to activate uncoupling
proteins in the mitochondria of muscle and adipose cells (in brown adipose
tissue, there is good evidence that saturated fats can drive uncoupling; brown
adipose is a highly functional cell type that exists for this sort of thing
rather than storage, so I’m going to ignore it for now).[2,3]
I’m really interested in fuel use by muscle. The big, novel question in physiology today bar none is the lean mass hyper-responder lipid profile discovered by Dave Feldman (@DaveKeto). Because this relates to muscle mass/fat mass (and activity) ratio, and because different fatty acids in people eating normal diets have differential effects on lipid profiles, it’s necessary to know how muscles use fats before we investigate whether this can influence a lipid profile.
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| Effect of fatty acids on D-[U-14C]glucose oxidation in 1h incubated rat soleus (A) and extensor digitorium longus (EDL) (B) muscles. Muscles were incubated for 1 h in the absence or presence of 10 mU/mL insulin and/or 100 μM of different fatty acids. |
Here’s a study on two types of muscle cell isolated from rats
which shows a different effect of saturated vs unsaturated fats in extensor digitorium muscle (the soleus muscle, A, is less clear but I'm going with B for now; however the faster oxidising (medium chain) SFAs in A behave like palmitate in B).[4] To summarise
the findings, unsaturated fats activate uncoupling; that is, a proportion of
the potential energy released by their beta-oxidation is wasted, instead of
generating ATP (the more double bonds, the more uncoupling). And this wastage –
which will produce extra heat - allows the cell to burn extra glucose at the same
time to make up the shortfall in ATP.
This is what is meant by unsaturated fats improving insulin
sensitivity. Glucose and saturated fatty acids are the two preferred fuels of
muscle cells, but they exist in competition. At times of energy excess, they
would be at loggerheads if both were available together without other “softer”
fuels. The effect of unsaturated (uncoupling) fats is to buffer the potentially harmful
effect of this competition, by occupying the beta-oxidation mechanism
(carnitine etc) yet leaving some ADP free for both glucose and SFA catabolism
to convert to ATP. When glucose is restricted, the saturated fat level of the blood
falls, despite a higher intake, because the competing effect of glucose and its
insulin-driven uptake is removed. At this extreme, the buffering effect of
unsaturated fat is unnecessary. At fat intakes below 37%, on the other hand, a
differential effect on insulin sensitivity can more easily be detected, because
glucose is the primary fuel, and insulin is driving SFA synthesis and
retention.
(Thus the low fat diet, especially with refined carbs at current availability, was the very thing that painted us into the corner where there might be some reason to worry about the types of fat we use! Who the hell wants to be in that shithole.)
(Thus the low fat diet, especially with refined carbs at current availability, was the very thing that painted us into the corner where there might be some reason to worry about the types of fat we use! Who the hell wants to be in that shithole.)
Strictly speaking we don’t need to consume unsaturated fats
(beyond tiny EFA amounts of PUFA) because we can make oleic acid MUFA from SFA by DNL
elongation and desaturation, although there is genetic variation in the ability
to do this. Realistically speaking, this separation of SFA from MUFA in the diet is never going to happen anyway. Humans eat fat of all types, not SFA, MUFA or PUFA.
Although linoleic acid was an uncoupling fat in muscle in
vitro, muscle in vivo may not be using much of this fuel. LA has a high rate of
conversion to other lipids (cholesterol and SFA) in liver, is used to make
eicosanoids and is otherwise peroxidizable, and is still stored in adipose in amounts
that seem excessive in proportion to dietary intakes. In practical terms, oleic
acid (C18:1) is probably always the dominant uncoupling fatty acid in muscle,
and the more unsaturated fats (which would uncouple more) are lousy fuels. This might(?) help to explain the prevalence of CPT1A mutations, which suppress fatty acid oxidation on high fat diets, in populations with a high take of fat from oily fish
(Inuit, Faroe Islands, Northern Japan).[5]
There’s another pathway by which UFA protects against
SFA-glucose competition in muscle – in humans, triglyceride synthesis always
requires at least one UFA.[6] So you can’t store any excess of SFA that turns up
in a cell without some UFA; this is also a form of buffering that clears the
track for whichever of the preferred fuels is dominant. Without it, incoming
glucose would drive SFA elongation into excess ceramide, and the cell would be
stuffed.
So in our critically ill population, an enteral diet very
high in unsaturated fats produced a higher REE through uncoupling, and improved
insulin sensitivity non-significantly (the control diet was relatively high in
UFA by normal standards anyway). I’m not sure what the split of muscle vs
adipose and other tissue fuel use would have been for bed-rest REE (I'm only using that study for a kicking-off point here). I’m told
that elevated REE isn’t desirable in the critically ill. Maybe one day a more
sensible enteral formula including, say, beef fat will be tested.
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references
[1] Wewalka M, Drolz A, Seeland B, et al. Different enteral nutrition formulas have no effect on glucose homeostasis but on diet-induced thermogenesis in critically ill medical patients: a randomized controlled trial. European Journal of Clinical Nutrition. 2018;72,496–503
doi:10.1038/s41430-018-0111-4
[2] Graier WF, Trenker M, Malli R. Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3? Cell calcium. 2008;44(1):36-50. doi:10.1016/j.ceca.2008.01.001.
[3] Romestaing C, Piquet M-A, Bedu E, et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutrition & Metabolism. 2007;4:4. doi:10.1186/1743-7075-4-4. LINK
[4] Hirabaraa SM, Silveiraa LR, Alberic LC, et al. Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle. Biochimica et Biophysica Acta (BBA) - Bioenergetics
Volume 1757, Issue 1, January 2006, Pages 57-66. LINK
[5] https://yk-health.org/images/3/36/Arctic-Variant-CPT-1.pdf
[6] Henique C, Mansouri A, Fumey G, et al. Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis. J Biol Chem. 2010;
285, 36818-36827. LINK