Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants

Summary

Background & aims

Oral ketone supplements may mimic the beneficial effects of endogenous ketones on energy metabolism as β-hydroxybutyrate has been proposed to increase energy expenditure and improve body weight regulation. Therefore, our objective was to compare the effects of a one-day isocaloric ketogenic diet, fasting and supplementation with ketone salts on energy expenditure and appetite perception.

Methods

Eight healthy young adults (4 women, 4 men, age 24 ± 3 years, BMI 24.3 ± 3.1 kg/m²) participated in a randomized cross-over trial with four 24 h-interventions in a whole room indirect calorimeter at a physical activity level of 1.65: (i) total fasting (FAST), (ii) isocaloric ketogenic diet (3.1% energy from carbohydrates (CHO), KETO), (iii) isocaloric control diet (47.4% energy from CHO, ISO), and (iv) ISO supplemented with 38.7 g/d ketone salts (exogenous ketones, EXO). Effects on serum ketone levels (15 h-iAUC), energy metabolism (total energy expenditure, TEE; sleeping energy expenditure, SEE; macronutrient oxidation) and subjective appetite were measured.

Results

Compared to ISO, ketone levels were considerably higher with FAST and KETO and little higher with EXO (all p > 0.05). Total and sleeping energy expenditure did not differ between ISO, FAST and EXO whereas KETO increased TEE (+110 ± 54 kcal/d vs. ISO, p < 0.05) and SEE (+201 ± 90 kcal/d vs. ISO, p < 0.05). CHO oxidation was slightly decreased with EXO compared to ISO (−48 ± 27 g/d, p < 0.05) resulting in a positive CHO balance (p < 0.05). No differences between the interventions were found for subjective appetite ratings (all p > 0.05).

Conclusion

A 24 h-ketogenic diet may contribute to maintain a neutral energy balance by increasing energy expenditure. Exogenous ketones in addition to an isocaloric diet did not improve regulation of energy balance.

Clinical trial registration

NCT04490226 https://clinicaltrials.gov/.

Introduction

A low carbohydrate (CHO), high fat ketogenic diet (KD) has been shown to be a successful weight loss strategy [1,2] and therefore remains highly popular. Advantages of the KD are proposed to be explained by a higher total energy expenditure (TEE) [3,4] and appetite suppressant effects of the ketone bodies beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) [[5], [6], [7], [8]]. Within 14 days, an ad libitum KD thus led to a spontaneous weight loss in patients with obesity and type 2 diabetes [9]. As KDs provide only <50 g/d CHO, glycemia and insulin levels are naturally low and increasing levels of ketone bodies serve as energy substrate, thus altering fuel partitioning from CHO to ketone oxidation [10].

Although a KD has several beneficial health effects, there are also some disadvantages (e.g. increased LDL cholesterol) [11]. Long-term compliance to this diet can be difficult, because of restricted food choice and undesirable side effects such as gastro-intestinal upset [12]. Short-term diets for 24-h like intermittent fasting have therefore become an attractive alternative. However, total fasting exerts a decrease in energy expenditure (EE) [13] and an increase in appetite [14]. A 24 h-KD may thus be a more favorable option. In the last years, exogenous ketones have become commercially available as ketone esters (KE, D-BHB) or racemic ketone salts (KS, D/L-BHB) which can be used as supplements to achieve ketosis more comfortable than with a KD [15].

Appetite suppressant effects of exogenous ketone supplementation are, however, controversial with some results showing that KE are able to mimic the appetite suppressant effect of a KD, by reducing ghrelin levels and subjective hunger compared to dextrose supplementation [16,17]. Whereas other authors found no effect of oral consumption or intravenous administration of KS on subjective appetite [18].

In summary, there are discrepant findings between the effects of exogenous ketones and a KD. The latter discrepancy may result from a negative energy balance that often accompanies a KD which cannot be separated from the effect of ketosis.

The aim of our study was therefore to compare the acute effects of an isocaloric KD vs. total fasting on energy metabolism (EE and energy partitioning) and appetite perception. In addition, we investigated if KS supplementation with a normal CHO (47% energy, %E) isocaloric diet can mimic the effects of an isocaloric KD.