Decrease In Respiratory Quotient Research Articles

Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

ObjectiveOne of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. MethodsSpecific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male LeprCre/+ and LeprCre/+;NpyFlp/+ mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. ResultsSelective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. ConclusionsTogether, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.

Metabolic flexibility during sleep

Known as metabolic flexibility, oxidized substrate is selected in response to changes in the nutritional state. Sleep imposes an extended duration of fasting, and oxidized substrates during sleep were assumed to progressively shift from carbohydrate to fat, thereby gradually decreasing the respiratory quotient (RQ). Contrary to this assumption, whole-room indirect calorimetry with improved time resolution revealed that RQ re-ascended prior to awakening, and nadir of RQ in non-obese young adults occurred earlier in women than men after bedtime. The transient decrease in RQ during sleep was blunted in metabolically inflexible men with smaller amplitude of diurnal rhythm in RQ. Similarly, the effect of 10 years difference in age on RQ became significant during sleep; the decrease in RQ during sleep was blunted in older subjects. Inter-individual difference in RQ become apparent during sleep, and it might serve as a window to gain insight into the early-stage pathogenesis of metabolic inflexibility.

Metabolic Flexibility During Sleep

SummaryKnown as metabolic flexibility, oxidized substrate is selected in response to changes in the nutritional state. Sleep imposes an extended duration of fasting, and oxidized substrates during sleep were assumed to progressively shift from carbohydrate to fat, thereby gradually decreasing the respiratory quotient (RQ). Contrary to this assumption, whole-room indirect calorimetry with improved time resolution revealed that RQ re-ascended prior to awakening, and nadir of RQ in non-obese young adults occurred earlier in women than men after bedtime. The transient decrease in RQ during sleep was blunted in metabolically inflexible men with smaller amplitude of diurnal rhythm in RQ. Similarly, the effect of 10 years difference in age on RQ became significant during sleep; the decrease in RQ during sleep was blunted in older subjects. Inter-individual difference in RQ become apparent during sleep, and it might serve as a window to gain insight into the early-stage pathogenesis of metabolic inflexibility.

Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults.

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals’ susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual’s capacity to oxidize dietary fat is a metabolic determinant of weight change.

Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of the individual susceptibility to weight gain. Seventy-nine healthy, weight-stable subjects underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL; 50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard (SOF: 50% carbohydrate, 30% fat), high-fat (FNP: 60% fat, 20% carbohydrate), and high-carbohydrate (CNP: 75% carbohydrate, 5% fat) overfeeding diets. Free-living weight change was assessed after 6 and 12 months. Compared to EBL, RQ decreased on average by 9% during fasting and by 4% during FNP, while increasing by 4% during SOF and by 8% during CNP. Smaller decrease in RQ, reflecting smaller increase in lipid oxidation rate, during FNP but not during other diets, predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute, high-fat overfeeding identify individuals prone to gain weight, indicating that the individual capacity to oxidize dietary fat is a metabolic predictor of weight change.

Phosphorus ingestion with a high-carbohydrate meal increased the postprandial energy expenditure of obese and lean individuals.

Phosphorus ingestion with glucose was reported to stimulate the postprandial peripheral uptake of both phosphorus and glucose, a process that favors energy production. The aim of this study was to determine whether phosphorus ingestion with a meal can affect energy metabolism. Overnight fasted men (eight lean and seven obese) consumed a high-carbohydrate meal (648 kcal) with either placebo or phosphorus (500 mg) tablets in a random order. Energy expenditure and substrate oxidation were monitored for 240 min using ventilated hood indirect calorimetry. Phosphorus ingestion with a meal increased the postprandial energy expenditure of both lean and obese individuals (P < 0.001), although in different patterns. Alterations in postprandial substrate oxidation was highly noticeable from time 120 min onward, where phosphorus-treated lean participants exhibited a significant decrease in respiratory quotient. Phosphorus ingestion with a high-carbohydrate meal alters postprandial energy metabolism mainly by enhancing postprandial energy expenditure that may ultimatly favor weight loss.

