The major determinant of whether the liver will produce ketone bodies is the amount of liver glycogen present (8). The primary role of liver glycogen is to maintain normal blood glucose levels. When dietary carbohydrates are removed from the diet and blood glucose falls, glucagon signals the liver to break down its glycogen stores to glucose which is released into the bloodstream. After approximately 12-16 hours, depending on activity, liver glycogen is almost completely depleted. At this time, ketogenesis increases rapidly. In fact, after liver glycogen is depleted, the availability of FFA will determine the rate of ketone production. (12)
At day 29 of the study, animals were euthanized and brain, lungs, liver, kidneys, spleen and heart were harvested and weighed. Organ weights were normalized to body weight. Ketone supplementation did not significantly change brain, lung, kidney, or heart weights compared to controls (Fig. 5a, b, d, f). MCT supplemented animals had significantly larger livers compared to their body weight (p < 0.05) (Fig. 5c). Ketone supplements BMS + MCT, MCT and BD caused a significant reduction in spleen size (BMS + MCT p < 0.05, MCT p < 0.001, BD p < 0.05) (Fig. 5e). Rats administered KE gained significantly less weight over the entire study compared to controls. BMS + MCT, BMS, and BD supplemented rats gained significantly less weight than controls during weeks 2 – 4, and MCT animals gained less weight than controls at weeks 3 – 4 (Fig. 6). Increased gastric motility (increased bowel evacuation and changes to fecal consistency) was visually observed in rats supplemented with 10 g/kg MCT, most notably at the 8 and 12-h time points. All animals remained in healthy weight range for their age even though the rate of weight gain changed with ketone supplementation [53–54]. Food intake was not measured in this study. However, there was not a significant change in basal blood glucose or basal blood ketone levels over the 4 week study in any of the rats supplemented with ketones (Fig. 7).

Ketone supplementation did not affect the size of the brain, lungs, kidneys or heart of rats. As previously mentioned, the rats were still growing during the experimental time frame; therefore, organ weights were normalized to body weight to determine if organ weight changed independently to growth. There could be several reasons why ketones influenced liver and spleen weight. The ratio of liver to body weight was significantly higher in the MCT supplemented animals (Fig. 5). MCTs are readily absorbed in the intestinal lumen and transported directly to the liver via hepatic portal circulation. When given a large bolus, such as in this study, the amount of MCTs in the liver will likely exceed the β-oxidation rate, causing the MCTs to be deposited in the liver as fat droplets [94]. The accumulated MCT droplets in the liver could explain the higher liver weight to body weight percentage observed with MCT supplemented rats. Future toxicology and histological studies will be needed to determine the cause of the observed hepatomegaly. It should be emphasized that the dose in this study is not optimized in humans. We speculate that an optimized human dose would be lower and may not cause hepatomegaly or potential fat accumulation. Nutritional ketosis achieved with the KD has been shown to decrease inflammatory markers such as TNF-α, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1 [8, 46], which may account for the observed decrease in spleen weight. As previously mentioned, Veech and colleagues demonstrated that exogenous supplementation of 5 mM βHB resulted in a 28 % increase in hydraulic work in the working perfused rat heart and a significant decrease in oxygen consumption [28, 41, 42]. Ketone bodies have been shown to increase cerebral blood flow and perfusion [95]. Also, ketone bodies have been shown to increase ATP synthesis and enhance the efficiency of ATP production [14, 28, 40]. It is possible that sustained ketosis results in enhanced cardiac efficiency and O2 consumption. Even though the size of the heart did not change for any of the ketone supplements, further analysis of tissues harvested from the ketone-supplemented rats will be needed to determine any morphological changes and to understand changes in organ size. It should be noted that the Harlan standard rodent chow 2018 is nutritionally complete and formulated with high-quality ingredients to optimize gestation, lactation, growth, and overall health of the animals. The same cannot be said for the standard American diet (SAD). Therefore, we plan to investigate the effects of ketone supplements administered with the SAD to determine if similar effects will be seen when the micronutrient deficiencies and macronutrient profile mimics what most Americans consume.


The metabolic phenotype of endogenous ketosis is characterized by lowered blood glucose and elevated FFA concentrations, whereas both blood glucose and FFA are lowered in exogenous ketosis. During endogenous ketosis, low insulin and elevated cortisol increase adipose tissue lipolysis, with hepatic FFA supply being a key determinant of ketogenesis. Ketone bodies exert negative feedback on their own production by reducing hepatic FFA supply through βHB-mediated agonism of the PUMA-G receptor in adipose tissue, which suppresses lipolysis (Taggart et al., 2005). Exogenous ketones from either intravenous infusions (Balasse and Ooms, 1968; Mikkelsen et al., 2015) or ketone drinks, as studied here, inhibit adipose tissue lipolysis by the same mechanism, making the co-existence of low FFA and high βHB unique to exogenous ketosis.


