Effect of exogenous and endogenous ketones on respiratory exchange ratio and glucose metabolism in healthy subjects.

This study examined the effect of exogenous ketone bodies (KB) on oxygen consumption (V̇o2), carbon dioxide production (V̇co2), and glucose metabolism. The data were compared with the effects of endogenous ketonemia during both, a ketogenic diet or fasting. Eight healthy individuals [24.1 ± 2.5 yr, body mass index (BMI) 24.3 ± 3.1 kg/m2] participated in a crossover intervention study and were studied in a whole-room indirect calorimeter (WRIC) to assess macronutrient oxidation following four 24-h interventions: isocaloric controlled mixed diet (ISO), ISO supplemented with ketone salts (38.7 g of ß-hydroxybutyrate/day, EXO), isocaloric ketogenic diet (KETO), and total fasting (FAST). A physical activity level of 1.65 was obtained. In addition to plasma KB, 24-h C-peptide and KB excretion rates in the urine and postprandial glucose and insulin levels were measured. Although 24-h KB excretion increased in response to KETO and FAST, there was a modest increase in response to EXO only (P < 0.05). When compared with ISO, V̇o2 significantly increased in KETO (P < 0.01) and EXO (P < 0.001), whereas there was no difference in FAST. V̇co2 increased in EXO but decreased in KETO (both P < 0.01) and FAST (P < 0.001), resulting in 24-h respiratory exchange ratios (RER) of 0.828 ± 0.024 (ISO) and 0.811 ± 0.024 (EXO) (P < 0.05). In response to EXO there were no differences in basal and postprandial glucose and insulin levels, as well as in insulin sensitivity. When compared with ISO, EXO, and KETO, FAST increased homeostatic model assessment ß-cell function (HOMA-B) (all P < 0.05). In conclusion, at energy balance exogenous ketone salts decreased respiratory exchange ratio without affecting glucose tolerance.NEW & NOTEWORTHY Our findings revealed that during isocaloric nutrition, additional exogenous ketone salts increased V̇o2 and V̇co2 while lowering the respiratory exchange ratio (RER). Ketone salts had no effect on postprandial glucose metabolism.

Impact of energy turnover on fat balance in healthy young men during energy balance, energetic restriction and overfeeding.

Body weight control is thought to be improved when physical activity and energy intake are both high (high energy turnover (ET)). The aim of the present study was to investigate the short-term impact of ET on fat balance during zero energy balance (EB), energetic restriction (ER) and overfeeding (OF). In a randomised crossover study, nine healthy men (BMI: 23·0 (SD 2·1) kg/m2, 26·6 (SD 3·5) years) passed 3 × 3 d in a metabolic chamber: three levels of ET (low, medium and high; physical activity level = 1·3-1·4, 1·5-1·6 and 1·7-1·8) were performed at zero EB, ER and OF (100, 75 and 125 % of individual energy requirement). Different levels of ET were obtained by walking (4 km/h) on a treadmill (0, 165 and 330 min). Twenty-four-hour macronutrient oxidation and relative macronutrient balance (oxidation relative to intake) was calculated, and NEFA, 24-h insulin and catecholamine secretion were analysed as determinants of fat oxidation. During EB and OF, 24-h fat oxidation increased with higher ET. This resulted in a higher relative fat balance at medium ET (EB: +17 %, OF: +14 %) and high ET (EB: +23 %, OF: +17 %) compared with low ET (all P < 0·05). In contrast, ER led to a stimulation of 24-h fat oxidation irrespective of ET (no differences in relative fat balance between ET levels, P > 0·05). In conclusion, under highly controlled conditions, a higher ET improved relative fat balance in young healthy men during OF and EB compared with a sedentary state.

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

BACKGROUND & AIMS: Oral ketone supplements may mimic the beneficial effects of endogenous ketones on energy metabolism as ß-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/.

Validity and reproducibility of a whole-room indirect calorimeter for the estimation of VO2 , VCO2 , and resting metabolic rate.