INTERMITTENT FASTING WITH 72 HOURS FASTING AND 96 HOURS REFEEDING PROMOTES FAT OXIDATION AND WEIGHT SUPPRESSION

Objective: Intermittent fasting (IF) has been shown to have benefits in increasing insulin sensitivity, stress resistance and lowering blood pressure. However, the underlining mechanism for the beneficial effects has not been elucidated yet. Design and method: Mice were subjected to a severe IF regimen, in which they were fasted for 72 hours and then refed ad libitum for subsequent 96 hours. This regimen was consecutively repeated 4 times to enforce the effects. After 4 courses of the IF regimen, mice were fed a high-fat diet (HFD) ad-libitum for subsequent 4 weeks of observational period. The body weight (BW) was monitored throughout the study period in the IF and ad-libitum feeding groups. At the 2 different time points: just after 4 courses of the IF regimen and after subsequent 4 weeks of observational ad-libitum feeding period, the glucose tolerance and respiratory gas were examined. Results: There was no significant difference in the BW between the adlib eating and IF groups just after 4 courses of the IF regimen. Glucose tolerance tests showed a significant decrease in the glucose level of IF group. Respiratory gas analysis showed a significant increase in oxygen uptake and a significant decrease in respiratory quotient of IF group. In PCR analysis, expressions of genes responsible for fat oxidation and thermogenesis (ACO, HSL and UCP1 et al.) were significantly increased in the harvested tissues (the skeletal muscle, white and brown adipose tissues). After subsequent 4 weeks of observational feeding period, the BW in IF group was significantly lower than ad-libitum feeding group. At the time-point, the glucose tolerance, respiratory gas and expression of genes maintained the similar changes observed just after 4 courses of the IF regimen. Conclusions: The 72 hours fasting IF regimen resulted in a suppression of the BW after HFD administration, in addition to a decrease in the blood glucose level. PCR analysis suggested that promotion of fat oxidation and thermogenesis in the skeletal muscle and adipose tissue of the IF group contributed to suppression of the BW.

GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy

This study examined the effects of redox status markers on metabolic syndrome (MetS) and obesity before and after dietary intervention and exercise for weight loss. A total of 103 adults suffering from MetS and obesity participated in this study and followed a personalized diet plan for 6 months. Body weight, body fat (BF) percentage (BF%), respiratory quotient (RQ) and the redox status markers, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and protein carbonyls (CARB), were measured twice in each individual, before and after intervention. Dietary intervention resulted in weight loss, a reduction in BF% and a decrease in RQ. The GSH levels were significantly decreased following intervention, while the levels of TBARS and CARB were not affected. Based on the initial GSH levels, the patients were divided into 2 groups as follows: The high GSH group (GSH, >3.5 µmol/g Hb) and the low GSH group (GSH <3.5 µmol/g Hb). Greater weight and BF loss were observed in patients with high GSH levels. It was observed that patients with MetS and obesity with high GSH values responded better to the dietary therapy, exhibiting more significant changes in weight and BF%. This finding underscores the importance of identifying redox status markers, particularly GSH, in obese patients with MetS. Knowing the levels of GSH may aid in developing a better design of an individualized dietary plan for individuals who wish to lose weight.

Capsaicin and capsiate could be appropriate agents for treatment of obesity: A meta-analysis of human studies

ABSTRACTConsumption of capsaicin or its nonpungent analogues, capsinoids has been reported to affect energy expenditure and fat oxidation, although available data are still controversial. The aim of the present study was to conduct a meta-analysis regarding the effects of these substances on energy expenditure and respiratory quotient, with special emphasis on the role of body mass index (BMI) of the participants. Medical databases were systematically searched for papers. Of the 627 trials identified, 9 provided results suitable to be included in analysis. Data analysis showed that after ingestion of capsaicin or capsinoids the energy expenditure increased (245 kJ/day, 58.56 kcal/day, p = 0.030) and the respiratory quotient decreased (by 0.216; p = 0.031) indicating a rise in fat oxidation. Studies with mean BMI of the participants below 25 kg/m2 failed to report any effect of capsaicin or capsinoids on the energy expenditure (p = 0.718) or on the respiratory quotient (p = 0.444), but studies with mean BMI exceeding 25 kg/m2 demonstrated an increase in energy expenditure (292 kJ/day, 69.79 kcal/day, p = 0.023) and a marked decrease in respiratory quotient (−0.257, p = 0.036). Our data clearly suggest that capsaicin or capsiate could be a new therapeutic approach in obesity promoting a negative energy balance and increased fat oxidation.

