From Chef To Chef’s

Heat acclimation & ketogenic diet – Designed By Nature

What does heat acclimation do to ketogenesis or is there any effect of the ketogenic diet on heat acclimation that is different from a more common SAD diet?  

I recently have been exposed to a hot climate and observed some weight loss (sweating, appetite loss, higher cycling mileage, …) and what felt like a reduction in body heat production.  

If you are on a low carb high fat diet like me, does that mean more or perhaps less ketogenesis?  What are the adaptations in the body?  Are these adaptations the same in all tissues or do we see different changes in the organs?

Plenty of questions and probably only a few answers as the research on a ketogenic diet in combination with heat acclimation essentially doesn’t exist.  If you are interested and looking for a thesis subject.. You’ll be the first to step in!

I’ll see how far I get but have to puzzle together some pieces.  Therefore, keep in mind it should be regarded as speculative until some robust research is in place to confirm any of this.

Research has indicated that heat shock protein 90 (HSP90) stabilizes and augments HIF-1alpha (HIF1a).  HIF1a is sensitive to oxygen and is known to increase its activity under hypoxic conditions but heat also activates it thanks to HSP90.

What is unclear is the level at which that is occuring when you compare the two.  If I could make a guess, HSP90 would have a mild but more systemic wide effect while hypoxia would be more strongly but hopefully also in a very limited area.  We can’t live in a hypoxic place so systemic hypoxia will lead to death rapidly.

“Heat-shock-protein 90 protects from downregulation of HIF-1α in calcineurin-induced myocardial hypertrophy” 

“Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis” 

“A Novel Mechanism for Cross-Adaptation between Heat and Altitude Acclimation: The Role of Heat Shock Protein 90” 

There are a number of adaptations triggered by HIF1a showing us why it is beneficial.  Some of which we’ll see below.

Increased glucose uptake

One of HIF1a stabilization effects, under hypoxia, is that it increases GLUT1 translocation to the cell membrane so that more glucose can be absorbed.

“Hypoxia induces the translocation of glucose transporter 1 to the plasma membrane in vascular endothelial cells”

More glucose could be important to support the move towards anaerobic glycolysis as you’ll see under “Energy efficiency”.


Another downstream effect is that HIF1a helps to improve vascularization.  

“Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodeling” 

This could be particularly useful because in hot climates, the heat needs to be transferred out of our body.  By increasing vascularization, more heat can be picked up via the blood and flow towards the skin for cooling when we are sweating.

Energy efficiency

Under normoxic conditions, HIF1a drives towards an ATP production away from mitochondria.

HIF-1α-dependent metabolic reprogramming directs glucose away from synthetic pathways, allowing the cell to decrease its ATP consumption, and into anaerobic glycolysis to increase ATP production.

The ability of HIF-1α to suppress normoxic cell growth and proliferation at first seems paradoxical.

Paradoxical because under hypoxia we see it associated with cancer cell proliferation.

“The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis”

Energy that is created via the mitochondria results in heat production via the electron transport chain (ETC) when oxygen atoms are bound with hydrogen protons to form H2O (water) in complex IV of the ETC.  

Reducing electrons passing via the ETC thus reduces heat production.

HIF1a also inactivates pyruvate dehydrogenase.  This means that glucose-turned-pyruvate does not further follow the path towards ATP production in the mitochondria.  

HIF-1 activates the gene encoding pyruvate dehydrogenase (PDH) kinase 1 (PDK1), which phosphorylates and inactivates the catalytic subunit of PDH, the enzyme that converts pyruvate to acetyl coenzyme A (AcCoA) for entry into the mitochondrial tricarboxylic acid (TCA) cycle [25].

“Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning”

So there is a drive away from the mitochondria as a place where ATP is produced.  There is also a modulation to improve the ETC efficiency in complex IV.

HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV

“Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning”


Instead it activates lactate dehydrogenase, increasing pyruvate-to-lactate or anaerobic ATP production via translation of the ldha gene.

