Leptin-induced endothelial dysfunction in obesity

Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O2−), and peroxynitrite (ONOO−) nanosensors were placed near the surface (5 ± 2 μm) of a single human umbilical vein endothelial cell (HUVEC) exposed to leptin or aortic endothelium of obese C57BL/6J mice, and concentrations of calcium ionophore (CaI)-stimulated NO, O2−, ONOO− were recorded. Endothelial NO synthase (eNOS) expression and l-arginine concentrations in HUVEC and aortic endothelium were measured. Leptin did not directly stimulate NO, O2−, or ONOO− release from HUVEC. However, a 12-h exposure of HUVEC to leptin increased eNOS expression and CaI-stimulated NO (625 ± 30 vs. 500 ± 24 nmol/l control) and dramatically increased cytotoxic O2− and ONOO− levels. The [NO]-to-[ONOO−] ratio ([NO]/[ONOO−]) decreased from 2.0 ± 0.1 in normal to 1.30 ± 0.1 in leptin-induced dysfunctional endothelium. In obese mice, a 2.5-fold increase in leptin concentration coincided with 100% increase in eNOS and about 30% decrease in intracellular l-arginine. The increased eNOS expression and a reduced l-arginine content led to eNOS uncoupling, a reduction in bioavailable NO (250 ± 10 vs. 420 ± 12 nmol/l control), and an elevated concentration of O2− (240%) and ONOO− (70%). l-Arginine and sepiapterin supplementation reversed eNOS uncoupling and partially restored [NO]/[ONOO−] balance in obese mice. In obesity, leptin increases eNOS expression and decreases intracellular l-arginine, resulting in eNOS an uncoupling and depletion of endothelial NO and an increase of cytotoxic ONOO−. Hyperleptinemia triggers an endothelial NO/ONOO− imbalance characteristic of dysfunctional endothelium observed in other vascular disorders, i.e., atherosclerosis and diabetes

The role of IL-6 in exercise-induced anorexia in normal-weight boys.

Background: Our previous study showed that Interleukin-6 (IL-6) is associated with a suppression of appetite after high-intensity exercise (HIEX), but an independent role within food intake (FI) was not defined. Hypothesis: IL-6 after HIEX (75% VO2peak) is independent of appetite-hormones in suppressing appetite and FI in normal-weight (NW) boys. Objective: To investigate the effect of HIEX, with and without the inflammation inhibitor, ibuprofen (IBU), on IL-6 and selective biomarkers of inflammation and appetite on FI and ratings of appetite in NW boys. Design: Fifteen NW boys (aged 13-18y) were randomly assigned in a crossover design to four sessions: 1)Water+Rest; 2)Rest+IBU; 3)Water+HIEX; 4)HIEX+IBU. HIEX consisted of three 10min bouts of HIEX at 60-70RPM75% VO2max with 1:30min active rest interposed. IBU was given in a 300mg liquid solution. EI, ratings and plasma biomarkers of appetite, inflammation, stress and glucose control were measured. Results: FI was not affected by HIEX or IBU. Appetite increased over TIME (p=0.002) but was lower after HIEX (pThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Decreased Appetite after High-Intensity Exercise Correlates with Increased Plasma Interleukin-6 in Normal-Weight and Overweight/Obese Boys

BACKGROUND: High-intensity exercise (HIEX) suppresses appetite in adults and is thought to be mediated by appetite-regulating hormones. However, the effects of HIEX-induced inflammatory and stress biomarkers on appetite control and body weight have not been reported in children or adults. OBJECTIVE: The objective of this study was to describe the effects of acute HIEX at 70% peak oxygen consumption (VO2peak) on postexercise appetite and selective biomarkers of inflammation, stress, and appetite regulatory hormones in normal-weight (NW) and in overweight/obese boys. METHODS: NW (n = 11) and overweight/obese (n = 11) boys aged 10–18 y were randomly assigned in a crossover design to either rest or HIEX. Visual analog scale appetite ratings and plasma biomarkers of appetite, inflammation, stress, and glucose control were measured after HIEX or rest. RESULTS: Appetite increased from baseline to 110 min (P < 0.001), but was lower after HIEX (P = 0.04), with no difference between body weight groups. HIEX also resulted in lower active ghrelin (P < 0.001) and increased interleukin-6 (IL-6; P < 0.001), tumor necrosis factor-α (P < 0.001), and cortisol (P < 0.001) concentrations, independent of body weight. It increased blood glucose (P = 0.002) and insulin (P = 0.028) concentrations in NW but not overweight and obese boys. Leptin, glucagon-like peptide 1, peptide tyrosine tyrosine, C-reactive protein, and cortisol were not affected by HIEX. An inverse correlation was found between IL-6 and appetite (r = −0.379; P = 0.012), but not any other biomarkers. CONCLUSIONS: HIEX resulted in reduced appetite that correlated with an increase in IL-6 in both NW and overweight/obese boys. However, although a role for IL-6 in the response can be suggested, the suppression of appetite was potentially mediated by the decrease in active ghrelin and/or increase in cortisol. This trial was registered at clinicaltrials.gov as NCT02619461