A novel clinical approach to evaluating changes in fat oxidation in healthy, overnight-fasted subjects

Obesity is characterized by impaired fat oxidation, and, therefore, the development of therapeutics designed to enhance fat oxidation for treating obesity is a growing focus in drug discovery. Evaluating such agents, however, is challenging in a clinical setting; requisite overnight fasting prior to a study visit increases whole body fat oxidation in lean, healthy subjects, making incremental increases potentially difficult to detect. We recruited 16 lean/overweight participants and eight obese participants to evaluate novel methodology designed to optimally detect increases in fat oxidation. Carbohydrate intake was increased for three days leading up to the overnight test visit and evaluated as either a standalone strategy to suppress overnight fasting-related increases in fat oxidation or was combined with overnight administration of IV glucose in a subset of lean/overweight subjects. Indirect calorimetry was performed the following morning to examine the degree to which these interventions were able to diminish fasting related increases in fat oxidation. Fat oxidation was then subsequently stimulated by challenging patients with a lipid infusion to determine the importance of the preceding interventions on the ability to detect statistically significant increases in fat oxidation. In lean/overweight subjects, suppression of fasting-related increases in fat oxidation via increased dietary carbohydrate intake was not necessary to detect subsequent meaningful increases in fat oxidation rates following Intralipid infusion; however, a statistically significant decrease in respiratory quotient following Intralipid infusion could only be observed when the infusion was preceded with high carbohydrate dietary intake. Glucose infusion, which further suppressed fasting-related fat oxidation, in turn led to more dramatic increases in Intralipid-driven fat oxidation. Both lean/overweight and obese subjects could demonstrate statistically significant increases in fat oxidation following Intralipid infusion, a finding which supports the inclusion of obese subjects in similar future clinical studies. Lastly, serum levels of β-hydroxybutyrate correlated strongly with fat oxidation rates, as well as respiratory quotient, suggesting potential as a surrogate biomarker of fax oxidation. Taken together, we demonstrate the utility of novel methodology to facilitate measuring changes in fat oxidation in lean/overweight and obese human volunteers in a clinical setting similar to that needed to test drugs designed to increase fat oxidation.

Seven Day Blackberry Feeding Affects the Energy Substrate Profile in Males And Improves Insulin Sensitivity

In the obesogenic environment, bioactive food components show promise in ameliorating metabolic dysfunction related to type 2 diabetes and metabolic syndrome. Preliminary animal studies on berries indicate that body composition, weight, and clinical markers of glucose regulation may be positively impacted by consumption of anthocyanin rich blue and black raspberries. The aim of our pilot study was to determine the influence of blackberry feeding on clinical markers related to glucose regulation as well as substrate utilization measured by indirect calorimetry in humans. This randomized, controlled, cross-over study was conducted at the USDA Beltsville Human Nutrition Research Center. Fifteen overweight or obese male subjects (age range 31–69) were fed a controlled, high fat diet (40% en from fat) for 7 days that included either 600 g/d of fresh blackberries (BB) or an isocaloric amount of gelatin (control). There was a 7 day washout period between treatments. For the last 24 hours of each treatment period, subjects remained inside of a room-sized indirect calorimeter, where a breakfast meal tolerance test (MTT, 75 g of sugar from waffle and syrup) was administered with their treatment, and timed blood draws (−15, 0, 30, 60, 90, 120, 180, 240 min) were collected and analyzed for glucose, insulin, and nonesterified fatty acids. Energy expenditure (EE), substrate oxidation, and respiratory quotient (RQ) were measured from gas exchange for the total 24 hr period as well as specific isolated time periods. Data were analyzed with mixed models using BMI, age, and treatment order, and their interactions with treatment as covariates. AUC of glucose was not different between BB and gelatin treatment (4286 vs 5027 mg·dL−1·min, respectively, p=0.17). However, AUC of insulin was lower after consumption of BB compared to gelatin (5322 vs 7325 uU·ml−1·min, p=0.008). During this 4 hr MTT period, EE was not different between the 2 treatments (BB, 405 kcal; gelatin, 399 kcal, p=0.79). However, preliminary data suggest that an interaction between BMI and treatment may be affecting RQ such that RQ is lower in higher BMI subjects fed BB compared to gelatin. Across the 24 hr period, RQ and EE were not different between the two treatments (.82 vs .83, 2184 vs 2124 kcal, respectively; BB vs gelatin treatments). However, during the 4 hr period that started with dinner, preliminary data suggest that a significant interaction of treatment and BMI for EE and RQ were observed (p=0.0385 and p=0.0059, respectively) where the BMI effect is the opposite of what was observed for the MTT time period; subjects with lower BMIs had a greater EE and lower RQ when fed BBs and the effect was attenuated with higher BMI subjects. The 24 hr stay in the calorimeter included 30 min of treadmill walking in the afternoon following the MTT. During this time period, a significant interaction of BMI with treatment demonstrated a decrease in RQ in higher BMI subjects fed BBs compared to gelatin (p for interaction = 0.041). In addition to improved insulin sensitivity, our data suggest a potential for anthocyanin rich BBs to change adiposity as RQ was indicative of preferential oxidation of fat for energy in higher BMI subjects during the MTT as well as during a bout of non-strenuous activity. Further, beneficial effects of BBs may not be limited to overweight/obese subjects in terms of switching substrates to increase fat oxidation. More subjects are being enrolled to confirm these preliminary findings. Support or Funding Information This study is funded by the USDA. Serum insulin by treatment across the 4 hour meal tolerance test. Serum glucose by treatment across the 4 hour meal tolerance test.