With oral ketone supplementation, we observed a significant elevation in blood βHB without dietary restriction and with little change in lipid biomarkers (Fig. 1). Over the 4 week study, MCT-supplemented rats demonstrated decreased HDL compared to controls. No significant changes were observed in any of the triglycerides or lipoproteins (HDL, LDL) with any of the remaining exogenously applied ketone supplements. It should be noted that the rats used for this study had not yet reached full adult body size [79]. Their normal growth rate and maturation was likely responsible for the changes in triglyceride and lipoprotein levels observed in the control animals over the 4 week study (baseline data not shown, no significant differences) [80, 81]. Future studies are needed to investigate the effect of ketone supplementation on fully mature and aged animals. Overall, our study suggests that oral ketone supplementation has little effect on the triglyceride or lipoprotein profile after 4 weeks. However, it is currently unknown if ketone supplementation would affect lipid biomarkers after a longer duration of consumption. Further studies are needed to determine the effects of ketone supplements on blood triglyceride and lipoproteins after chronic administration and as a means to further enhance the hyperketonemia and improve the lipid profile of the clinically implemented (4:1) KD.
That said, there also remains the question of the relative benefits of AcAc versus BOHB, both as independent signaling molecules and as redox modulators in peripheral (aka non-hepatic) tissues. Seen from this perspective, AcAc generated in the liver acts as a NAD+ donor for the periphery, whereas pure BOHB taken orally, to the extent that it is retro-converted to AcAc (Sherwin 1975), potentially deprives the periphery of NAD+.
Serial drinks or a continuous NG infusion of KE effectively kept blood ketone concentrations >1 mM for 9 h (Figure ​(Figure6).6). With drinks every 3 h, blood d-βHB rose and then fell, but had not returned to baseline (~ 0.1 mM) when the next drink was consumed. There was no significant difference in d-βHB Cmax between drinks 2 and 3 (3.4 ± 0.2 mM vs. 3.8 ± 0.2 mM p = 0.3), as the rate of d-βHB appearance fell slightly with successive drinks (0.07 ± 0.01 mmol.min−1 and 0.06 ± 0.01 mmol.min−1 p = 0.6). d-βHB elimination was the same after each bolus (142 ± 37 mmol.min, 127 ± 45 mmol.min; and 122 ± 54 mmol.min). When KE was given via a nasogastric tube, the initial bolus raised blood d-βHB to 2.9 ± 0.5 mM after 1 h, thereafter continuous infusion maintained blood d-βHB between 2–3 mM. Total d-βHB appearance in the blood was identical for both methods of administration (Serial drinks AUC: 1,394 ± 64 mmol.min; NG infusion AUC: 1,305 ± 143 mmol.min. p = 0.6).

You may wonder why we are emphasizing on using these specific oils. Well, this is because the extra virgin oil is an unprocessed form, and contains lauric acid that is antimicrobial in nature and is good for brain health. (This is the same lauric acid that is naturally found in breast milk as well.) Its antibacterial property also indirectly supports the growth of Candida that keep your gut healthy.
And zero-carb, followed by fasting for two meals, and then followed up by a second zero-carb meal is almost always all you need to get into ketosis fast. By Sunday or Monday morning, after a second night of no carbs, you'll be in a deep enough ketosis that hunger will crash and your energy will surge to help you transition into your low-carb diet of choice.
The ketone esters are, hands-down, the worst tasting compounds I have ever put in my body. The world’s worst scotch tastes like spring water compared to these things. The first time I tried 50 mL of BHB monoester, I failed to mix it with anything (Dom warned me, but I was too eager to try them to actually read his instructions). Strategic error. It tasted as I imagine jet fuel would taste. I thought I was going to go blind. I didn’t stop gagging for 10 minutes. (I did this before an early morning bike ride, and I was gagging so loudly in the kitchen that I woke up my wife, who was still sleeping in our bedroom.) The taste of the AcAc di-ester is at least masked by the fact that Dom was able to put it into capsules. But they are still categorically horrible. The salts are definitely better, but despite experimenting with them for months, I was unable to consistently ingest them without experiencing GI side-effects; often I was fine, but enough times I was not, which left me concluding that I still needed to work out the kinks. From my discussions with others using the BHB salts, it seems I have a particularly sensitive GI system.