Whole-room indirect calorimeters (WRICs) provide accurate instruments for the measurement of respiratory exchange, energy expenditure, and macronutrient oxidation. Here, we aimed to determine the validity and reproducibility of a 7500 L WRIC for the measurement of ventilation rates and resting metabolic rate (RMR). Technical validation was performed with propane combustion tests (n = 10) whereas biological reproducibility was tested in healthy subjects (13 women, 6 men, mean ± SD age 39.6 ± 15.3) in two 60 min measurements separated by 24 h. Subjects followed a run-in protocol prior to measurements. The coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for ventilation rates of O2 (VO2), CO2 (VCO2), the respiratory quotient (RQ; VCO2/VO2), and RMR. Technical validation showed good validity with CVs ranging from 0.67% for VO2 to 1.00% for energy expenditure. For biological reproducibility, CVs were 2.89% for VO2 ; 2.67% for VCO2 ; 1.95% for RQ; and 2.68% for RMR. With the exception of RQ (74%), ICCs were excellent for VO2 (94%), VCO2 (96%) and RMR (95%). Excluding participants that deviated from the run-in protocol did not alter results. In conclusion, the 7500 L WRIC is technically valid and reproducible for ventilation rates and RMR.

Validation of energy expenditure and macronutrient oxidation measured by two new whole-room indirect calorimeters.

OBJECTIVE: The aim of this study was to validate two new whole-room indirfect calorimeters according to Room Indirect Calorimetry Operating and Reporting Standards (RICORS 1.0). METHODS: For technical validation, 16 propane combustion tests were performed to determine accuracy and precision of energy expenditure (EE) and ventilation rates of oxygen (VO2 ), carbon dioxide (VCO2 ), and respiratory exchange ratio (VCO2 /VO2 ). For biological validation, eight participants (mean [SD], age 24.1 [2.5] years; BMI 24.3 [3.1] kg/m2 ) underwent four 24-hour protocols under highly standardized conditions: (1) isocaloric sedentary, (2) fasting sedentary, (3) isocaloric active, and (4) fasting active. Reliability (coefficients of variation [CV]) and minimal detectable changes (MDC) were calculated for 24-hour EE, sleeping metabolic rate (SMR), physical activity energy expenditure (PAEE), thermic effect of food (TEF), and macronutrient oxidation rates. RESULTS: Technical validation showed high reliability and recovery rates for VO2 (0.75% and 100.8%, respectively), VCO2 (0.49% and 100.6%), and EE (0.54% and 98.2%). Biological validation revealed CV and MDC for active conditions of 1.4% and 4.3% for 24-hour EE, 1.7% and 5.9% for SMR, and 30.2% and 38.4% for TEF, as well as 5.8% and 10.5% for PAEE, respectively. Mean CV and MDC for macronutrient oxidation rates were 9.9% and 22.9%, respectively. CONCLUSIONS: The precision of 24-hour EE and SMR was high, whereas it was lower for PAEE and poor for TEF.

What Is the Impact of Energy Expenditure on Energy Intake?

Coupling energy intake (EI) to increases in energy expenditure (EE) may be adaptively, compensatorily, or maladaptively leading to weight gain. This narrative review examines if functioning of the homeostatic responses depends on the type of physiological perturbations in EE (e.g., due to exercise, sleep, temperature, or growth), or if it is influenced by protein intake, or the extent, duration, timing, and frequency of EE. As different measures to increase EE could convey discrepant neuronal or humoral signals that help to control food intake, the coupling of EI to EE could be tight or loose, which implies that some ways to increase EE may have advantages for body weight regulation. Exercise, physical activity, heat exposure, and a high protein intake favor weight loss, whereas an increase in EE due to cold exposure or sleep loss likely contributes to an overcompensation of EI, especially in vulnerable thrifty phenotypes, as well as under obesogenic environmental conditions, such as energy dense high fat-high carbohydrate diets. Irrespective of the type of EE, transient elevations in the metabolic rate seem to be general risk factors for weight gain, because a subsequent decrease in energy requirement is not compensated by an adequate adaptation of appetite and EI.

Impact of Energy Turnover on the Regulation of Energy and Macronutrient Balance.

Energy turnover, defined as the average daily total metabolic rate, can be normalized for basal metabolic rate in order to compare physical activity level between individuals, whereas normalization of energy turnover for energy intake (energy flux) allows investigation of its impact on regulation of energy partitioning independent of energy balance. Appetite sensations better correspond to energy requirements at a high compared with a low energy turnover. Adaptation of energy intake to habitual energy turnover may, however, contribute to the risk of weight gain associated with accelerated growth, pregnancy, detraining in athletes, or after weight loss in people with obesity. The dose-response relationship between energy turnover and energy intake as well as the metabolic effects of energy turnover varies with the habitual level of physical activity and the etiology of energy turnover (e.g., cold-induced thermogenesis, growth, or lactation; aerobic vs. anaerobic exercise). Whether a high energy turnover due to physical activity or exercise may compensate for adverse effects of overfeeding or an unhealthy diet needs to be further investigated using the concept of energy flux. In summary, the beneficial effects of a high energy turnover on regulation of energy and macronutrient balance facilitate the prevention and treatment of obesity and associated metabolic risk.