Novel Mitochondrial Cationic Uncoupler C4R1 Is an Effective Treatment for Combating Obesity in Mice.

Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30and 12-14µmol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30µmol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat massby 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27µmol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity.

Lipopolysaccharide inhibits ghrelin-excited neurons of the arcuate nucleus and reduces food intake via central nitric oxide signaling

Lipopolysaccharide (LPS) induces anorexia and expression of inducible nitric oxide synthase (iNOS) in the hypothalamic arcuate nucleus (Arc). Peripheral administration of the iNOS inhibitor 1400 W counteracts the anorectic effects of LPS. Here we investigated the role of central NO signaling in LPS anorexia. In electrophysiological studies we tested whether 1400 W counteracts the iNOS-dependent inhibition of Arc neurons triggered by in vivo or in vitro stimulation with LPS. We used the hormone ghrelin as a functional reference stimulus because ghrelin is known to activate orexigenic Arc neurons. Further, we investigated whether in vitro LPS stimulation induces an iNOS-mediated formation of the second messenger cGMP. Since the STAT1 pathway contributes to the regulation of iNOS expression we investigated whether LPS treatment induces STAT1 phosphorylation in the Arc. Finally we tested the effect of intracerebroventricular injection of 1400 W on LPS-induced anorexia. Superfusion with 1400 W (10(-4) M) increased neuronal activity in 37% of neurons in Arc slices from LPS treated (100 μg/kg ip) but not from saline treated rats. Similarly, 1400 W excited 45% of Arc neurons after in vitro stimulation with LPS (100 ng/ml). In both approaches, a considerable percentage of 1400 W sensitive neurons were excited by ghrelin (10(-8)M; 50% and 75%, respectively). In vitro stimulation with LPS induced cGMP formation in the Arc, which was blocked by co-incubation with 1400 W. LPS treatment elicited a pSTAT1 response in the Arc of mice. Central 1400 W injection (4 μg/rat) attenuated LPS-induced anorexia and counteracted the LPS-dependent decrease in respiratory quotient and energy expenditure. In conclusion, the current findings substantiate a role of central iNOS dependent NO formation in LPS-induced effects on eating and energy homeostasis. A pharmacological blockade of NO formation might be a therapeutic approach to ameliorate disease-related anorexia.

Water Uptake and Reduced Pressure of Intercellular Space Induced by Respiration Related to Sweet Cherry Fruit Cracking

The water uptake inducing cracking of sweet cherry fruit (Prunus avium L.) was investigated in relation to the reduced pressure in flesh intercellular space caused by respiration of the fruit. The respiratory quotient decreased from 0.74 on 28 DAB to 0.43 on 60 DAB, and highly correlated with DAB in a quadratic equation. Flesh intercellular space capacity was increased from the immature stage with fruit growth, then it attained maximum of 129.4 μL/fruit on 55 DAB. However it decreased greatly to 95.6 μL/fruit on 57 DAB, and it did not change until 60 DAB. The pressure of flesh intercellular space was around 3–10 Pa lower than ambient air pressure, and negative correlation was found between the respiratory quotient of the fruit and the flesh intercellular space pressure. These results suggested that water on the fruit surface was apparently sucked into flesh intercellular spaces by that decreased pressure, which resulted from the decrease of the respiratory quotient.

