Prolonged cortisol elevation alters whole body and tissue metabolism in rainbow trout (Oncorhynchus mykiss).

Chronic elevation of circulating cortisol is known to have deleterious effects on fish, but information about the consequences of prolonged cortisol elevation on the metabolism of fish is scarce. To test the effects of chronic cortisol elevation on the aerobic performance of rainbow trout, we examined how two severities of chronically elevated plasma cortisol levels affected the oxygen uptake during rest and after exhaustive exercise using a high (HC) and a medium cortisol (MC) treatment. High cortisol doses significantly affected standard (SMR) and maximum metabolic rates (MMR) compared to control fish. In comparison, the medium cortisol treatment elevated maximum metabolic rates (MMR) but did not significantly influence SMR compared to a sham group (S) and control group (C). The medium cortisol treatment resulted in a significantly increased metabolic scope due to an elevation of MMR, an effect that was abolished in the HC group due to co-occuring elevations in SMR. The elevated SMR of the HC-treated fish could be explained by increased in vitro oxygen uptake rates (MO2) of specific tissues, indicating that the raised basal metabolism was caused, in part, by an increase in oxygen demand of specific tissues. Haematological results indicated an increased reliance on anaerobic metabolic pathways in cortisol-treated fish under resting conditions.

Branched Chain Amino Acid Supplementation to a Hypocaloric Diet Does Not Affect Resting Metabolic Rate but Increases Postprandial Fat Oxidation Response in Overweight and Obese Adults after Weight Loss Intervention.

BACKGROUND: Branched chain amino acids (BCAA) supplementation is reported to aid in lean mass preservation, which may in turn minimize the reduction in resting metabolic rate (RMR) during weight loss. Our study aimed to examine the effect of BCAA supplementation to a hypocaloric diet on RMR and substrate utilization during a weight loss intervention. METHODS: A total of 111 Chinese subjects comprising 55 males and 56 females aged 21 to 45 years old with BMI between 25 and 36 kg/m2 were randomized into three hypocaloric diet groups: (1) standard-protein (14%) with placebo (CT), (2) standard-protein with BCAA, and (3) high-protein (27%) with placebo. Indirect calorimetry was used to measure RMR, carbohydrate, and fat oxidation before and after 16 weeks of dietary intervention. RESULTS: RMR was reduced from 1600 ± 270 kcal/day to 1500 ± 264 kcal/day (p < 0.0005) after weight loss, but no significant differences in the change of RMR, respiratory quotient, and percentage of fat and carbohydrate oxidation were observed among the three diet groups. Subjects with BCAA supplementation had an increased postprandial fat (p = 0.021) and decreased postprandial carbohydrate (p = 0.044) oxidation responses compared to the CT group after dietary intervention. CONCLUSIONS: BCAA-supplemented standard-protein diet did not significantly attenuate reduction of RMR compared to standard-protein and high-protein diets. However, the postprandial fat oxidation response increased after BCAA-supplemented weight loss intervention.

Variants of the cry 1 gene may influence the effect of fat intake on resting metabolic rate in women with overweight of obesity: a cross-sectional study.

BACKGROUND: Previous studies have shown that the minor allele (C allele) for Cry 1 rs2287161, may be associated with increased risk of cardiovascular diseases (CVDs). Low resting metabolic rate (RMR) caused by the diet has been shown to have, potentially, unfavorable effects on obesity. This study sought to investigate the interactions between the Cry 1 Gene and fat intake on RMR in women with overweight of obesity. METHODS: This comparative cross-sectional study was conducted on 377 Iranian women with overweight of obesity. A food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. Individuals were categorized into two groups based on the rs2287161 genotype. Body composition, dietary intake, and RMR were assessed for all participants. RESULTS: There was a significant difference between genotypes for fasting blood sugar (FBS) (P = 0.04), fat free mass (FFM) (P = 0.0009), RMR per FFM (P = 0.05), RMR per body mass index (BMI) (P = 0.02), and RMR deviation (P = 0.01). Our findings also showed significant interactions between total fat and C allele carrier group on RMR per kg body weight, RMR per body surface area (BSA), RMR per FFM, and RMR deviation (P for interaction < 0.1), in addition to a significant interaction between CC + CG group genotype and polyunsaturated fatty acids (PUFA) intake on RMR per BMI (P for interaction =0.00) and RMR per kg (P for interaction = 0.02) and RMR per BSA (P = 0.07), compared to the GG group, after control for confounder factors. CONCLUSION: These results highlight that dietary compositions, gene variants, and their interaction, should be acutely considered in lower RMR.

Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model.

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

Capsiate Intake with Exercise Training Additively Reduces Fat Deposition in Mice on a High-Fat Diet, but Not without Exercise Training.

While exercise training (ET) is an efficient strategy to manage obesity, it is recommended with a dietary plan to maximize the antiobesity functions owing to a compensational increase in energy intake. Capsiate is a notable bioactive compound for managing obesity owing to its capacity to increase energy expenditure. We aimed to examine whether the antiobesity effects of ET can be further enhanced by capsiate intake (CI) and determine its effects on resting energy expenditure and metabolic molecules. Mice were randomly divided into four groups (n = 8 per group) and fed high-fat diet. Mild-intensity treadmill ET was conducted five times/week; capsiate (10 mg/kg) was orally administered daily. After 8 weeks, resting metabolic rate and metabolic molecules were analyzed. ET with CI additively reduced the abdominal fat rate by 18% and solely upregulated beta-3-adrenoceptors in adipose tissue (p = 0.013) but did not affect the metabolic molecules in skeletal muscles. Surprisingly, CI without ET significantly increased the abdominal fat rate (p = 0.001) and reduced energy expenditure by 9%. Therefore, capsiate could be a candidate compound for maximizing the antiobesity effects of ET by upregulating beta-3-adrenoceptors in adipose tissue, but CI without ET may not be beneficial in managing obesity.

The effects of pre-sleep consumption of casein protein on next-morning measures of RMR and appetite compared between sedentary pre- and postmenopausal women.

The purpose of the present study was to compare next-morning responses of RMR and appetite to pre-sleep consumption of casein protein (CP) in pre- and postmenopausal women. The study was a randomised, crossover, double-blind, placebo-controlled trial. Seven sedentary premenopausal (age: 19·9 (sd 1·2) years; BMI: 23·1 (sd 2·6) kg/m2) and seven sedentary postmenopausal (age: 56·4 (sd 4·9) years; BMI: 26·3 (sd 3·5) kg/m2) women participated. During visit one, anthropometrics and body composition were measured. Following visit one, subjects consumed either CP (25 g) or placebo (PL) ≥2 h after their last meal and ≤30 min prior to sleep on the night before visits two and three. Visits two and three occurred ≥1 week after visit one and were 48 h apart. During visits two and three, RMR (VO2), RER and appetite were measured via indirect calorimetry and visual analogue scale, respectively. Anthropometrics and body composition were analysed by one-way ANOVA. RMR and measures of appetite were analysed using a 2 × 2 (menopause status × CP/PL) repeated-measures ANOVA. Significance was accepted at P ≤ 0·05. RMR was significantly lower in postmenopausal compared with premenopausal women under both conditions (P = 0·003). When consumed pre-sleep CP did not alter RMR, RER or appetite compared with PL when assessed next morning in pre- and postmenopausal women. These data contribute to growing evidence that pre-sleep consumption of protein is not harmful to next-morning metabolism or appetite. In addition, these data demonstrate that menopause may not alter next-morning RMR, RER or appetite after pre-sleep consumption of CP.

Vitamin D Supplementation Does Not Impact Resting Metabolic Rate, Body Composition and Strength in Vitamin D Sufficient Physically Active Adults.

Supplementation with the most efficient form of Vitamin D (VitD3) results in improvements in energy metabolism, muscle mass and strength in VitD deficient individuals. Whether similar outcomes occur in VitD sufficient individuals' remains to be elucidated. The aim of this study is to determine the effect of VitD3 supplementation on resting metabolic rate (RMR), body composition and strength in VitD sufficient physically active young adults. Participants completed pre-supplementation testing before being matched for sunlight exposure and randomly allocated in a counterbalanced manner to the VitD3 or placebo group. Following 12 weeks of 50 IU/kg body-mass VitD3 supplementation, participants repeated the pre-supplementation testing. Thirty-one adults completed the study (19 females and 12 males; mean ± standard deviation (SD); age = 26.6 ± 4.9 years; BMI = 24.2 ± 4.1 kg·m2). The VitD group increased serum total 25(OH)D by 30 nmol/L while the placebo group decreased total serum concentration by 21 nmol/L, reaching 123 (51) and 53 (42.2) nmol/L, respectively. There were no significant changes in muscle strength or power, resting metabolic rate and body composition over the 12-week period. Physically active young adults that are VitD sufficient have demonstrated that no additional physiological effects of achieving supraphysiological serum total 25(OH)D concentrations after VitD3 supplementation.