Circulating sDPP-4 is Increased in Obesity and Insulin Resistance but Is Not Related to Systemic Metabolic Inflammation.

CONTEXT: Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings. OBJECTIVES: We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases. DESIGN: sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis. RESULTS: sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight. CONCLUSIONS: Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.

Lithium-Rich Mineral Water is a Highly Bioavailable Lithium Source for Human Consumption.

SCOPE: Lithium is an important trace element in human nutrition and medicine. Mineral and medicinal waters may represent a significant source of dietary lithium intake. METHODS AND RESULTS: The lithium concentration of 360 German mineral and 21 medicinal waters is determined. Based on a systematic screening, three different mineral waters exhibiting low (1.7 µg L-1 ), medium (171 µg L-1 ), and high lithium (1724 µg L-1 ) concentrations are chosen for an acute bioavailability study in male healthy volunteers. In Germany, a north-east to south-west gradient of analyzed lithium concentrations is observed in the 381 tested waters. The lithium concentration in the water is significantly correlated with its sodium (r = 0. 810), potassium (r = 0.716), and magnesium (r = 0.361), but not with its calcium concentration. In a randomized cross-over trial, volunteers (n = 3×10 each) drink 1.5 L of the respective mineral waters, and lithium concentrations in serum and urine are monitored over 24 h. Consumption of the mineral waters with a medium and high lithium content results in a dose-dependent response in serum lithium concentrations and total urinary lithium excretion. CONCLUSION: Lithium-rich mineral and medicinal waters may be an important and highly bioavailable lithium source for human consumption.

Correction: Impact of energy turnover on the regulation of glucose homeostasis in healthy subjects.

Since publication of this article the authors noted that the legend for Table 1 was incomplete, as the subtitle was missing. The complete table should appear as given below. This has been corrected in both the PDF and HTML versions of the Article.

Impact of energy turnover on the regulation of glucose homeostasis in healthy subjects.

OBJECTIVE: Sedentary lifestyle increases the risk of type 2 diabetes. The aim of this study was to investigate the impact of different levels of energy turnover (ET; low, medium, and high level of physical activity and the corresponding energy intake) on glucose metabolism at zero energy balance, caloric restriction, and overfeeding. METHODS: Sixteen healthy individuals (13 men, 3 women, 25.1 ± 3.9 years, BMI 24.0 ± 3.2 kg/m2) participated in a randomized crossover intervention under metabolic ward conditions. Subjects passed 3 × 3 intervention days. Three levels of physical activity (PAL: low 1.3, medium 1.6, and high 1.8 achieved by walking at 4 km/h for 0, 3 × 55, or 3 × 110 min) were compared under three levels of energy balance (zero energy balance (EB): 100% of energy requirement (Ereq); caloric restriction (CR): 75% Ereq, and overfeeding (OF): 125% Ereq). Continuous interstitial glucose monitoring, C-peptide excretion, and HOMA-IR, as well as postprandial glucose and insulin were measured. RESULTS: Daylong glycemia and insulin secretion did not increase with higher ET at all conditions of energy balance (EB, CR, and OF), despite a correspondingly higher CHO intake (Δ low vs. high ET: +86 to 135 g of CHO/d). At CR, daylong glycemia (p = 0.02) and insulin secretion (p = 0.04) were even reduced with high compared with low ET. HOMA-IR was impaired with OF and improved with CR, whereas ET had no effect on fasting insulin sensitivity. A higher ET led to lower postprandial glucose and insulin levels under conditions of CR and OF. CONCLUSION: Low-intensity physical activity can significantly improve postprandial glycemic response of healthy individuals, independent of energy balance.

Appetite Control Is Improved by Acute Increases in Energy Turnover at Different Levels of Energy Balance.

