Lean Men Research Articles

Dynamic interplay of cortisol and BDNF in males under acute and chronic psychosocial stress – A randomized controlled study

The neurotrophic protein brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain function and is affected by acute and chronic stress. We here investigate the patterns of BDNF and cortisol stress reactivity and recovery under the standardized stress protocol of the TSST and the effect of perceived chronic stress on the basal BDNF levels in healthy young men. Twenty-nine lean young men underwent the Trier Social Stress Test (TSST) and a resting condition. Serum BDNF and cortisol were measured before and repeatedly after both conditions. The perception of chronic stress was assessed by the Trier Inventory for Chronic Stress (TICS). After the TSST, there was a significant increase over time for BDNF and cortisol. Stronger increase in cortisol in response to stress was linked to an accelerated BDNF decline after stress. Basal resting levels of BDNF was significantly predicted by chronic stress perception. The increased BDNF level following psychosocial stress suggest a stress-induced neuroprotective mechanism. The presumed interplay between BDNF and the HPA-axis indicates an antagonistic relationship of cortisol on BDNF recovery post-stress. Chronically elevated high cortisol levels, as present in chronic stress, could thereby contribute to reduced neurogenesis, and an increased risk of neurodegenerative conditions in persons suffering from chronic stress.

Beta2-adrenergic agonist salbutamol exhibits enantioselective disposition in skeletal muscle of lean young men following oral administration.

Salbutamol is a common short-acting beta2-adrenergic agonist used in treatment of asthma and exercise-induced bronchoconstriction but also possesses anabolic and metabolic actions in skeletal muscle. As a chiral compound, salbutamol is a racemic 1:1 mixture of two enantiomers, (R)-salbutamol and (S)-salbutamol, which exhibit divergent pharmacokinetic and pharmacodynamic actions. Despite salbutamol being available for decades, information on the enantioselective disposition of salbutamol enantiomers in human skeletal muscle is absent. In this study, we determined concentrations of (R)-salbutamol and (S)-salbutamol by UHPLC-MS/MS in arterial plasma and vastus lateralis muscle samples from 12 lean young men 2½ and 7 h following ingestion of 24 mg oral salbutamol. Mean (range) arterial plasma concentrations were 10-fold higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol, being 33(9-62) and 49(30-84) ng·mL-1 for (S)-salbutamol and 4 (1-6) and 4 (2-5) ng·mL-1 for (R)-salbutamol 2½ and 7 h following administration, respectively, reflecting faster elimination of the (R)-enantiomer. Mean (range) muscle concentrations were higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol 2½h (0.17 [0.1-0.26] vs. 0.04 [0.02-0.06]) and 7 h (0.31 [0.21-0.46] vs. 0.06 [0.04-0.12] ng·mgd.w. -1) after administration. However, muscle:plasma partition coefficient was two-fold higher (p < 0.001) for (R)-salbutamol than (S)-salbutamol 7 h following administration. These observations demonstrate that oral salbutamol exhibits enantioselective disposition in systemic circulation and muscle favoring the (S)-enantiomer but with higher relative partitioning of the (R)-enantiomer in skeletal muscle. Furthermore, the concentration-time profiles of salbutamol enantiomers are different in skeletal muscle and systemic circulation following oral ingestion. These findings have implications for the application of chiral switch (R)-salbutamol in doping control.