Metabolic and Hematological Responses to Endotoxin-Induced Inflammation in Chicks Experiencing Embryonic 2,3,7,8-Tetrachlorodibenzodioxin Exposure.

Dioxin exposure during bird embryonic development disrupts immunity as well as mechanisms involved in energy metabolism, potentially affecting negatively acute-phase responses to pathogens. Thus, we hypothesized that embryonic exposure to 2,3,7,8-tetrachlorodibenzodioxin (TCDD) changes the metabolism and blood physiology of domestic chicks, affecting their physiological competence for responding to immune challenges. To test this hypothesis, we injected doses of 0, 1.5, and 3 ng TCDD/egg (based on survival experiments) on embryonic day 4 and then measured O2 consumption and CO2 production for metabolic rate, ventilation, and body temperature (TB ) in 5-d-old chicks. Then, chicks were injected with lipopolysaccharide (LPS, endotoxin) or saline prior to repeating the physiological measurements. A second chick group exposed to identical TCDD and LPS treatments had blood partial pressure of oxygen, partial pressure of carbon dioxide, pH, bicarbonate concentration, lactate concentration, osmolality, hemoglobin concentration, red blood cell concentration, and hematocrit, as well as TB , analyzed at 1 and 5 h after LPS injection. Metabolism in chicks embryonically exposed to 1.5 and 3 ng TCDD/egg was up to 37% higher, whereas body mass of chicks exposed to 3 ng TCDD/egg was approximately 6% lower. Chicks embryonically exposed to 3 ng TCDD/egg challenged with LPS showed a relative persistent hypometabolism accompanied by elimination of the normal hematological and osmotic responses to LPS. We conclude that embryonic exposure to TCDD affects posthatching metabolism as well as impairs metabolic, hematological, and osmotic responses to LPS. Environ Toxicol Chem 2020;39:2208-2220. © 2020 SETAC.

Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice.

Numerous epidemiological studies have reported that moderate alcohol drinking has beneficial effects. However, few studies have focused on the beneficial effects of ethanol, the common component in alcoholic beverages. Here we fed the C57BL/6 mice with 3.5% v/v ethanol as drinking water substitute to investigate the effects of long-term low-dose ethanol intake in vivo. We evaluated the metabolic rate and mitochondrial function of the long-term low-dose ethanol-intake (LLE) mice, assessed the exercise ability of LLE mice, and fed the LLE mice with a high-fat diet to investigate the potential impact of ethanol on it. The LLE mice showed improved thermogenic activity, physical performance, and mitochondrial function, as well as resistance against the high-fat diet-induced obesity with elevated insulin sensitivity and subdued inflammation. Our results suggest that long-term low-dose ethanol intake can improve healthspan and resist high-fat diet-induced obesity in mice. It may provide new insight into understanding the protective effects of moderate alcohol drinking.

The Effect of Zearalenone on the Cytokine Environment, Oxidoreductive Balance and Metabolism in Porcine Ileal Peyer's Patches.

The aim of the present study was to determine the effect of zearalenone (ZEN), administered per os to gilts at doses equivalent to 50%, 100%, and 150% of no-observed-adverse-effect level (NOAEL) values for 14, 28, and 42 days during weaning, on changes in the parameters of the oxidoreductive balance, cytokine secretion, and basal metabolism in ileal Payer's patches. Immunoenzymatic ELISA tests and biochemical methods were used to measure the concentrations of interleukin 1α, interleukin 1ß, interleukin 12/23p40, interleukin 2, interferon γ, interleukin 4, interleukin 6, interleukin 8, tumor necrosis factor α, interleukin 10, transforming growth factor ß, malondialdehyde, sulfhydryl groups, fructose, glucose, and proline, as well as the activity of peroxidase, superoxide dismutase and catalase. The study demonstrated that ZEN doses corresponding to 50%, 100%, and 150% of NOAEL values, i.e., 5 µg, 10 µg, and 15 µg ZEN/kg BW, respectively, have proinflammatory properties, exacerbate oxidative stress responses, and disrupt basal metabolism in ileal Payer's patches in gilts.