We have now analyzed in greater detail the regulation of ALDA and ENO1 transcription in hypoxic cells, identified novel HIF-1 binding sites in the ALDA, ENO1, and Ldha genes, correlated HIF-1 binding with transcriptional activation, and demonstrated transcriptional activation in non-hypoxic cells by forced expression of HIF-1α. These studies provide further evidence for the coordinate regulation of genes encoding glycolytic enzymes by HIF-1 and demonstrate that the presence of a HIF-1 binding site is necessary but not sufficient to direct hypoxia inducible transcription.

“Hypoxia Response Elements in the Aldolase A, Enolase 1, and Lactate Dehydrogenase A Gene Promoters Contain Essential Binding Sites for Hypoxia-inducible Factor 1”


Although I’m curious about what it does when on a ketogenic diet, I’ll have to stick to high carb habituated subjects.

With the above noted increase in efficiency we can expect this to be reflected in exercise performance.

“Heat acclimation improves exercise performance”

Some more details on the metabolism in skeletal muscle during exercise is puzzling to me.

On one hand it shows adaptation in glycogen.  After heat acclimation, we see a reduction in glycogen use.  That could testify for the increase in efficiency but it could also indicate that less lactate is produced.  These are not exclusive from each other though.

One should also be careful with these numbers because other research has shown that as the glycogen levels decline, so does its breakdown.  It is unfortunate that they didn’t all start with close to identical glycogen before exercise.  And perhaps their starting glycogen content is a sign of the adaptation?  We don’t know.

When we look at the muscle lactate concentration, I can’t tell if the reduction is meaningful in the rested state but during exercise we see a great reduction in lactate production during heat acclimated exercise.  The result of the more efficient mitochondrial energy production?

The muscle lactate concentration also translated well to plasma lactate levels.

“Skeletal muscle metabolism during exercise is influenced by heat acclimation”

Contrary to the observed lower glycogen pre exercise in our human subjects, under controlled conditions in rats we do find a higher buildup of glycogen.  And with an interesting remark where they recognise this as an effect of heat acclimation through HIF1a:

Furthermore, the increase in glycogen storage observed after HA combined with endurance training, without the improvement of pyruvate oxidation, appears to be a hypoxic metabolic phenotype.

4.6. Heat‐induced hypoxia‐like adaptations of metabolism

The increase of muscle glycogen content not associated with a proportional elevation of pyruvate oxidation appears to be similar to a metabolic phenotype previously described for hypoxia (Aragonés et al., 2008; Papandreou et al., 2006) and glycolytic pathway (Semenza, 2012).

This does not mean that hypoxic stimulus is responsible for the alteration observed after heat acclimation, even some cellular argument could support the participation of hypoxia‐inducible factor (HIF) in response to cellular protection induced by heat (Liu et al., 2007; Liu & Semenza, 2007). The interaction between heat acclimation and endurance training for complex IV protein content we found here, may support this hypothesis because this respiratory complex is particularly sensitive to hypoxia and changes in its isoforms have been well described through the activation of HIF‐dependant pathways (Desplanches et al., 2014; Fukuda et al., 2007).

“Effect of heat acclimation on metabolic adaptations induced by endurance training in soleus rat muscle” 

Beta-hydroxybutyrate (BHB) is processed by the enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) to convert it towards acetyl-coa so that it can serve as an energy substrate in the TCA cycle.

Researching on the ketones, I found that BHB reduces HIF1a stability.  That is the case in response to hypoxia but I can’t tell whether this is also the case when HSP90 is involved and under normoxic conditions.  Does it override the actions of BHB, does BHB enhance the effect of HSP90, is BHB neutral in effect under normoxia?  No answers to date.

This question is important as we also find that potentially a higher availability can lead to less usage of BHB as a fuel.