Diabetes surpasses obesity as a risk factor for low serum testosterone level

BackgroundMale obesity is one of the most associated factors with substandard testosterone levels. However, there is growing evidence linking low testosterone levels to insulin resistance and diabetic complications. We aimed to study the impact of diabetes mellitus on testosterone levels and to assess the correlation of various clinical and biochemical factors with hypogonadism.Subjects and methodsThis case-control study was conducted on 160 adult males categorized into four equal groups (40 each); Group A: lean men with T2DM, Group B: obese with T2DM, Group C: lean with normal glycemic profile, Group D: obese with normal glycemic profile. Serum total testosterone (TT), SHBG and HbA1c have been measured. Free testosterone (cFT) and HOMA-IR were calculated.ResultsA significant negative correlation of serum TT and cFTwith BMI (r -0.16, p 0.04/ r -0.26, p < 0.001, respectively) and with waist circumference (WC) (r -0.23, p 0.003 and r -0.3, p < 0.001, respectively). A significant decrease in TT and cFT in the diabetes group versus the non-diabetes one (p < 0.001 for both). TT level was significantly lower in the diabetic lean group than in the non-diabetic lean (p < 0.001), and even significantly lower than in the non-diabetic obese (p < 0.001). TT level in the diabetic obese group was lower than in the non-diabetic obese (p < 0.001). The same for cFT level, lower in the diabetic lean group than in non-diabetic lean (p < 0.001) and lower in the diabetic obese than in the non-diabetic obese (p < 0.001). Concomitant significant reduction in SHBG in the diabetes group (p < 0.001). Linear regression analysis revealed that TT significantly correlated with HOMA-IR. HOMA-IR with WC, age and the duration of diabetes correlated significantly with cFT. In our model, HOMA-IR and HbA1c accounted for approximately 51.3% of TT variability (adjusted R-squared 0.513).ConclusionsThe impact of T2DM on serum testosterone levels was more significant than that of obesity. Our study showed a decrease in SHBG together with cFT among the diabetes group. Hypogonadism is significantly correlated to insulin resistance and poor glycemic control, which implies another perspective on the impact of suboptimal glycemic control on the development of hypogonadism.

Intestinal expression profiles and hepatic expression of LEAP2, ghrelin and their common receptor, GHSR, in humans

Liver-expressed antimicrobial peptide 2 (LEAP2) and ghrelin have reciprocal effects on their common receptor, the growth hormone secretagogue receptor (GHSR). Ghrelin is considered a gastric hormone and LEAP2 a liver-derived hormone and both have been proposed to be involved in the pathophysiology of obesity and type 2 diabetes (T2D). We investigated the mRNA expression of LEAP2, ghrelin and GHSR along the intestinal tract of individuals with and without TD2, and in the liver of men with and without obesity. Mucosal biopsies retrieved with 30-cm intervals throughout the small intestine and from 7 well-defined locations along the large intestine from 12 individuals with T2D and 12 healthy controls together with liver biopsies from 15 men with obesity and 15 lean men were subjected to bulk transcriptomics analysis. Both in individuals with and without T2D, mRNA expression of LEAP2 increased through the small intestine until dropping at the ileocecal valve, with little LEAP2 mRNA expression in the large intestine. Pronounced LEAP2 expression was observed in the liver of men with and without obesity. Robust ghrelin mRNA expression was observed in the duodenum of individuals with and without T2D, gradually decreasing along the small intestine with little expression in the large intestine. Ghrelin mRNA expression was not detected in the liver biopsies, and GHSR mRNA expression was not. In conclusion, we provide unique mRNA expression profiles of LEAP2, ghrelin and GHSR along the human intestinal tract showing no T2D-associated changes, and in the liver showing no differences between men with and without obesity.

The effects of the β1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3-adrenergic receptor (β3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1-AR antagonist could suppress these unwanted effects and increase the stimulation of the β3-AR and β2-AR in BAT. We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

FRI035 Comparative Study Of The Changes In Body Composition According To Age And The Associations With The Risk Of Diabetes Mellitus By Races

Abstract Disclosure: S. Jang: None. K. Kim: None. C. Kim: None. S. Park: None. Introduction: The changes in body composition with aging are known to be associated with the risk of various chronic diseases. But the body composition changes with age among different races, is not well studied. This study aimed to investigate the racial differences in the changes of body composition according to age and the association with prevalent diabetes mellitus. Methods: A total of 37,153 participants was include in the study. 27,864 Korean from the Korea National Health and Nutrition Examination Surveys (KNHANES) 2008-2011 and 9,289 from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 whose age ranged from 20 to 85 years were analyzed. Body composition was measured by dual-energy X-ray absorptiometry (Hologic Horizon) in both cohorts. Relative body composition measures based on young adult (20-29 years) were compared. The association of body composition measures and diabetes were analyzed. Results: Compare to other three races from NHANES, Korean men and women had a lower BMI. Total percentage fat tended to increase with age in all races, but degree of increase with age was not higher in Korean men than in other races and a similar trend was observed in Korean women. Regarding the changes in lean mass, men and women showed different patterns. In men, non-Hispanic white showed peak levels in their 40s and then tended to decrease. All other races showed peaks in their 20s and 30s, and subsequently decreased. Compared to other races, the decline according to age was the largest in Korean men. For women, in all races, the pattern was maintained even after their 20s until their 40s or 50s, and then decreased. The degree of decline was similar in all races. In men, higher fat percentage and lower lean mass were associated with prevalent diabetes in all races. In women, however, higher fat percentage and lower lean mass were associated with prevalent diabetes in only Korean and non-Hispanic white. Conclusion: The changes in body composition according to age vary by race and its association with prevalent diabetes also differs. The clinical significance of changes in body composition according to age and race in chronic diseases needs to be further clarified. Presentation: Friday, June 16, 2023