Long-term high intake of 9-PAHPA or 9-OAHPA increases basal metabolism and insulin sensitivity but disrupts liver homeostasis in healthy mice.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have antidiabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA, on the metabolism of mice. C57Bl/6J male mice, 6 weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies.

Characterization of basal and estrogen-regulated antisense transcription in breast cancer cells: Role in regulating sense transcription.

Estrogen-responsive breast cancer cells exhibit both basal and estrogen-regulated transcriptional programs, which lead to the transcription of many different transcription units (i.e., genes), including those that produce coding and non-coding sense (e.g., mRNA, lncRNA) and antisense (i.e., asRNA) transcripts. We have previously characterized the global basal and estrogen-regulated transcriptomes in estrogen receptor alpha (ERα)-positive MCF-7 breast cancer cells. Herein, we have mined genomic data to define three classes of antisense transcription in MCF-7 cells based on where their antisense transcription termination sites reside relative to their cognate sense mRNA and lncRNA genes. These three classes differ in their response to estrogen treatment, the enrichment of a number of genomic features associated with active promoters (H3K4me3, RNA polymerase II, open chromatin architecture), and the biological functions of their cognate sense genes as analyzed by DAVID gene ontology. We further characterized two estrogen-regulated antisense transcripts arising from the MYC gene in MCF-7 cells, showing that these antisense transcripts are 5'-capped, 3'-polyadenylated, and localized to different compartments of the cell. Together, our analyses have revealed distinct classes of antisense transcription correlated to different biological processes and response to estrogen stimulation, uncovering another layer of hormone-regulated gene regulation.

Effects of Sodium Reduction on Energy, Metabolism, Weight, Thirst, and Urine Volume: Results From the DASH (Dietary Approaches to Stop Hypertension)-Sodium Trial.

Two recent studies challenged traditional paradigms of mammalian sodium physiology, suggesting that sodium reduction might cause weight gain by altering metabolism. This new theory has important implications for population-wide dietary recommendations. However, these observations have not been confirmed. In the DASH (Dietary Approaches to Stop Hypertension)-Sodium trial, 412 adults with systolic blood pressure of 120 to 159 mm Hg and diastolic blood pressure of 80 to 95 mm Hg not taking antihypertensive medications were randomly assigned to the DASH diet or a control diet (parallel design). On their assigned diet, participants randomly consumed each of the 3 sodium levels for 4 weeks (crossover design). Participants were provided all meals but could drink noncaloric beverages (eg, water) freely. Throughout the trial, energy intake was adjusted to maintain weight constant. The 3 sodium levels (at 2100 kcal/day) were: low (1150 mg of Na/day), medium (2300 mg of Na/day), and high (3450 mg of Na/day). Energy intake, weight, self-reported thirst, and 24-hour urine volume were assessed after each period. Participants were 57% women and 57% black; mean age was 48 years [SD, 10]). Among those assigned the control, mean weight increased slightly with higher sodium but not among those assigned DASH. Energy intake did not vary across sodium levels in either diet (P-trends ≥0.36). Higher sodium resulted in more thirst (P-trends <0.001 on both diets) and higher urine volume (suggesting higher fluid intake) during the control diet (P-trend=0.007). Reducing sodium did not increase energy requirements to maintain stable weights but did decrease thirst and urine volume (control diet only), findings consistent with the traditional understanding of mammalian sodium physiology. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000608.

A Commercially Available Thermogenic Dietary Supplement Increases Resting Metabolic Rate in Physically Active Males: A Randomized, Double-Blind, Placebo-Controlled Investigation.