Effect of Bariatric Surgery on Physical Function and Metabolic Rate

Laparoscopic banding and gastric bypass surgeries have demonstrated to be effective methods for inducing weight loss in the morbidly obese. Limited information is available regarding the changes in physical function, metabolic rate and respiratory quotient (RQ) associated with weight loss experienced post bariatric surgery. The purpose of this study was to determine physical function, metabolic rate, resting energy expenditure and RQ associated with weight loss experienced post bariatric surgery. METHODS: Six morbidly obese 160.08 ± 60.48 kg, BMI = 56.08 ± 10.13 male (n=2) and female (n=4) subjects age 41.50 ± 8.22 years were recruited from a private surgical practice to participate in the study. Five subjects underwent laparoscopic banding and one subject gastric bypass. Subjects completed pre-operative testing (T-1) 46.83 ± 35.36 days before surgery and post-operative testing (T-2) 52.83 ± 17.23 days after surgery. Testing consisted of height, weight, heart rate, blood pressure, sit to stand test, 4m walk test, electrical impedance of the upper extremity, lower extremity, resting energy expenditure and RQ. RESULTS: Weight decreased significantly and there was a non-significant trend toward a decrease in RQ. There were no significant changes in sit to stand test, 4 m walk test and energy expenditure when corrected for body weight measured by oxygen consumption.TABLECONCLUSION: Weight loss was associated with a trend toward increased fat metabolism as indicated by decreased RQ. Despite the significant reduction in weight there were no changes in sit to stand test or 4 m walk test. These findings suggest that movement patterns are primarily influenced by established neurological patterns independent of weight loss.

Regulation of food intake and body weight by recombinant proghrelin

Ghrelin is a 28-amino-acid hormone derived from the endoproteolytic processing of its prehormone proghrelin. Although ghrelin has been reported to regulate food intake and body weight, it is still unknown whether proghrelin exercises any biological function. Here we show that recombinant proghrelin alters food intake and energy metabolism in mice. After intraperitoneal administration of recombinant proghrelin (100 nmol/kg body wt), cumulative food intake was significantly increased at days 1, 2, and 3 (6 +/- 0.3, 13 +/- 0.5, and 20 +/- 0.8 g vs. 5 +/- 0.2, 10 +/- 0.2, and 16 +/- 0.3 g of the control mice receiving normal saline, respectively, n = 6, P < 0.05). Twelve-hour cumulative food intake in the light photo period in mice treated with proghrelin increased significantly relative to the control (2.1 +/- 0.04 vs. 1.3 +/- 0.2 g, n = 6, P < 0.05). No change in 12-h cumulative food intake in the dark photo period was observed between mice treated with proghrelin and vehicle (4.2 +/- 0.6 vs. 4.3 +/- 0.6 g, n = 6, P > 0.05). This is associated with a decrease in body weight (0.42 +/- 0.04 g) for mice treated with proghrelin, whereas control animals gained body weight (0.31 +/- 0.04 g). Mice treated with proghrelin demonstrate a significant decrease in respiratory quotient, indicating an increase in fat consumption. Recombinant proghrelin is functionally active with effects on food intake and energy metabolism.

Effects of a leucine‐containing nutraceutical on fat oxidation in overweight and obese adults

We have previously shown leucine to modulate energy partitioning between adipose tissue and myocytes by suppressing adipocyte lipid storage, increasing myocyte fatty acid oxidation and stimulating mitochondrial biogenesis in both cell types. Consequently, we have now evaluated the efficacy of a nutraceutical preparation (InnutriaTM) containing 2.25 g leucine/d in 3 daily doses on fat oxidation. 20 overweight and obese subjects were randomized to receive Innutria‐supplemented or control tea three times/day for 28 days. All subjects maintained their usual diets and modestly increased their physical activity by walking (steps increased from baseline 3882+713 steps/day to 8406+925 steps/day during treatment; no difference between groups). Respiratory quotient (RQ) and fat oxidation were assessed by respiratory gas exchange on day 0 and day 28. There were no significant changes in RQ or fat oxidation in the control group (RQ change, 0.011; fat oxidation change, ‐0.23+0.28 g/hr, ‐5.6 g/d, NS), while the supplemented group exhibited a decrease in RQ (‐0.019, p&lt;0.04) and a corresponding increase in fat oxidation (+1.4+0.4 g/hr, 33.6 g/d, p&lt;0.01). These data demonstrate that a nutraceutical blend containing leucine effectively increases fat oxidation and may thereby contribute to weight management in overweight and obese subjects.