Associations between urinary biomarkers of exposure to disinfection byproducts and semen parameters: A repeated measures analysis

Toxicological studies have demonstrated that disinfection byproducts (DBPs), particularly haloacetic acids, cause testicular toxicity. However, evidence from human studies is sparse and inconclusive. This study included 1230 reproductive-aged men from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between repeated measures of DBP exposures and semen parameters. Urinary dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures and semen parameters in up to three samples from each man were assessed. The linear mixed effect models were applied to explore the associations between urinary biomarkers of DBP exposures and semen parameters. We found inverse associations of urinary DCAA with sperm count, progressive motility, and total motility (e.g., −14.86%; 95% CI: −19.33%, −10.15% in sperm total motility for the highest vs. lowest quartiles; all P for trends < 0.05). Moreover, urinary TCAA modeled as a continuous variable was negatively associated with sperm progressive motility and total motility, while the inverse associations across increasing urinary TCAA quartiles were seen among leaner men (BMI < 25 kg/m2). Exposure to DBPs reflected by urinary DCAA and TCAA was inversely associated with sperm motility and such effects were more evident among leaner men.

Elevated Insulin Levels Engage the Salience Network during Multisensory Perception

Introduction: Brain insulin reactivity has been reported in connection with systematic energy metabolism, enhancement in cognition, olfactory sensitivity, and neuroendocrine circuits. High receptor densities exist in regions important for sensory processing. The main aim of the study was to examine whether intranasal insulin would modulate the activity of areas in charge of olfactory-visual integration. Methods: As approach, a placebo-controlled double-blind within crossover design was chosen. The experiments were conducted in a research unit of a university hospital. On separate mornings, twenty-six healthy normal-weight males aged between 19 and 31 years received either 40 IU intranasal insulin or placebo vehicle. Subsequently, they underwent 65 min of functional magnetic resonance imaging whilst performing an odor identification task. Functional brain activations of olfactory, visual, and multisensory integration as well as insulin versus placebo were assessed. Regarding the odor identification task, reaction time, accuracy, pleasantness, and intensity measurements were taken to examine the role of integration and treatment. Blood samples were drawn to control for peripheral hormone concentrations. Results: Intranasal insulin administration during olfactory-visual stimulation revealed strong bilateral engagement of frontoinsular cortices, anterior cingulate, prefrontal cortex, mediodorsal thalamus, striatal, and hippocampal regions (p ≤ 0.001 familywise error [FWE] corrected). In addition, the integration contrast showed increased activity in left intraparietal sulcus, left inferior frontal gyrus, left superior frontal gyrus, and left middle frontal gyrus (p ≤ 0.013 FWE corrected). Conclusions: Intranasal insulin application in lean men led to enhanced activation in multisensory olfactory-visual integration sites and salience hubs which indicates stimuli valuation modulation. This effect can serve as a basis for understanding the connection of intracerebral insulin and olfactory-visual processing.

2'-fucosyllactose alone or combined with resistant starch increases circulating short-chain fatty acids in lean men and men with prediabetes and obesity.

Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal colonic SCFA production and improves metabolic parameters. In this randomized, crossover study, 10 lean (BMI 20-24.9 kg/m2) and nine men with prediabetes and overweight/obesity (BMI 25-35 kg/m2) were supplemented with either 2'-FL, 2'-FL+RS, or placebo one day before a clinical investigation day (CID). During the CID, blood samples were collected after a overnight fast and after intake of a liquid high-fat mixed meal to determine plasma SCFA (primary outcomes). Secondary outcomes were fasting and postprandial plasma insulin, glucose, free fatty acid (FFA), glucagon-like peptide-1, and peptide YY concentrations. In addition, fecal SCFA and microbiota composition, energy expenditure and substrate oxidation (indirect calorimetry), and breath hydrogen excretion were determined. In lean men, supplementation with 2'-FL increased postprandial plasma acetate (P = 0.017) and fasting H2 excretion (P = 0.041) compared to placebo. Postprandial plasma butyrate concentration increased after 2'-FL and 2'-FL+RS as compared to placebo (P < 0.05) in lean men and men with prediabetes and overweight/obesity. Additionally, 2'-FL+RS decreased fasting and postprandial plasma FFA concentrations compared to placebo (P < 0.05) in lean men. Supplementation of 2'-FL with/without RS the day before investigation increased systemic butyrate concentrations in lean men as well as in men with prediabetes and obesity, while acetate only increased in lean men. The combination of 2'-FL with RS showed a putatively beneficial metabolic effect by lowering plasma FFA in lean men, indicating a phenotype-specific effect. nr. NCT04795804.

Lower abdominal adipose tissue cannabinoid type 1 receptor availability in young men with overweight.

Cannabinoid type 1 receptors (CB1R) modulate feeding behavior and energy homeostasis, and the CB1R tone is dysgulated in obesity. This study aimed to investigate CB1R availability in peripheral tissue and brain in young men with overweight versus lean men. Healthy males with high (HR, n = 16) or low (LR, n = 20) obesity risk were studied withfluoride 18-labeled FMPEP-d2 positron emission tomography to quantify CB1R availability in abdominal adipose tissue, brown adipose tissue, muscle, and brain. Obesity risk was assessed by BMI, physical exercise habits, and familial obesity risk, including parental overweight, obesity, and type 2 diabetes. To assess insulin sensitivity, fluoro-[18 F]-deoxy-2-D-glucose positron emission tomography during hyperinsulinemic-euglycemic clamp was performed. Serum endocannabinoids were analyzed. CB1R availability in abdominal adipose tissue was lower in the HR than in the LR group, whereas no difference was found in other tissues. CB1R availability of abdominal adipose tissue and brain correlated positively with insulin sensitivity and negatively with unfavorable lipid profile, BMI, body adiposity, and inflammatory markers. Serum arachidonoyl glycerol concentration was associated with lower CB1R availability of the whole brain, unfavorable lipid profile, and higher serum inflammatory markers. The results suggest endocannabinoid dysregulation already in the preobesity state.

1634-P: Brown Adipose Tissue and Muscle Responses to Tolerable Cold in Black and White Young Lean Men

There has been a renewed interest in brown adipose tissue (BAT) as a therapeutic target for diabetes and obesity treatments due to its ability to consume glucose and expend energy in response to cold temperatures and Beta-adrenergic stimulation. However, comparisons of BAT in different races are limited. To address this knowledge gap, we directly compared healthy, young, lean Black and White men in a controlled inpatient study using a whole-room indirect calorimeter. 12 Black and 12 White men completed a 6-13-day protocol with randomized calorimeter temperatures between 18-31°C for 5 hours. Resting metabolic rate (RMR) was measured under reclined, fasted conditions with standard clothing. Body composition was measured by dual x-ray absorptiometry and BAT and muscle glucose uptake activity was quantified using 18-F Fluorodeoxyglucose (18-F FDG) PET-CT following the last chamber study where each individual's coldest tolerable temperature (Tct) was used. Basal metabolic rate (BMR) was defined as minimum RMR and the cold-induced thermogenesis (CIT) was calculated as the percentage increase of RMR above BMR in the cold. The groups were similar in age (23.8±4.7 yrs) and BMI (23.1±1.5 kg/m2) and their Tct (21.0±1.4°C; p=0.54) and CIT (12.1±8.1 kcal/h; p=0.8) were not different. While White males had significantly higher BAT volume (334 ± 188mL vs 242 ± 89mL; p=0.045), BAT volume was comparable between the groups after normalizing to body volume. BAT activity was similar between the groups. Among all muscle activity measured, the intercostal muscles in the Black males had significantly higher activity (p=0.002) and activity was present in all 12 Black participants but only 4 of 12 White males. Individual BAT or muscle activity did not correlate with each other nor with Tct or CIT. Our data suggest that the cold-induced BAT activity was comparable in Black and White young, lean men. The surprising difference in intercostal muscle activity warrants further investigation. Disclosure R.J.Thomas: None. R.Brychta: None. A.B.Courville: None. S.Mcgehee: None. A.M.Cypess: None. K.Y.Chen: None.