BACKGROUND: Weight control is hypothesized to be improved when physical activity and energy intake are both high [high energy turnover (ET)]. OBJECTIVE: The impact of three levels of ET on short-term appetite control is therefore investigated at fixed levels of energy balance. DESIGN: In a randomized crossover trial, 16 healthy adults (25.1 ± 3.9 y of age; body mass index, 24.0 ± 3.2 kg/m2) spent three daylong protocols for four times in a metabolic chamber. Four conditions of energy balance (ad libitum energy intake, zero energy balance, -25% caloric restriction, and +25% overfeeding) were each performed at three levels of ET (PAL 1.3 low, 1.6 medium, and 1.8 high ET; by walking on a treadmill). Levels of appetite hormones ghrelin, GLP-1, and insulin (total area under the curve) were measured during 14 hours. Subjective appetite ratings were assessed by visual analog scales. RESULTS: Compared with high ET, low ET led to decreased GLP-1 (at all energy balance conditions: P < 0.001) and increased ghrelin concentrations (caloric restriction and overfeeding: P < 0.001), which was consistent with higher feelings of hunger (zero energy balance: P < 0.001) and desire to eat (all energy balance conditions: P < 0.05) and a positive energy balance during ad libitum intake (+17.5%; P < 0.001). CONCLUSION: Appetite is regulated more effectively at a high level of ET, whereas overeating and consequently weight gain are likely to occur at low levels of ET. In contrast to the prevailing concept of body weight control, the positive impact of physical activity is independent from burning up more calories and is explained by improved appetite sensations.

High intake of orange juice and cola differently affects metabolic risk in healthy subjects.

BACKGROUND: Higher consumption of sugar-containing beverages has been associated with an elevated risk of type 2 diabetes and gout. Whether this equally applies to cola with an unhealthy image and orange juice (OJ) having a healthy image remains unknown. METHODS: In order to investigate whether OJ and cola differently affect metabolic risk 26 healthy adults (24.7 ± 3.2 y; BMI 23.2 ± 3.3 kg/m2) participated in a 2 × 2-wk intervention and consumed either OJ or caffeine-free cola (20% Ereq as sugar from beverages) in-between 3 meals/d at ad libitum energy intake. Glycemic control, uric acid metabolism and gut microbiota were assessed as outcome parameters. RESULTS: Fecal microbiota, body weight, basal and OGTT-derived insulin sensitivity remained unchanged in both intervention periods. Levels of uric acid were normal at baseline and did not change with 2-wk cola consumption (-0.03 ± 0.67 mg/dL; p > 0.05), whereas they decreased with OJ intervention (-0.43 ± 0.56 mg/dL; p < 0.01) due to increased uric acid excretion (+130.2 ± 130.0 mg/d; p < 0.001). Compared to OJ, consumption of cola led to a higher daylong glycemia (ΔiAUC: 36.9 ± 83.2; p < 0.05), an increase in glucose variability (ΔMAGE-Index: 0.29 ± 0.44; p < 0.05), and a lower 24 h-insulin secretion (ΔC-peptide excretion: -31.76 ± 38.61 µg/d; p < 0.001), which may be explained by a decrease in serum potassium levels (-0.11 ± 0.24 mmol/L; p < 0.05). CONCLUSION: Despite its sugar content, regular consumption of large amounts of OJ do not increase the risk of gout but may even contribute to lower uric acid levels. The etiology of impaired insulin secretion with cola consumption needs to be further investigated.

High orange juice consumption with or in-between three meals a day differently affects energy balance in healthy subjects.

Sugar-containing beverages like orange juice can be a risk factor for obesity and type 2 diabetes although the underlying mechanisms are less clear. We aimed to investigate if intake of orange juice with or in-between meals differently affects energy balance or metabolic risk. Twenty-six healthy adults (24.7 ± 3.2 y; BMI 23.2 ± 3.2 kg/m2) participated in a 4-week cross-over intervention and consumed orange juice (20% of energy requirement) either together with 3 meals/d (WM) or in-between 3 meals/d (BM) at ad libitum energy intake. Basal and postprandial insulin sensitivity (primary outcome), daylong glycaemia, glucose variability and insulin secretion were assessed. Body fat mass was measured by air-displacement plethysmography. After BM-intervention, fat mass increased (+1.0 ± 1.8 kg; p < 0.05) and postprandial insulin sensitivity tended to decrease (ΔMatsudaISI: -0.89 ± 2.3; p = 0.06). By contrast, after WM-intervention fat mass and gamma-glutamyl transferase (GGT) decreased (-0.30 ± 0.65 kg; -2.50 ± 3.94; both p < 0.05), whereas glucose variability was higher (ΔMAGE: +0.45 ± 0.59, p < 0.05). Daylong glycaemia, insulin secretion, changes in basal insulin sensitivity, and triglycerides did not differ between WM- and BM-interventions (all p > 0.05). In young healthy adults, a conventional 3-meal structure with orange juice consumed together with meals had a favorable impact on energy balance, whereas juice consumption in-between meals may contribute to a gain in body fat and adverse metabolic effects.