α2-AMPK activity is not essential for an increase in fatty acid oxidation during low-intensity exercise

A single bout of exercise increases glucose uptake and fatty acid oxidation in skeletal muscle, with a corresponding activation of AMP-activated protein kinase (AMPK). While the exercise-induced increase in glucose uptake is partly due to activation of AMPK, it is unclear whether the increase of fatty acid oxidation is dependent on activation of AMPK. To examine this, transgenic mice were produced expressing a dominant-negative (DN) mutant of alpha(1)-AMPK (alpha(1)-AMPK-DN) in skeletal muscle and subjected to treadmill running. alpha(1)-AMPK-DN mice exhibited a 50% reduction in alpha(1)-AMPK activity and almost complete loss of alpha(2)-AMPK activity in skeletal muscle compared with wild-type littermates (WT). The fasting-induced decrease in respiratory quotient (RQ) ratio and reduced body weight were similar in both groups. In contrast with WT mice, alpha(1)-AMPK-DN mice could not perform high-intensity (30 m/min) treadmill exercise, although their response to low-intensity (10 m/min) treadmill exercise was not compromised. Changes in oxygen consumption and the RQ ratio during sedentary and low-intensity exercise were not different between alpha(1)-AMPK-DN and WT. Importantly, at low-intensity exercise, increased fatty acid oxidation in response to exercise in soleus (type I, slow twitch muscle) or extensor digitorum longus muscle (type II, fast twitch muscle) was not impaired in alpha(1)-AMPK-DN mice, indicating that alpha(1)-AMPK-DN mice utilize fatty acid in the same manner as WT mice during low-intensity exercise. These findings suggest that an increased alpha(2)-AMPK activity is not essential for increased skeletal muscle fatty acid oxidation during endurance exercise.

Loss of prokineticin receptor 2 signaling predisposes mice to torpor

The genes encoding prokineticin 2 polypeptide (Prok2) and its cognate receptor (Prokr2/Gpcr73l1) are widely expressed in both the suprachiasmatic nucleus and its hypothalamic targets, and this signaling pathway has been implicated in the circadian regulation of behavior and physiology. We have previously observed that the targeted null mutation of Prokr2 disrupts circadian coordination of cycles of locomotor activity and thermoregulation. We have now observed spontaneous but sporadic bouts of torpor in the majority of these transgenic mice lacking Prokr2 signaling. During these torpor bouts, which lasted for up to 8 h, body temperature and locomotor activity decreased markedly. Oxygen consumption and carbon dioxide production also decreased, and there was a decrease in respiratory quotient. These spontaneous torpor bouts generally began toward the end of the dark phase or in the early light phase when the mice were maintained on a 12:12-h light-dark cycle and persisted when mice were exposed to continuous darkness. Periods of food deprivation (16-24 h) induced a substantial decrease in body temperature in all mice, but the duration and depth of hypothermia was significantly greater in mice lacking Prokr2 signaling compared with heterozygous and wild-type littermates. Likewise, when tested in metabolic cages, food deprivation produced greater decreases in oxygen consumption and carbon dioxide production in the transgenic mice than controls. We conclude that Prokr2 signaling plays a role in hypothalamic regulation of energy balance, and loss of this pathway results in physiological and behavioral responses normally only detected when mice are in negative energy balance.

Carnitine and Fatty Acid Oxidation in Sepsis

Fatty acid oxidation is usually thought of as being a preferred ATP source during sepsis, as shown by the decrease in respiratory quotient in septic patients and animals. However, fatty acid oxidation may be impaired relative to circulating triglyceride levels, resulting in increased cycling between triglycerides and non-esterified fatty acids. The rate of fatty acid oxidation is critically dependent on the stage of sepsis. Carnitine may be depleted during sepsis by a combination of muscle wasting, erythrocyte haemolysis, decreased tissue uptake, reduced kidney reabsorption of free carnitine, and increased excretion of acyl-carnitines. Whether there may be any beneficial effects of carnitine supplementation during sepsis, is, as yet, uncertain.