Targeting adrenergic receptors to activate brown fat without cardiovascular effects

Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) agonist mirabegron only elicited small increases in brown adipose tissue (BAT) thermogenesis when ingested at the maximal allowable dose (200 mg). This led to off-target binding of the β1- and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. We hypothesize that a balanced activation between β1- and β3-AR is key to stimulating metabolic benefits without cardiovascular side effects. Method: We performed a randomized crossover trial in 8 lean men over two study days. The intervention consisted of oral administration of mirabegron (200 mg) with or without the cardio selective β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT scans were performed sequentially starting at 210 min after oral administration of mirabegron ± bisoprolol. Results: Compared to baselines measures, mirabegron alone or with bisoprolol increased energy expenditure (EE) by 27% (+18.2±6.7 kcal/h) and 11% (7.4±8.1 kcal/h), respectively. However, EE was significantly lower when mirabegron was co-ingested with bisoprolol (P=0.0402) Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.631±0.267 vs 1.695±1.097 min-1 from the [11C]-acetate, P=0.0421), but was not different from mirabegron with bisoprolol (1.273±0.651 min-1). Metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron combined with bisoprolol (24±10 vs 16±8 nmol/g/min, P=0.0284). Mirabegron also increased systolic blood pressure (+5±5 vs -6±10 mmHg, P=0.0252) and heart rate (6±7 vs -5±6 beats·min-1, P=0.0081) relative to baseline levels, which was prevented with bisoprolol. The glycerolipid-fatty acid cycling was not different between mirabegron without or with bisoprolol treatment (total cycling: 118.1±346.9 vs 168.5±439.5 μmol·min-1, P=0.8023). Conclusion: The administration of a β1-AR antagonist decreases the adverse cardiovascular effects of mirabegron. However, at the provided dose, it also restricts the stimulating effects of mirabegron on the thermogenesis. Public foundation grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The catabolism of bilirubin to urobilin might be a leading factor in obesity-induced insulin resistance: New findings in human studies

For unknown reasons, plasma bilirubin levels are lower in obese humans and rodents. One possible explanation is that the hepatic expression of enzymes that regulate its half-life, such as the UGT1A1 UDP-glucuronosyltransferase, is higher in the obese compared to lean persons. Bilirubin is marked for excretion within the liver by the conjugation of two glucuronyl groups by UGT1A1, where it is then transported to the intestines by the biliary system. Once in the intestines, the gut microbiota containing bilirubin reductase remove the glucornyl groups and modify the structure to produce urobilin which can be absorbed via the hepatic portal vein and enter the systemic circulation. Previous correlation studies indicate that urobilin might be a factor that induces visceral obesity and cardiovascular disease. However, the physiological function of urobilin is unknown. The purpose of our study was to determine if there is a correlation between bilirubin and urobilin compared to adiposity and insulin resistance in lean and obese women and men. We hypothesized that bilirubin would be lower and urobilin higher in the plasma of obese humans compared to lean. We found that the plasma levels of urobilin and bilirubin are inversely correlated in women and men. Urobilin levels were positively associated with adiposity (BMI R 2 =0.29 and body fat percentage R 2 =0.25) and insulin resistance (blood glucose R 2 =0.05, insulin R 2 =0.22, and HOMA IR R 2 =0.18) in obese women. Urobilin was only correlated with adiposity in males (BMI R 2 =0.025 and body fat percentage R 2 =0.03). However, the males were not insulin resistant and had no significant difference in HOMA IR compared to lean men. In both women (BMI R 2 =0.065 and body fat percentage R 2 =0.05) and men (BMI R 2 =0.24 and body fat percentage R 2 =0.13), plasma bilirubin levels were negatively associated with adiposity. We observed that plasma bilirubin levels are negatively associated with adiposity, which has been previously reported. The new findings in our study indicate that urobilin is positively associated with adiposity and insulin resistance. Based on these data, we propose that bilirubin and urobilin are maintained at inverse levels in humans via the UGT1A1 axis and that activity is higher in the obese, reducing plasma bilirubin and providing more substrates to produce urobilin in the gut. These events cause an elevation in plasma urobilin levels that commence obesity-associated comorbidities. Future work to determine the role of urobilin in obesity-associated comorbidities such as insulin-resistant diabetes is warranted and may provide a biomarker for the early This work was supported by the National Institutes of Health R01DK121797 (T.D.H.J.). The sample collection was supported by the Center for Clinical and Translational Science (CCTS) grant UL1TR001998 at the University of Kentucky. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Adipose tissue angiogenesis genes are down-regulated by grape polyphenols supplementation during a human overfeeding trial