I eat one meal a day during a one-hour window and fast 23 or more hours every day. I want to use your ketones to get back into ketosis faster after that meal. Will that work? I am confused, because say at the end of my hour eating window I drink your ketones, sure there are lots of ketones suddenly in my body but I also have a big meal in my stomach. My body has to digest and use that food energy, so how do exogenous ketones help me in that case?
Now that you have fasted for quite a long time, you can break your fast at around 4 to 5 pm. Try having some good fat for this purpose, such as coconut oil or MCT oil, butter, or any other healthy fat. MCT oil might come in as a better option in this case since it gets quickly absorbed by the body. It swiftly bypasses the gallbladder and reaches the liver where it is transformed to ketones rapidly.
Dusty you assume only everyone wants fat burning. I think this is silly. The brain and heart will prefer ketones over carbohydrates when both are present in the blood stream. Look at the research and mechanism. I don’t want fat loss, I want better brain function. I also regularly eat carbs myself. This is one of the reasons I myself use exogenous ketones. No this isn’t a magic fat loss powder, but don’t sit here and quote T-nation trying to rebuttal this article acting like that is a credible source.
I’m already following a ketogenic diet and have been fat adapted for about 3 months. Since I’m already in ketosis would this product help me or hinder my fat loss? My thought is that if I’m already in a fat burning state and then I take exogenous ketones does my body stop burning my fat to burn the ingested ketones like taking a break or does the product enhance the fat burning that is already taking place?
On day 29, rats were sacrificed via deep isoflurane anesthesia, exsanguination by cardiac puncture, and decapitation 4–8 h after intragastric gavage, which correlated to the time range where the most significantly elevated blood βHB levels were observed. Brain, lungs, liver, kidneys, spleen and heart were harvested, weighed (AWS-1000 1 kg portable digital scale (AWS, Charleston, SC)), and flash-frozen in liquid nitrogen or preserved in 4 % paraformaldehyde for future analysis.
In a keto-adapted individual where ketone metabolism is brisk with up to 100 grams or more being oxidized (i.e., ‘burned for energy’) daily, the small amount lost in breath and urine as acetone is minor. But because this breakdown occurs spontaneously without needing the help of enzymes, it also happens to AcAc in a stored beverage or food (even in an air-tight container), making the shelf-life of AcAc-containing products problematic. Thus all current ketone supplements consist of BOHB in some form rather than the naturally occurring mix of BOHB and AcAc produced by the liver.
In conclusion, drinks containing exogenous ketones, in either ester or salt form, can raise concentrations of blood βHB in humans, although elevation of l-βHB lasts longer after racemic KS consumption. Both KE and KS drinks mildly altered acid-base balance. Exogenous ketones lowered blood glucose and lipids without inhibiting endogenous insulin secretion. The KE delivered highly repeatable blood concentrations of d-βHB, although ketosis was decreased by a meal. Uptake and elimination of d-βHB were similar when several drinks were consumed in succession. The dietary KE could maintain ketosis using drinks taken regularly around a normal meal pattern, or using a continuous infusion via a nasogastric tube. Therefore, ketone drinks are a viable and practical alternative to dietary strategies to achieve ketosis.

Great information. And apparently I have found out what my problem is. I got into Keto a few weeks ago. Transitioned into ketosis after a week, and then had to travel….while I followed a keto diet as best I could, (I took your powdered MCT Oil with me and it is great), but I did fall out of ketosis. Now it’s been 2 weeks and I can’t seem to get back into ketosis.


It is important to define what it means to be “in ketosis”. If being “in ketosis” means having ketones in your blood, then of course ketone supplements get you into ketosis. But that is different from being in an endogenous ketogenic, fat-burning state as a result of following a ketogenic diet. Getting this distinction right will go a long way towards stopping ketone salts companies from using misleading marketing about the issue. We need to reach a consensus about what being “in ketosis” means and then force companies to use that definition.
This molecule is quite essential if you are using your own fat for fuel, or taking BHB as an exogenous ketone supplement to increase energy production — essentially to be in nutritional ketosis. If you’re not certain about what ketones are or what nutritional ketosis is, you should back up a little bit and read more about that on my company site, Perfect Keto.