Males seeking to improve body composition may ingest thermogenic dietary supplements with the goal of elevating resting metabolic rate. The purpose of this study was to examine the effects of a commercially available dietary supplement (containing ingredients that promote thermogenesis) on resting metabolic rate (RMR) in a randomized, double-blind, placebo-controlled cross-over study. Ten healthy, physically active males (age: 26.5 ± 6.4 years; height: 177.6 ± 7.2 cm; body weight: 80.5 ± 10.8 kg) underwent two testing sessions separated by approximately 7 days. Following baseline assessments of RMR, heart rate (HR), and blood pressure (BP), each participant ingested a thermogenic dietary supplement or a placebo. Assessments were repeated at 60, 120, and 180 minutes postingestion. Approximately 1 week later, participants ingested the alternative supplement and the assessments were repeated. Post hoc analyses revealed that the dietary supplement treatment demonstrated significant elevations in RMR during the postingestion period (p < 0.05) from 1,859 ± 266 kcal to 2,027 ± 288 kcal (increase of 9%) to 2,072 ± 292 kcal (increase of 11.5%) and to 2,040 ± 271 kcal (increase of 9.7%) at 60, 120, and 180 minutes postingestion, respectfully. No significant elevations were observed in the placebo treatment at any time point. HR and BP measures were within normal clinical values throughout the intervention.

Basal insulin secretion capacity predicts the initial response and maximum levels of beta-hydroxybutyrate during therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin, in relation to weight loss.

AIMS: To investigate predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. METHODS: We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max-BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. RESULTS: Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2 , respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* µmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max-BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C-peptide levels compared with the lower three quartiles. CONCLUSIONS: Lower basal insulin secretion capacity might predict greater initial BHB elevations and max-BHB levels during long-term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.

Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio).

Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfluorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3 h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein 11a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.

Naringenin Increases Insulin Sensitivity and Metabolic Rate: A Case Study.

Our studies in primary human adipocytes show that naringenin, a citrus flavonoid, increases oxygen consumption rate and gene expression of uncoupling protein 1 (UCP1), glucose transporter type 4, and carnitine palmitoyltransferase 1ß (CPT1ß). We investigated the safety of naringenin, its effects on metabolic rate, and blood glucose and insulin responses in a single female subject with diabetes. The subject ingested 150 mg naringenin from an extract of whole oranges standardized to 28% naringenin three times/day for 8 weeks, and maintained her usual food intake. Body weight, resting metabolic rate, respiratory quotient, and blood chemistry panel including glucose, insulin, and safety markers were measured at baseline and after 8 weeks. Adverse events were evaluated every 2 weeks. We also examined the involvement of peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), protein kinase A (PKA), and protein kinase G (PKG) in the response of human adipocytes to naringenin treatment. Compared to baseline, the body weight decreased by 2.3 kg. The metabolic rate peaked at 3.5% above baseline at 1 h, but there was no change in the respiratory quotient. Compared to baseline, insulin decreased by 18%, but the change in glucose was not clinically significant. Other blood safety markers were within their reference ranges, and there were no adverse events. UCP1 and CPT1ß mRNA expression was reduced by inhibitors of PPARα and PPARγ, but there was no effect of PKA or PKG inhibition. We conclude that naringenin supplementation is safe in humans, reduces body weight and insulin resistance, and increases metabolic rate by PPARα and PPARγ activation. The effects of naringenin on energy expenditure and insulin sensitivity warrant investigation in a randomized controlled clinical trial.

Slowing down the metabolic engine: impact of early-life corticosterone exposure on adult metabolism in house sparrows (Passer domesticus).

Whole-organism metabolism is an integrative process that determines not only the energy cost of living but also the energy output that is available for behavioral and physiological processes during the life cycle. Developmental challenge is known to affect growth, development of several organs, and several physiological mechanisms (such as HPA responsiveness, oxidative stress or immunity), which may altogether affect adult metabolism. All of these developmental effects are likely to be mediated by glucocorticoids, but the impact of developmental glucocorticoid exposure on adult metabolism has rarely been studied and the results are equivocal. In this study, we examined the impact of developmental exposure to corticosterone (CORT, the main avian glucocorticoid hormone) on resting metabolic rate (RMR, measured in thermoneutrality, 25°C) and thermoregulatory metabolic rate (TMR, measured in cold challenge conditions, 5°C) in the house sparrow. Following experimental administration of CORT at the nestling stage, house sparrows were kept in captivity until adulthood, when their metabolism was measured. We found that post-natal CORT exposure decreased both RMR and TMR in adult sparrows. This CORT-mediated reduction of metabolism was also associated with a reduced overnight body mass loss. Therefore, our results suggest that developmental CORT exposure can orient the phenotype towards an energy-saving strategy, which may be beneficial in a constraining environmental context.

Stimulation of histamine H4 receptor participates in cold-induced browning of subcutaneous white adipose tissue.

Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.

A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. METHOD: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. RESULTS: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. CONCLUSION: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.