The adaptive response to overfeeding is associated with profound modifications of gene expression in adipose tissue to support lipid storage and weight gain. The objective of this study was to assess in healthy lean men whether a supplementation with polyphenols could interact with these molecular adaptations. Abdominal subcutaneous adipose tissue biopsies were sampled from 42 subjects participating to an overfeeding protocol providing an excess of 50% of their total energy expenditure for 31 days, and who were supplemented with 2 g/day of grape polyphenols or a placebo. Gene expression profiling was performed by RNA sequencing.Overfeeding led to a modification of the expression of 163 and 352 genes in the placebo and polyphenol groups, respectively. The GO functions of these genes were mostly involved in lipid metabolism, followed by genes involved in adipose tissue remodeling and expansion. In response to overfeeding, 812 genes were differentially regulated between groups. Among them, a set of 41 genes were related to angiogenesis and were down-regulated in the polyphenol group. Immunohistochemistry targeting PECAM1, as endothelial cell marker, confirmed reduced angiogenesis in this group. Finally, quercetin and isorhamnetin, two polyphenol species enriched in the plasma of the volunteers submitted to the polyphenols, were found to inhibit human umbilical vein endothelial cells migration in vitro.Polyphenol supplementation do not prevent the regulation of genes related to lipid metabolism in human adipose tissue during overfeeding, but impact the angiogenesis pathways. This may potentially contribute to a protection against adipose tissue expansion during dynamic phase of weight gain.

Antioxidant Enzyme Activity and Serum HSP70 Concentrations in Relation to Insulin Resistance and Lipid Profile in Lean and Overweight Young Men.

Oxidants are generated by all cells during normal oxidative respiration, and as long as they are under the control of appropriate mechanisms, they act as intracellular signaling molecules participating in complex functions. Oxidative stress can also affect insulin levels in the body. The production of reactive oxygen species by-products can lead to insulin resistance. Heat shock proteins (70 kDa) protect cells from the damaging effects of heat shock but also oxidative stress. The aim of the study was to investigate the serum concentration of HSP70 in young, non-obese but overweight men (BMI ≤ 30 kg/m2) and to assess its association with the insulin resistance, lipid profile and antioxidant system of red blood cells. Fifty-seven young men were examined and divided into two groups: lean men (n = 30) and men overweight (n = 27). A statistically significant difference was observed in the BMI (p < 0.007), HSP70 concentration (p < 0.000), serum insulin concentration (p < 0.000), HOMA-IR (p < 0.0001), superoxide dismutase (p < 0.02) and glutathione peroxidase (p < 0.05) between the studied groups. There was a negative correlation between the concentration of HSP70 with the insulin level (r = -0.50; p < 0.0004) and with the HOMA-IR (r = -0.50; p < 0.0004). These changes were associated with an increase in the activity of antioxidant enzymes. Our findings suggest that measuring the extracellular concentration of HSP70 can be an important indicator in disorders of glucose homeostasis.