You see, when someone says ketosis is a natural state, they mean that ketosis is the body’s backup plan for those times when there isn’t any food to eat. It’s an evolutionary adaptation that developed over hundreds of thousands of years and springs from a time when our distant ancestors often had to go many days between decent meals. Fortunately, these days actual starvation is pretty rare so most people will never be in ketosis. But the physiological mechanism is still there, lurking in the background, readily accessible to anyone who is willing to trick their body into thinking it’s starving.
Another factor to consider is that in nutritional ketosis the liver makes a steady supply of ketones and continuously releases them into the circulation. In contrast, most ketone supplement protocols involve bolus intakes that don’t mimic the endogenous release pattern. The extent to which this impacts metabolic and signaling responses across different tissues remains unclear.
There are many different variations of intermittent fasting as well. Dr. Dom D’Agostino, the well-known ketogenic diet researcher, suggests doing a longer intermittent fast for 3 days, 3 times a year. This means not eating for 3 days, and eating normally until the next fast. Daily intermittent fasts are recommended as well. He says that it is ideal to have one to two meals after fasting for most of the day to reap the benefits of intermittent fasting every day.
All data are presented as the mean ± standard deviation (SD). Data analysis was performed using GraphPad PRISM™ version 6.0a and IBM SPSS Statistics 22.0. Results were considered significant when p < 0.05. Triglyceride and lipoprotein profile data were analyzed using One-Way ANOVA. Blood ketone and blood glucose were compared to control at the applicable time points using a Two-Way ANOVA. Correlation between blood βHB and glucose levels in ketone supplemented rats was compared to controls using ANCOVA analysis. Organ and body weights were analyzed using One-Way ANOVA. Basal blood ketone and blood glucose levels were analyzed using Two-Way ANOVA. All mean comparisons were carried out using Tukey’s multiple comparisons post-hoc test.
Yes — you read that correctly — 24 hours of intermittent fasting without any resistance training and these subjects were able to preserve more muscle mass than the subjects that ate fewer calories every day without fasting at all. This finding contradicts our common sense, but when we dig deeper into autophagy we can find the mechanism behind this result.
Why is this desirable? Think about energy production in your body much like macro energy consumption on a planetary level. Coal is gross and dirty and messes tons of different things up. You need to continue to burn it to get energy. Solar power is free, clean and pretty much limitless. This is pretty much the same story when you are burning carbs (coal) versus fats (solar) for energy.
The famous keto-breath is powerful enough to throw shade on your increasingly ripped rig. The mouth-based ketones are released when your body scalds fat are responsible for the pong. Going into ketosis by changing your diet means your body doesn’t have carbs as a fuel source, so you’re using fats and proteins for energy, which fuels the potency of the fireworks seeping from your grill. The same can happen when taking supplements, but not by the same degree – proving that changing your diet it obviously a more potent fat burning tool. A lot of people also report gastric distress, so you could offend those you’re co-habituating with. What’s more, they can have a slight diuretic effect, which can deplete your magnesium, potassium and sodium stores, so make sure your levels are topped up when you’re out for a extra long exercise stint. Research in Nutrition and Metabolism on animals, found there were no negative side effects, but whether this extends to humans is still up for discussion. Fortunately, you’re more likely benefit from the upsides such as improved endurance, appetite suppression and fat burning.
Ketoacidosis is driven by a lack of insulin in the body.  Without insulin, blood sugar rises to high levels and stored fat streams from fat cells.  This excess amount of fat metabolism results in the production of abnormal quantities of ketones. The combination of high blood sugar and high ketone levels can upset the normal acid/base balance in the blood and become dangerous.  In order to reach a state of ketoacidosis, insulin levels must be so low that the regulation of blood sugar and fatty acid flow is impaired.
Ketone supplements: are they a groundbreaking boost to a low-carb diet, or should you be wary of the broad claims that companies make about their benefits? In this article you’ll learn all about exogenous ketone supplements and, what’s more, you’ll read about the experiment we ran on the supplements at our head office in Stockholm. How did ketone supplements perform when we put them to the test? Do they work? Read on to find out our verdict!
Hey Staci, great to hear you’re getting back into it! To answer your question, it really depends on the individual but there are definitely things you can do to get back into ketosis faster – working out to deplete your glycogen stores or implementing intermittent fasting into your regimen – these are 2 common ways that should kick start you back in the right direction!
Ketones are an alternate energy or fuel source for brain and body that our bodies have naturally produced and used for millennia. Ketones have recently leapt to the forefront of health and wellness conversations worldwide as the scientific body of research that seeks to understand their numerous unique properties and profound systemic effects has begun to grow (see below).

