Thermic Effect Research Articles

Effect of electromagnetic induction on the heat transmission in engine oil-based hybrid nano and ferrofluids: A nanotechnology application

This analysis investigates the control of electromagnetic induction over the flow and heat transmission in shear-thickening hybrid nano and ferrofluids for cooling/heating applications. The stream is time-free and not turbulent. The leading equations are equipped with buoyancy, irregular heat sink/source, and thermic heat effects. The transformed, resulting equalities are resolved with the help of the bvp5c package. Twin expositions are discussed for the hybrid nano (engine oil (EO) + aluminum oxide (Al2O3) + titanium dioxide (TiO2)) and hybrid ferro (EO + iron oxide (Fe3O4) + cobalt ferrite (CoFe2O4)) cases. Numerical momentum, magnetic induction, and thermal profiles are obtained via graphical illustrations. Also, the tables present the friction factor and the measure of thermic transport. It divulges from consequences that the hybrid ferrofluids have a more conducive rate than hybrid nanoliquids, and the Nusselt number shrinks for uneven heat sink/source constraint values. Also, electromagnetic induction controls hybrid ferroliquid more than hybrid nanofluids. The prime application of the current research glimpsed in engineering practices viz. metal extrusion, synthetic fiber, microfluidics, glass fiber manufacture, etc.

Brown fat-associated postprandial thermogenesis in humans: Different effects of isocaloric meals rich in carbohydrate, fat, and protein.

The increase of whole-body energy expenditure seen after a single meal ingestion, referred to as diet-induced thermogenesis (DIT), substantially varies depending on the meal's macronutrient composition. Brown adipose tissue (BAT), a site of non-shivering thermogenesis, was reported to be involved in DIT. To examine the effects of meal composition on BAT-associated DIT in humans, healthy male participants underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity, and respiratory gas analysis for 2 h after ingestion of a carbohydrate-, protein-, or fat-rich meal (C-meal, P-meal, and F-meal, respectively). The calculated DIT at 2 h was 6.44 ± 2.01%, 3.49 ± 2.00%, and 2.32 ± 0.90% of the ingested energy after the P-meal, C-meal, and F-meal, respectively. The DIT after C-meal ingestion correlated positively with BAT activity (P = 0.011), and was approximately twice greater in the group with high-BAT activity than in the group with low-BAT activity (4.35 ± 1.74% vs. 2.12 ± 1.76%, P < 0.035). Conversely, the DIT after F-meal or P-meal ingestion did not correlate with BAT activity, with no difference between the two groups. Thus, BAT has a significant role in DIT after ingestion of a carbohydrate-rich meal, but hardly after ingestion either protein- or fat-rich meal.

Time-restricted feeding mitigates obesity through adipocyte thermogenesis.

Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.

Prediction of activity-related energy expenditure under free-living conditions using accelerometer-derived physical activity

The purpose of the study was to develop prediction models to estimate physical activity (PA)-related energy expenditure (AEE) based on accelerometry and additional variables in free-living adults. In 50 volunteers (20–69 years) PA was determined over 2 weeks using the hip-worn Actigraph GT3X + as vector magnitude (VM) counts/minute. AEE was calculated based on total daily EE (measured by doubly-labeled water), resting EE (indirect calorimetry), and diet-induced thermogenesis. Anthropometry, body composition, blood pressure, heart rate, fitness, sociodemographic and lifestyle factors, PA habits and food intake were assessed. Prediction models were developed by context-grouping of 75 variables, and within-group stepwise selection (stage I). All significant variables were jointly offered for second stepwise regression (stage II). Explained AEE variance was estimated based on variables remaining significant. Alternative scenarios with different availability of groups from stage I were simulated. When all 11 significant variables (selected in stage I) were jointly offered for stage II stepwise selection, the final model explained 70.7% of AEE variance and included VM-counts (33.8%), fat-free mass (26.7%), time in moderate PA + walking (6.4%) and carbohydrate intake (3.9%). Alternative scenarios explained 53.8–72.4% of AEE. In conclusion, accelerometer counts and fat-free mass explained most of variance in AEE. Prediction was further improved by PA information from questionnaires. These results may be used for AEE prediction in studies using accelerometry

Infrared Thermography for the Detection of Changes in Brown Adipose Tissue Activity.

Measuring brown adipose tissue (BAT) activity by positron emission tomography computed tomography (PET-CT) via the accumulation of 18F-fluorodeoxyglucose (FDG) after a meal or in obese or diabetic patients fails as the method of choice. The main reason is that 18F-FDG competes with the postprandial high glucose plasma concentration for the same glucose transporter on the membrane of BAT cells. In addition, BAT uses fatty acids as a source of energy as well, which is not visible with PET-CT and could be changed along with glucose concentration in obese and diabetic patients. Therefore, to estimate the physiological importance of BAT in animals and humans, a new infrared thermography method used in recent publications is applied. After overnight fasting, BAT activity was measured by infrared thermography before and after a meal in human volunteers andfemale wild-type mice. The camera software calculates the object's temperature using distance from the object, skin emissivity, reflected room temperature, air temperature, and relative humidity. In mice, the shaved area above the BAT was a region of interest for which average and maximal temperatures were measured. The phase of the estrous cycle in female mice was determined after an experiment by vaginal smears stained with cresyl violet (0.1%) stain solution. In healthy volunteers, two skin areas of the neck were selected: the supraclavicular area (above the collarbone, where BAT cells are present) and the interclavicular area (between the collarbones, where there is no BAT tissue detected). BAT activity is determined by the subtraction of those two values. Also, the average and maximal temperatures of skin areas could be determined in animals and human participants. Changes in BAT activity after a meal measured by infrared thermography, a non-invasive and more sensitive method, were shown to be sex, age, and phase of the estrous cycle dependent in laboratory animals. As part of diet-induced thermogenesis, BAT activation in humans was also proven to be sex, age, and body mass index dependent. Further determining the pathophysiological changes in BAT activity after a meal will be of great importance for participants with high glucose plasma concentrations (obesity and diabetes mellitus type 2), as well as in different laboratory animals (knock-out mice). This method is also a variable tool for determining possible activating drugs that could rejuvenate BAT activity.

NPFF signalling is critical for thermosensory and dietary regulation of thermogenesis

Thermogenesis is a centrally regulated physiological process integral for thermoregulation and energy homeostasis. However, the mechanisms and pathways involved remain poorly understood. Importantly, in this study we uncovered that in an environment of 28 °C that is within the mouse thermoneutral zone, lack of NPFF signalling leads to significant increases in energy expenditure, resting metabolic rate and brown adipose tissue (BAT) thermogenesis, which is associated with decreased body weight gain and lean tissue mass. Interestingly, when exposed to a high-fat diet (HFD) at 28 °C, Npff−/− mice lost the high energy expenditure phenotype observed under chow condition and exhibited an impaired diet-induced thermogenesis. On the other hand, under conditions of increasing levels of thermal demands, Npff−/− mice exhibited an elevated BAT thermogenesis at mild cold condition (22 °C), but initiated comparable BAT thermogenic responses as WT mice when thermal demand increased, such as an exposure to 4 °C. Together, these results reveal NPFF signalling as a novel and critical player in the control of thermogenesis, where it regulates thermosensory thermogenesis at warm condition and adjusts thermoregulation under positive energy balance to regulate diet-induced thermogenesis.

Ginger infusion increases diet-induced thermogenesis in healthy individuals: A randomized crossover trial

The purpose of this study is to evaluate the acute effect of ingesting ginger infusion on energy metabolism, appetite responses, and food intake in healthy individuals. This is a clinical (RBR-9ZJGQM), randomized, open, and crossover study with a minimum interval of seven days between treatments. Two drinks, ginger infusion (2 g) and water (control) were served with a standard breakfast. It has 21 volunteers of both sexes (18–40 years old, 18.5–26 kg/m2). Consumption of ginger tea increased on average 95.5±27.4 kcal/day the non-nitrogen energy expenditure after 240 min of ingestion (p = 0.002). There was a significant effect of ginger on diet-induced thermogenesis (difference between ginger tea treatment vs. control: 113.0±43.0 kcal/day, p = 0.016). However, appetitive responses and prospective food intake did not differ between ginger tea and water intake.

Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice.

Background and aimCircadian clocks in most peripheral tissues are entrained mainly by feeding. Therefore, this study aimed to investigate whether the daily rhythm of core body temperature (CBT), including the effect of diet-induced thermogenesis, varies according to habitual feeding time.MethodsWild-type and uncoupling protein 1 (UCP1) knockout mice were fed only during the first 4 h (Breakfast group) or the last 4 h of the dark period (Dinner group) for 17 days. On day 18, both groups were fed twice for 2 h, at the same starting times. Locomotor activity and CBT were measured continuously during the experiment.ResultsOn day 18, CBT increased at the beginning of each feeding period, regardless of the group and strain. However, the CBT increase induced by the first meal decreased sharply in the Breakfast group and mildly in the Dinner group; the opposite was observed after the second meal. In UCP1 knockout, but not wild-type, mice, the total amount of CBT was significantly lower in the Dinner group than in the Breakfast group. These effects were mostly independent of the locomotor activity and food intake.ConclusionThese results reveal that the effect of habitual feeding time on the daily rhythm of CBT is sustained at least until the following day. These effects may be mediated by both UCP1-dependent and -independent mechanisms.

The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases

Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.

Energy balance in cancer survivors at risk of weight gain: a review.

The study of energy balance [i.e., energy intake (EI) and energy expenditure (EE)] is a powerful tool for understanding body weight regulation and may contribute to our understanding of rapid weight gain risk in certain cancer survivors post-diagnosis. The purpose of this review was to summarize studies that assessed longitudinal, prospective changes in components of energy balance from diagnosis/start of treatment to any duration of follow-up in cancer survivors with prior evidence of weight gain (breast, prostate, thyroid, gynecologic, testicular, and acute lymphoblastic leukemia) RESULTS: The available literature suggests that energy balance components may be altered in cancer survivors who have a heightened risk of weight gain post-diagnosis. The evidence for EI was overall inconsistent. Conversely, decreases in resting and physical activity EE during the active phases of treatment (e.g., chemotherapy, hypothyroid state) were commonly noted, which then slowly rebounded towards baseline levels at the end of treatment and during follow-up assessments. Much of this evidence is based on data collected from breast cancer survivors, which highlights a paucity of data currently available on other cancer types. While there is growing acknowledgement that weight management interventions in cancer survivors are needed, it is important to recognize that changes in both behavioral (EI, physical activity EE) and passive (resting EE, thermic effect of food) components of energy balance may occur post-diagnosis. This information can help to inform weight management interventions which often entail modifications in diet and/or physical activity.

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

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). 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. 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. The precision of 24-hour EE and SMR was high, whereas it was lower for PAEE and poor for TEF.

Cinnamon Infusion Reduces Satiety and Increases Energy Intake: A Randomized Crossover Trial

Background/Aims: This study aimed to evaluate the effects of the intake of a single dose of cinnamon infusion on energy metabolism, appetite responses, and food intake in healthy individuals. Methods: This was an open randomized crossover clinical trial, with a minimum washout of 7 days, in which two standardized breakfasts were served randomly: one with cinnamon infusion (2 g, Cinnamomum sp.) and one with water (control). The study included 21 healthy volunteers. Energy expenditure (EE), diet-induced thermogenesis (DIT), respiratory quotient (RQ), substrate oxidation, and appetite responses were evaluated, as well as prospective food intake. Results: Ingestion of cinnamon infusion did not alter EE, DIT, RQ, or substrate oxidation. The incremental area under the curve for hunger, satiety, and desire to eat did not differ between the treatment with cinnamon infusion and water; however, there was a reduction in the feeling of satiety (p = 0.021) compared to the control treatment. The energy consumption of the first meal after treatment was higher (p = 0.05) in the treatment with cinnamon infusion than in the control treatment. Regarding macronutrients or food intake throughout the day, there was no difference between treatments. Conclusions: Although it did not affect energy metabolism, consuming a single dose of cinnamon infusion promoted less feeling of satiety and increased energy intake in the first meal after treatment. The study protocol was registered at the Brazilian Clinical Trials Registry Platform (RBR-5ftg3z).

Activation of thermogenesis pathways in testis of diet-induced obesity mice

High-fat diet (HFD) induced obesity (DIO) has been shown impacts on metabolism, hormonal profile, male fertility, and spermatogenesis. We employed genome-wide transcriptional analysis on the testis of diet induced obesity (DIO) and normal chow (NC) C57BL/6 J male mice to search genes regulated by obesity in testis. Both blood glucose and lipids contents significantly increased in DIO mice after 8 weeks fat-rich feeding. RNA-seq analysis revealed 371 down-regulated and 460 up-regulated transcripts in DIO group comparing to NC group. Chromosome 3, 4, 9, 16, and 18 were significantly more active, while chromosome 5, 10, and 19 were significantly more inactive after 8-week fat-diet feeding. Wilcoxon enrichment analysis discovered that the thermogenesis pathway (KEGG) was significantly enriched in the testis of DIO group (with 8 enriched up-regulated genes: Smarca2, Adcy3, Atp5pb, Creb1, Gnas, Rps6kb2, Upcrc1 and Dpf1). Real-time PCR further confirmed that Smarca2 and Atp5pb were upregulated in the testis of DIO mice. These finding implied that diet-induced thermogenesis pathways could be altered in the testis of DIO mice.

Ensiling and thermic treatment effects on nutrient content, protein solubility, and in vitro fermentation of partial crop faba beans

Legumes such as faba beans have a great potential to create local, independent, and high-quality protein resources for ruminant nutrition. Suitable methods for cost- and energy-effective preservation and protein stabilization against rapid fermentation in the rumen play an important role. Partial crop faba beans harvested with 500 or 708 g dry matter (DM)/kg were ensiled, toasted (160 °C, 60 min), or ensiled and toasted and it was investigated how this affects nutrient composition, protein solubility, carbohydrate fermentation, and in vitro organic matter digestibility (IVOMD). Non-protein nitrogen (NPN) concentrations increased and true protein (TP) concentrations decreased after ensiling, depending strongly on DM concentration of the plant (i.e., on maturity) – in NPN, from 15% to 35% (P < 0.001) and from 16% to 21% of crude protein (CP) (P > 0.05), and in TP, from 85% to 65% and from 83% to 79% of CP with 500 and 708 g DM/kg, respectively (P > 0.05) – whereas concentrations of soluble protein did not increase as much as expected. Toasting reduced soluble protein concentration in native faba beans from 56% to 29% and from 54% to 40% of CP with 500 and 708 g DM/kg, respectively (P < 0.001) and in ensiled faba beans from 58% to 38% and from 60% to 34% of CP with 500 and 708 g DM/kg, respectively, compared to the native material (P < 0.001). Ensiling and toasting slightly affected other crude nutrient or metabolizable energy concentrations, carbohydrate fermentation, and IVOMD.

Effects of Early Time-Restricted Eating on Intestinal Energy Absorption in Healthy Adults: The DIGEST Study Protocol

ObjectivesAligning energy intake with circadian rhythms and extending periods of fasting within a 24-h cycle improves whole-body metabolism. However, it is unknown if these improvements are related to changes in intestinal nutrient absorption (i.e., digestibility). The primary objective of the DIGEST study is to determine the impact of early time-restricted eating (eTRE) on energy and macronutrient digestibility, metabolizable energy, intestinal health and microbial composition, energy expenditure, glycemic variability, and circulating metabolites. A secondary objective is to identify factors that predict energy digestibility efficiency. MethodsHealthy adults (n = 16, 20–45 y) will participate in a randomized, crossover, controlled feeding trial consisting of two 9-d weight maintenance diet periods, separated by at least a 2-wk washout. Participants will be randomized to follow an eTRE schedule (i.e., all calories consumed between 0800 and 1400) and a control eating schedule (i.e., all calories consumed between 0800 and 2000). Following a 3-d acclimation to the study diet and eating schedule, participants will consume a non-absorbable blue dye capsule to mark the beginning of stool collection. This will be repeated on day 7 to mark the end of stool collection. All urinary output will be collected on days 4, 5, and 6. Energy content of the diet, stool, and urine will be measured by bomb calorimetry. Digestible energy will be calculated as the difference between dietary energy intake and stool energy loss, and metabolizable energy as the difference between digestible energy and urinary energy loss. On day 5, participants will consume a capsule that measures intestinal transit time and hydrogen gas production. On day 6, thermic effect of food, circulating metabolites, and circadian gene expression will be measured in response to a mixed meal. A continuous glucose monitor will be worn during each study period to assess glucose concentrations and variability. ResultsTo date, 10 participants have been enrolled and randomized and 3 participants have completed the study. ConclusionsThis is the first study, to our knowledge, to investigate the effects of eTRE on energy digestibility, which may provide mechanistic insight regarding the benefits of eTRE on whole-body metabolism. Funding Sources2021 Herbalife Nutrition Scholarship, FSU Council on Research & Creativity.

Maternal Consumption of a Cafeteria Diet during Lactation Leads to Altered Diet-Induced Thermogenesis in Descendants after Exposure to a Western Diet in Adulthood.

This study investigates the ability of a maternal cafeteria diet during lactation to program brown adipose tissue (BAT) metabolic responses to an obesogenic diet re-exposure in the adult offspring after consuming a standard diet (SD). Nursing rats were fed an SD or a cafeteria diet during lactation. Their offspring (O-C and O-CAF, respectively) were weaned onto an SD, and at 16 weeks of age they were switched to a Western diet until week 24. Gene and protein expression in BAT were measured at PN22 and at 24 weeks. At PN22, compared to controls, O-CAF rats displayed lower mRNA levels of lipogenesis-related genes (Fasn), and higher expression of genes related to lipolysis (Pnpla2), fatty acid uptake (Cd36, Lpl), and oxidation (Cpt1b). Additionally, O-CAF animals displayed increased mRNA levels of Adrb3, Ucp1, and Cidea. In adulthood, these animals maintained lower mRNA levels of lipogenesis-related genes (Pparg, Srebf1, Fasn), but displayed lower expression of genes related to fatty acid uptake (Cd36), fatty acid oxidation (Cpt1b), lipolysis (Pnpla2), Adrb3, Ucp1, and Cidea. Thus, exposure to an obesogenic diet in nursing rats can affect long-term lipid metabolism and attenuate diet-induced thermogenesis in BAT in response to a new obesogenic dietary challenge later in life.

Acute Cannabidiol Administration Does Not Increase the Thermic Effect of Feeding in Men with Overweight and Obesity

The thermic effect of feeding (the increase in energy expenditure above resting metabolic rate following ingestion of food) is lower in adult humans with overweight and obesity compared to their lean counterparts. In animal models of obesity, the endocannabinoid system is upregulated and is thought to contribute to an unfavorable metabolic phenotype. The influence of cannabidiol, a non‐psychoactive component of Cannabis sativa L., on the thermogenic properties of the endocannabinoid system in humans is unclear. Accordingly, the purpose of the current study was to explore the hypothesis that acute administration of cannabidiol would increase the thermic effect of feeding. Metabolic rate, via indirect calorimetry, was determined at rest and over 4‐hours following ingestion of a liquid, mixed macronutrient meal (22% fat, 62% carbohydrate, 16% protein) equivalent to 40% of resting metabolism, in 11 adult men with body mass index greater than 25 kg/m2 (age: 26 ± 9 years; body mass: 93.7 ± 13.0 kg; body mass index: 29.8 ± 3.0 kg/m²; body fat: 29.4% ± 4.6% (mean ± SD)) on two separate occasions. Immediately following meal ingestion, participants were administered either 30 mg of cannabidiol or placebo, in a randomized, single‐blind crossover fashion. Resting metabolic rate did not differ between trials (1745 ± 311 vs. 1744 ± 288 kcal/day; P=0.98). Compared with rest, energy expenditure was increased after ingestion of the liquid meal (P&lt;0.01) but was unaffected by cannabidiol (Time x Placebo vs. Cannabidiol: P = 0.21). The area under the thermic effect of feeding response curve was also unaffected by cannabidiol (57 ± 24 vs. 58 ± 16 kcal/min x min; P=0.92). Respiratory exchange ratio, an indicator of substrate utilization, was not different between trials at rest (0.81 ± 0.04 vs. 0.79 ± 0.04; P=0.09). Ingestion of the meal increased respiratory exchange ratio (P&lt;0.01), indicative of increased reliance on carbohydrate oxidation, but again this response was unaffected by cannabidiol (Time x Placebo vs. Cannabidiol: P=0.08). These preliminary data suggest that a single 30 mg dose of cannabidiol does not influence the thermic effect of feeding, a significant contributor to total daily energy expenditure, in men with overweight or obesity. Cannabidiol has been purported to have multiple beneficial effects on physiological function, it appears that these effects may be independent of any influence on the thermic effect of feeding.

Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole ‘nitazene’ synthetic opioid

Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles ('nitazenes'), are being exploited to create new μ-opioid receptor (MOR) agonists. Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods. A series of analytically confirmed fatalities is described to complement preclinical findings. Radioligandbinding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09nM) over δ-opioid (Ki = 959nM) and κ-opioid (Ki = 980nM) receptors. In a MOR-β-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348nM), similar to etonitazene (EC50 = 0.360nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9nM) and morphine (EC50 = 290nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antinociceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209mg/kg) and morphine (ED50 = 3.940mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace.

Sympathetic blockade on diet induced thermogenesis in the congenic LA/Ntul//-cp rat

The effects of overfeeding highly palatable diets via the cafeteria feeding diet method (Café) has been shown to be a reliable experimental model to induce diet induced thermogenesis (DIT) in young adult normally lean rats of several strains. Groups of young adult lean LA/ Ntul//-cp rats were offered a Purina chow diet (CHOW) or the same diet plus a daily café supplement both ad libitum from 10 until 24 weeks of age. The drug α-methylparatyrosine (α-MPT) was administered to groups (250 mg α-MPT/kg BW, i.p.) to ablate sympathetic (SNS) activity or a sham injection of physiologic saline given, and measures of fasting resting thermogenesis obtained at thermal neutrality (30°C) before and after the α-MPT or sham administration. The Café diet resulted in a 67% increase in body weight (BW) and a ~25% increase in resting oxygen consumption (VO2) following café overfeeding in both groups, while only a 40% increase in BW and no additional increase in VO2 occurred in normally CHOW fed rats while the sham injection was without any variations from normal physiologic responses as predicted. Sympathetic blockade with α-MPT was associated with modest decreases in body temperature and an average ~12-15% decrease in VO2 in the café treated group, but when the VO2 data were arithmetically corrected to isothermal conditions only a net 3% decrease occurred in CHOW fed rats and was without effect on the SHAM group. Serum T3 concentrations increased by 92% and urinary catecholamine excretion of VMA &gt;250% following the café diet, but the urinary vanilmandelic acid (VMA) excretion was virtually nil following the sympathetic blockade. These observations indicate that the SNS-mediated contribution component to DIT following prolonged café overfeeding under conditions of thermal neutrality contribute approximately 50% of the thermic response. While under normal long term CHOW feeding the SNS component may be as little as 3% of the thermic response, and thus, the total thermic response of DIT likely represents a combination of short acting SNS and longer acting non-SNS mechanisms, including a likely significant thyroidal component in normally lean animals.

First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass.

N-Piperidinyl etonitazene ('etonitazepipne') represents a recent addition to the rapidly expanding class of 2-benzylbenzimidazole 'nitazene' opioids. Following its first identification in an online-sourced powder and in biological samples from a patient seeking help for detoxification, this report details its in-depth chemical analysis and pharmacological characterization. Analysis of the powder via different techniques (LC-HRMS, GC-MS, UHPLC-DAD, FT-IR) led to the unequivocal identification of N-piperidinyl etonitazene. Furthermore, we report the first activity-based detection and analytical identification of N-piperidinyl etonitazene in authentic samples. LC-HRMS analysis revealed concentrations of 1.21ng/mL in serum and 0.51ng/mL in urine, whereas molecular networking enabled the tentative identification of various (potentially active) urinary metabolites. In addition, we determined that the extent of opioid activity present in the patient's serum was equivalent to the in vitro opioid activity exerted by 2.5-10ng/mL fentanyl or 10-25ng/mL hydromorphone in serum. Radioligand binding assays in rat brain tissue revealed that the drug binds with high affinity (Ki = 14.3nM) to the µ-opioid receptor (MOR). Using a MOR-β-arrestin2 activation assay, we found that N-piperidinyl etonitazene is highly potent (EC50 = 2.49nM) and efficacious (Emax = 183% versus hydromorphone) in vitro. Pharmacodynamic evaluation in male Sprague Dawley rats showed that N-piperidinyl etonitazene induces opioid-like antinociceptive, cataleptic, and thermic effects, its potency in the hot plate assay (ED50 = 0.0205mg/kg) being comparable to that of fentanyl (ED50 = 0.0209mg/kg), and > 190 times higher than that of morphine (ED50 = 3.940mg/kg). Taken together, our findings indicate that N-piperidinyl etonitazene is a potent opioid with the potential to cause harm in users.