Elevated blood glucose (type 1 diabetes mellitus and high‐fat diet mice) was associated with reduced cardiac expression of β‐hydroxybutyrate‐dehydrogenase and succinyl‐CoA:3‐oxoacid CoA transferase. Increased myocardial β‐hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and β‐hydroxybutyrate oxidation. Moreover, elevated cardiac protein O‐GlcNAcylation (a glucose‐derived posttranslational modification) by dominant negative O‐GlcNAcase suppressed β‐hydroxybutyrate dehydrogenase expression.

“Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization” 


HIF1a doesn’t play a role in insulin but insulin plays a big role in the release of fatty acids.  We see that in a study of obese PCOS patients, heat treatment improved fasting insulin and adipose insulin sensitivity.  Is this the result of pushing more glucose through the anaerobic pathway?  If anything, we noticed a lower muscle lactate pre exercise and higher muscle glycogen in the animal study.  So where is the increased sensitivity coming from?  Is more of their stored fat used for energy?

“Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome”

The brain is very complex at sensing and adapting.  In order to reduce insulin there must be some reduction in one or a combination of glucose, lactate, (certain) amino acids, BHB (to keep it simple).

This in vitro study implies that heat acclimation also results in mitochondrial biogenesis which must be the result of low ATP production.  This could be the result of shunting glucose away from oxidation to glycolysis.

It would also help explain the increased insulin sensitivity as more fatty acids will have to be metabolized to generate sufficient ATP.

“Heat acclimation increases mitochondrial respiration capacity of C2C12 myotubes and protects against LPS-mediated energy deficit”

Homeostasis will be restored but it could explain sluggish behavior the first couple of days when hitting hot weather.  Simply because of lowered ATP production, until you are adapted.

We’ll need to be careful with our interpretation from rat studies but I could not find a human-equivalent study.  However, the study is worth it because it shows the adaptation over time.  As they summarized it themselves:

The time-dependent changes of duration of heat acclimation could be summarized in three phases: short-term heat exposure (1 to 24 h) with intensive glycogenolysis and gluconeogenesis to glucose; a period with temporary changes (24 h to 7 d) with tendency of normalization to control level, and prolonged heat acclimation (7 d to 60 d), which favors both direct and indirect glycogen synthesis.

“Changes in carbohydrate metabolism during acclimation to a moderate hyperthermic environment in rats” 

It gives me the impression that the adaptation effect from HIF1a is quick but the rest follows slowly.  It would be fitting that ATP levels fall and thus more glucose is consumed, until the mitochondrial biogenesis has catched up and helps preserve more glucose.

That means in this short early adaptation phase we should see higher lactate production.  Our exercise paper non-acclimated subjects in hot conditions show that higher lactate production.

This deserves specific attention because when you are on a ketogenic diet, the brain has increased ketone utilization while the rest of the body has increased fat utilization.  The effects of fat and ketones are not the same in metabolism and in actions.

The ketone body beta-hydroxybutyrate, in the brain, actually stimulates stabilization of HIF1a.  But this is presumably under normoxic, non-heat acclimated conditions.

“Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1” 

It tells us we have to be careful with interpretation and certainly consider different effects depending on the organ.

We do note HSP90 at high levels in the rabbit brain and also rat brain where it has been studied much more and shows a complex involvement in brain development.  It probably plays this important role in interaction with HIF1a so it is difficult to extract a specific modulation of BHB in response to heat acclimation.

“Expression of heat shock protein 90 (hsp90) in neural and nonneural tissues of the control and hyperthermic rabbit”

“Heat Shock Proteins Regulatory Role in Neurodevelopment” 

In the rat brain we do see an increase in HIF1a in response to heat acclimation.  The question remains, what if we throw BHB into the mix?  Given the first link in this chapter I would expect BHB will only enhance this effect.

“Heat acclimation increases hypoxia-inducible factor 1alpha and erythropoietin receptor expression: implication for neuroprotection after closed head injury in mice” 

In the brain we can also find that HSP70 is increased in response to heat.  In fact there are several heat shock protein to which we should be mindful of as they can all have some yet undiscovered interactions.