Effects of intraduodenal or intragastric administration of a bitter hop extract (Humulus lupulus L.), on upper gut motility, gut hormone secretion and energy intake in healthy-weight men

Gastrointestinal functions, particularly pyloric motility and the gut hormones, cholecystokinin and peptide YY, contribute to the regulation of acute energy intake. Bitter tastants modulate these functions, but may, in higher doses, induce GI symptoms. The aim of this study was to evaluate the effects of both dose and delivery location of a bitter hop extract (BHE) on antropyloroduodenal pressures, plasma cholecystokinin and peptide YY, appetite perceptions, gastrointestinal symptoms and energy intake in healthy-weight men. The study consisted of two consecutive parts, with part A including n = 15, and part B n = 11, healthy, lean men (BMI 22.6 ± 1.1 kg/m2, aged 25 ± 3 years). In randomised, double-blind fashion, participants received in part A, BHE in doses of either 100 mg (“ID-BHE-100”) or 250 mg (“ID-BHE-250”), or vehicle (canola oil; “ID-control”) intraduodenally, or in part B, 250 mg BHE (“IG-BHE-250”) or vehicle (“IG-control”) intragastrically. Antropyloroduodenal pressures, hormones, appetite and symptoms were measured for 180 min, energy intake from a standardised buffet-meal was quantified subsequently. ID-BHE-250, but not ID-BHE-100, had modest, and transient, effects to stimulate pyloric pressures during the first 90 min (P < 0.05), and peptide YY from t = 60 min (P < 0.05), but did not affect antral or duodenal pressures, cholecystokinin, appetite, gastrointestinal symptoms or energy intake. IG-BHE-250 had no detectable effects. In conclusion, BHE, when administered intraduodenally, in the selected higher dose, modestly affected some appetite-related gastrointestinal functions, but had no detectable effects when given in the lower dose or intragastrically. Thus, BHE, at none of the doses or routes of administration tested, has appetite- or energy intake-suppressant effects.

Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).

Bilirubin Levels Are Negatively Correlated with Adiposity in Obese Men and Women, and Its Catabolized Product, Urobilin, Is Positively Associated with Insulin Resistance.

Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, body mass index (BMI), adiposity, blood glucose and insulin, and HOMA IR in a small cohort of obese and lean men and women. We found that bilirubin levels negatively correlated with BMI and adiposity in obese men and women, as compared to their lean counterparts. Contrarily, urobilin levels were positively associated with adiposity and BMI. Only obese women were found to be insulin resistant based on significantly higher HOMA IR, as compared to lean women. The urobilin levels were positively associated with HOMA IR in both groups, but women had a stronger linear correlation. These studies indicate that plasma urobilin levels are associated with obesity and its comorbidities, such as insulin resistance.

Disinhibition augments thirst perception from two dehydrating stimuli in men

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (β = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (β = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (β = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink.

Effect of Acute Walking on Endothelial Function and Postprandial Lipemia in South Asians and White Europeans.

South Asians (SAs) have an elevated risk of cardiovascular disease (CVD) compared with White Europeans (WEs). Postprandial endothelial function (flow-mediated dilatation (FMD%)) in SA women and SA men with central obesity has not been investigated. Research in other populations has highlighted that a 1% higher FMD% is associated with a ~13% lower risk of future CVD events. We investigated whether FMD% and lipemia, two markers for CVD risk, were higher in SAs versus WEs, whether walking improved FMD% and lipemia, and if there were ethnic differences in the response. Lean premenopausal women (study 1; 12 SA, 12 WE) and men with central obesity (study 2; 15 SA, 15 WE) completed two 2-d trials. On day 1, participants walked for 60 min at 60% of their peak oxygen uptake or rested. On day 2, participants rested and consumed two high-fat meals over 8 h. Repeated ultrasound assessments of endothelial function and venous blood samples for CVD risk markers were taken. Compared with WEs, SAs had lower postprandial FMD% (study 1, -1.32%; study 2, -0.54%) and higher postprandial triacylglycerol concentrations (study 1, 0.31 mmol·L -1 ·h -1 ; study 2, 0.55 mmol·L -1 ·h -1 ). Walking improved postprandial FMD% (study 1, 1.12%; study 2, 0.94%) and resulted in no significant change or small reductions in postprandial triacylglycerol concentrations (study 1, -0.01 mmol·L -1 ·h -1 ; study 2, -0.25 mmol·L -1 ·h -1 ). Exercise-induced changes in FMD% and triacylglycerol were consistent between ethnic groups. Walking mitigated the adverse postprandial effect of a high-fat diet on FMD% to a similar extent in SA and WE women and men, even with no/small improvements in triacylglycerol. This study highlights the importance of exercise to clinically improve FMD% in SAs and WEs.