Expression of the Fatty Acid Receptors GPR84 and GPR120 and Cytodifferentiation of Epithelial Cells in the Gastric Mucosa of Mouse Pups in the Course of Dietary Transition.

During weaning, the ingested food of mouse pups changes from exclusively milk to solid food. In contrast to the protein- and carbohydrate-rich solid food, high fat milk is characterized primarily by fatty acids of medium chain length particularly important for the suckling pups. Therefore, it seems conceivable that the stomach mucosa may be specialized for detecting these important nutrients during the suckling phase. Here, we analyzed the expression of the G protein coupled receptors GPR84 and GPR120 (FFAR4), which are considered to be receptors for medium and long chain fatty acids (LCFAs), respectively. We found that the mRNA levels for GPR84 and GPR120 were high during the suckling period and progressively decreased in the course of weaning. Visualization of the receptor-expressing cells in 2-week-old mice revealed a high number of labeled cells, which reside in the apical as well as in the basal region of the gastric glands. At the base of the gastric glands, all GPR84-immunoreactive cells and some of the GPR120-positive cells also expressed chromogranin A (CgA), suggesting that they are enteroendocrine cells. We demonstrate that the majority of the CgA/GPR84 cells are X/A-like ghrelin cells. The high degree of overlap between ghrelin and GPR84 decreased post-weaning, whereas the overlap between ghrelin and GPR120 increased. At the apical region of the glands the fatty acid receptors were mainly expressed in unique cell types. These contain lipid-filled vacuole- and vesicle-like structures and may have absorptive functions. We detected decreased immunoreactivity for GPR84 and no lipid droplets in surface cells post-weaning. In conclusion, expression of GPR84 in ghrelin cells as well as in surface cells suggests an important role of medium chain fatty acids (MCFAs) in the developing gastric mucosa of suckling mice.

Impact of breakfast skipping compared with dinner skipping on regulation of energy balance and metabolic risk.

Background: Meal skipping has become an increasing trend of the modern lifestyle that may lead to obesity and type 2 diabetes.Objective: We investigated whether the timing of meal skipping impacts these risks by affecting circadian regulation of energy balance, glucose metabolism, and postprandial inflammatory responses.Design: In a randomized controlled crossover trial, 17 participants [body mass index (in kg/m2): 23.7 ± 4.6] underwent 3 isocaloric 24-h interventions (55%, 30%, and 15% carbohydrate, fat, and protein, respectively): a breakfast skipping day (BSD) and a dinner skipping day (DSD) separated by a conventional 3-meal-structure day (control). Energy and macronutrient balance was measured in a respiration chamber. Postprandial glucose, insulin, and inflammatory responses in leukocytes as well as 24-h glycemia and insulin secretion were analyzed.Results: When compared with the 3-meal control, 24-h energy expenditure was higher on both skipping days (BSD: +41 kcal/d; DSD: +91 kcal/d; both P < 0.01), whereas fat oxidation increased on the BSD only (+16 g/d; P < 0.001). Spontaneous physical activity, 24-h glycemia, and 24-h insulin secretion did not differ between intervention days. The postprandial homeostasis model assessment index (+54%) and glucose concentrations after lunch (+46%) were, however, higher on the BSD than on the DSD (both P < 0.05). Concomitantly, a longer fasting period with breakfast skipping also increased the inflammatory potential of peripheral blood cells after lunch.Conclusions: Compared with 3 meals/d, meal skipping increased energy expenditure. In contrast, higher postprandial insulin concentrations and increased fat oxidation with breakfast skipping suggest the development of metabolic inflexibility in response to prolonged fasting that may in the long term lead to low-grade inflammation and impaired glucose homeostasis. This trial was registered at clinicaltrials.gov as NCT02635139.