“Heat acclimation increases the basal HSP72 level and alters its production dynamics during heat stress” 

The evidence so far points us to stabilization of HIF1a in the brain by both BHB and HSP’s.  Perhaps it is less relevant what BHB does in the rest of the body because most of BHB will be reserved for the brain while the rest has increased fatty acid metabolism.

My first question with this finding is if this is only happening in the skeletal muscle?  This is the biggest heat generating tissue.  And being on a ketogenic diet, does this further lower blood glucose?  Does that mean lower insulin and therefore an even higher fat lipolysis?  If so, what happens to the fat because the skeletal muscles are using more glucose, thus less fat?, for energy?

There’s a general rule that the higher the surface area versus the volume, the more heat dissipation you can get.  By reducing our fat mass we decrease our volume thus increasing the ratio surface area/volume and thus easier release of heat.

By driving more glucose down the lactate pathway, the ATP yield per glucose molecule is much lower than via the mitochondrial ATP production.  Although ATP production is faster, does it equal the production rate?  If not then it has to be compensated by fatty acid metabolism.  So does it mean lower insulin and even greater release of circulating fatty acids and therefore potentially a higher ketone production?

Such studies still need to be done but we can see that on a high carb diet, there is a greater reliance on fat for fuel.  A big difference with a more temperate climate is that in the heat, glucose is pushed away in favor of more fat metabolism while at the same time reducing heat production.


The thyroid hormones also regulate the speed at which the cells work but a first search doesn’t provide much clarity.  It shows equal levels of T4 and T3, yet the disappearance rate is higher under cold conditions.  Is that an indication of slower metabolism?


It seems like a convenient way of reducing heat production and further adapting to maximize cooling possibilities while at the same time minimizing water loss.


Lowered insulin would then align with greater fat lipolysis.  As glucose is pushed away from the mitochondria, we’ll likely have more of the ATP produced from fatty acids.  This is another great survival advantage because fat oxidation produces water thus metabolizing more fatty acids generates more water.


Hot climates require more water but also high altitude and cold, arctic climates can be very dry.  A camel makes use of this concept by storing fat in its hump and then metabolize the fat in it for a supply of water (and energy).

“Metabolic Water and the Camel’s Hump” 

Still a lot of questions remain but I hope you appreciate the complexity.  Organ specific adaptations are not clear.  Ketones seem to stimulate HIF1a under normoxia and block HIF1a under hypoxia.  HIF1a blocks BHB as a fuel etc.

For sure the brain needs to regulate its heat exposure in a hot climate.  Our skull is a well isolated sphere that can heat up easily if not for all the adaptations.  We can suspect some mechanisms in the brain may assist in reduced heat production as we’ve seen by increased ATP production efficiency cascaded to HIF1a stability supported by HSP’s and BHB.

The bony and soft tissue anatomical features covering the brain—meninges, skull, scalp and hair -have different thermal properties shielding the brain from thermal challenges, collectively maintaining temperature homeostasis and providing a means of buffering the superficial cortical regions from extreme temperature changes. When surgically exposed, the cerebral cortex may have temperatures that drop 5–10°C below core body temperatures (Gorbach et al., 2003; Kalmbach and Waters, 2012). This change is especially notable when a large piece of skull is removed, often performed to relieve intracranial pressure after brain injury, thus increasing the brain’s thermal susceptibility to the external environment (Nakagawa et al., 2011; Suehiro et al., 2011).

“Thermal Regulation of the Brain—An Anatomical and Physiological Review for Clinical Neuroscientists”

In the 8 days that I have spent in 35°c Spain, I found I adapted in just a few days to tolerate the heat much more and didn’t experience any fatigue.  Subjective and not data driven but I have the impression that being on a low carb high fat diet doesn’t seem to cause any issues in the heat.  Perhaps the adaptation process goes quicker because of how the diet makes me more sensitive to insulin or because of my exercise level or both?

Feel free to write down your own experience in the comment section.

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