Animal procedures were performed in accordance with the University of South Florida Institutional Animal Care and Use Committee (IACUC) guidelines (Protocol #0006R). Juvenile male Sprague–Dawley rats (275–325 g, Harlan Laboratories) were randomly assigned to one of six study groups: control (water, n = 11), BD (n = 11), KE (n = 11), MCT (n = 10), BMS (n = 11), or BMS + MCT (n = 12). Caloric density of standard rodent chow and dose of ketone supplements are listed in Table 1. On days 1–14, rats received a 5 g/kg body weight dose of their respective treatments via intragastric gavage. Dosage was increased to 10 g/kg body weight for the second half of the study (days 15–28) for all groups except BD and KE to prevent excessive hyperketonemia (ketoacidosis). Each daily dose of BMS would equal ~1000–1500 mg of βHB, depending on the weight of the animal. Intragastric gavage was performed at the same time daily, and animals had ad libitum access to standard rodent chow 2018 (Harlan Teklad) for the duration of the study. The macronutrient ratio the standard rodent chow was 62.2, 23.8 and 14 % of carbohydrates, protein and fat respectively.
With oral ketone supplementation, we observed a significant elevation in blood βHB without dietary restriction and with little change in lipid biomarkers (Fig. 1). Over the 4 week study, MCT-supplemented rats demonstrated decreased HDL compared to controls. No significant changes were observed in any of the triglycerides or lipoproteins (HDL, LDL) with any of the remaining exogenously applied ketone supplements. It should be noted that the rats used for this study had not yet reached full adult body size [79]. Their normal growth rate and maturation was likely responsible for the changes in triglyceride and lipoprotein levels observed in the control animals over the 4 week study (baseline data not shown, no significant differences) [80, 81]. Future studies are needed to investigate the effect of ketone supplementation on fully mature and aged animals. Overall, our study suggests that oral ketone supplementation has little effect on the triglyceride or lipoprotein profile after 4 weeks. However, it is currently unknown if ketone supplementation would affect lipid biomarkers after a longer duration of consumption. Further studies are needed to determine the effects of ketone supplements on blood triglyceride and lipoproteins after chronic administration and as a means to further enhance the hyperketonemia and improve the lipid profile of the clinically implemented (4:1) KD.
We’ve all been taught that high sodium intake is bad for us, similar to how we’ve been told for decades that fat is the driver of coronary heart disease, and consuming large amounts will kill us.  Sodium has been thought to increase blood pressure, and therefore increase the risk of heart disease, kidney disease, stroke, osteoporosis, and stomach cancer. Thus, many of us tend to avoid consuming foods or supplements with labels that have high amounts of sodium.
Ketones may be a better source of fuel than glucose, and a far better beverage than Fruitopia, but it's a question of whether or not you can spare the extra fuel. Because just like adding sugar to a diet, it's like pressing pause on the fat burning process since the body preferentially burns it for fuel. Adding ketones to the diet does the same thing.
Serial drinks or a continuous NG infusion of KE effectively kept blood ketone concentrations >1 mM for 9 h (Figure ​(Figure6).6). With drinks every 3 h, blood d-βHB rose and then fell, but had not returned to baseline (~ 0.1 mM) when the next drink was consumed. There was no significant difference in d-βHB Cmax between drinks 2 and 3 (3.4 ± 0.2 mM vs. 3.8 ± 0.2 mM p = 0.3), as the rate of d-βHB appearance fell slightly with successive drinks (0.07 ± 0.01 mmol.min−1 and 0.06 ± 0.01 mmol.min−1 p = 0.6). d-βHB elimination was the same after each bolus (142 ± 37 mmol.min, 127 ± 45 mmol.min; and 122 ± 54 mmol.min). When KE was given via a nasogastric tube, the initial bolus raised blood d-βHB to 2.9 ± 0.5 mM after 1 h, thereafter continuous infusion maintained blood d-βHB between 2–3 mM. Total d-βHB appearance in the blood was identical for both methods of administration (Serial drinks AUC: 1,394 ± 64 mmol.min; NG infusion AUC: 1,305 ± 143 mmol.min. p = 0.6).
Increased levels of BHB in the body were found to be associated with greater cognitive performance through better performance in memory recall tests12 on a study of 20 subjects with Alzheimer’s disease or demonstration of a mild cognitive deficit. Similarly, BHB ketone esters helped to reverse symptoms of Alzheimer's Disease in one clinical case study.13 More research in humans is needed, but the various hypotheses are backed up by strong animal data.

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