The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment

The environment of the test laboratory affects the reproducibility of treatment effects on physiological phenotypes of rodents and may be attributed to the plasticity of the epigenome due to nutrient-gene-environment interactions. Here, we explored the reproducibility of adding a multi-vitamin-mineral (MVM) mix to a nutrient-balanced high-fat (HF) diet on obesity, insulin resistance (IR), and gene expression in the tissues of adult male mice. Experiments of the same design were conducted in three independent animal facilities. Adult C57BL/6J male mice were fed an HF diet for 6 weeks (diet induced-obesity model) and then continued for 9–12 weeks on the HF diet with or without 5-fold additions of vitamins A, B1, B6, B12, Zn, and 2-fold Se. The addition of the MVM affected body weight, fat mass, gene expression, and markers of IR in all three locations (p < 0.05). However, the direction of the main effects was influenced by the interaction with the experimental location and its associated environmental conditions known to affect the epigenome. In conclusion, MVM supplementation influenced phenotypes and expression of genes related to adipose function in obese adult male mice, but the experimental location and its associated conditions were significant interacting factors. Preclinical studies investigating the relationship between diet and metabolic outcomes should acknowledge the plasticity of the epigenome and implement measures to reproduce studies in different locations

High Choline Intake during Pregnancy Reduces Characteristics of the Metabolic Syndrome in Male Wistar Rat Offspring Fed a High Fat But Not a Normal Fat Post-Weaning Diet

Maternal choline intakes are below recommendations, potentially impairing the child’s later-life metabolic health. This study aims to elucidate the interaction between the choline content of the gestational diet (GD) and fat content of the post-weaning diet (PWD) on metabolic phenotype of male Wistar rats. Pregnant Wistar rats were fed a standard rodent diet (AIN-93G) with either recommended choline (RC, 1 g/kg diet choline bitartrate) or high choline (HC, 2.5-fold). Male pups were weaned to either a normal (16%) fat (NF) or a high (45%) fat (HF) diet for 17 weeks. Body weight, visceral adiposity, food intake, energy expenditure, plasma hormones, triglycerides, and hepatic fatty acids were measured. HC-HF offspring had 7% lower body weight but not food intake, and lower adiposity, plasma triglycerides, and insulin resistance compared to RC-HF. They also had increased hepatic n-3 fatty acids and a reduced n-6/n-3 and C 18:1 n-9/C18:0 ratios. In contrast, HC-NF offspring had 6–8% higher cumulative food intake and body weight, as well as increased leptin and elevated hepatic C16:1 n-7/C16:0 ratio compared to RC-NF. Therefore, gestational choline supplementation associated with improved long-term regulation of several biomarkers of the metabolic syndrome in male Wistar rat offspring fed a HF, but not a NF, PWD

High Choline Intake during Pregnancy Reduces Characteristics of the Metabolic Syndrome in Male Wistar Rat Offspring Fed a High Fat But Not a Normal Fat Post-Weaning Diet

Maternal choline intakes are below recommendations, potentially impairing the child’s later-life metabolic health. This study aims to elucidate the interaction between the choline content of the gestational diet (GD) and fat content of the post-weaning diet (PWD) on metabolic phenotype of male Wistar rats. Pregnant Wistar rats were fed a standard rodent diet (AIN-93G) with either recommended choline (RC, 1 g/kg diet choline bitartrate) or high choline (HC, 2.5-fold). Male pups were weaned to either a normal (16%) fat (NF) or a high (45%) fat (HF) diet for 17 weeks. Body weight, visceral adiposity, food intake, energy expenditure, plasma hormones, triglycerides, and hepatic fatty acids were measured. HC-HF offspring had 7% lower body weight but not food intake, and lower adiposity, plasma triglycerides, and insulin resistance compared to RC-HF. They also had increased hepatic n-3 fatty acids and a reduced n-6/n-3 and C 18:1 n-9/C18:0 ratios. In contrast, HC-NF offspring had 6–8% higher cumulative food intake and body weight, as well as increased leptin and elevated hepatic C16:1 n-7/C16:0 ratio compared to RC-NF. Therefore, gestational choline supplementation associated with improved long-term regulation of several biomarkers of the metabolic syndrome in male Wistar rat offspring fed a HF, but not a NF, PWD

High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (&gt;15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p &lt; 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p &lt; 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p &lt; 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p &lt; 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy