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INTRODUCTION We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle‐aged adults. METHODS We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme‐linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS Higher sOB‐R was associated with lower fractional anisotropy (FA, β = −0.114 ± 0.02, p < 0.001), and higher free water (FW, β = 0.091 ± 0.022, p < 0.001) and peak‐width skeletonized mean diffusivity (PSMD, β = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (β = 0.115 ± 0.027, p < 0.001) and lower FW (β = ‐0.096 ± 0.029, p = 0.001) and PSMD (β = ‐0.085 ± 0.028, p = 0.002). DISCUSSION Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle‐aged adults, supporting the putative neuroprotective role of leptin in late‐life dementia risk. Highlights Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (β FS ) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed β FS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (P linear  = 0.0001), which was accelerated at the higher concentrations (P quadratic  = 0.0003). β FS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, P difference  = 3.6 × 10 −6 ). Consistent with quantile-dependent expressivity, the β FS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP , LEPR , MnSOD , PPARγ , PPARγ2 , and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. β FS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (P linear  = 0.04 and P linear  = 8.5 × 10 −6 , respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

Purpose Abnormal leptin bioavailability has play key roles in the etiology of adolescent idiopathic scoliosis (AIS). Both leptin and its receptor levels may be modulated by the presence of genetic polymorphisms. This study aimed to evaluate the role of polymorphisms in the leptin ( LEP ) and its main receptor ( LEPR ) genes in the AIS susceptibility in girls. Methods A retrospective case–control study was conducted with 189 AIS and 240 controls. LEP rs2167270 and LEPR rs2767485 polymorphisms were genotyped using a TaqMan validated assay. Associations were evaluated by odds ratios (OR) and 95% confidence intervals (CI). Results The AIS group showed a predominance of girls under 18 years old ( n  = 140, 74.1%), 148 (78.3%) had low or normal BMI, 111 (58.7%) had Cobb ≥ 45º and 130 (68.7%) were skeletally mature. Minor allele frequencies of rs2167270 and rs2767485 were 35.7% and 18.3%, for AIS and 35.6% and 25.4% for controls, respectively. LEPR rs2767485 T and TC  +  TT were associated with higher risk of AIS (OR = 1.53; 95% CI = 1.09–2.13 and OR = 1.84; 95% CI = 1.69–2.01, respectively), since CC genotype was only present in the control group. In addition, the LEP rs2167270 GA  +  AA was more frequent in low weight group (BMI ≤ 24.9) of girls with AIS. There was no significant association between LEP rs2167270 and AIS susceptibility, and LEPR rs2767485 and BMI. Conclusion The LEPR rs2767485 was associated with the genetic susceptibility of AIS and LEP rs2167270 with low BMI. These data can contribute to the identification of genetic biomarkers to improve the diagnosis and treatment.

PurposeAnthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model.MethodsACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet.ResultsThe ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice.ConclusionACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity.

The ratio between circulating levels of leptin and soluble leptin receptor (sOB‐R), the free leptin index (FLI), is used as a marker of leptin resistance. Therefore, the aim of our study was to investigate the FLI in mild pre‐eclamptic pregnancies in a nested case–control study within a prospective observational study. Circulating levels of leptin and sOB‐R levels rise significantly during pregnancy in healthy (p < 0.05) (n = 46) and pre‐eclamptic pregnancies (p < 0.05) (n = 20). Serum levels of leptin were significantly higher in pre‐eclamptic compared to healthy pregnancies at second and third trimesters of pregnancy (p < 0.05). Additionally, serum levels of sOB‐R were significantly lower in pre‐eclamptic pregnancies during the second and third trimesters of pregnancy compared to healthy pregnancies (p < 0.05). Moreover, we found that FLI did not vary significantly during pregnancy in healthy women (p > 0.05), while it increases in pre‐eclamptic pregnancies (p < 0.05). Indeed, FLI was significantly higher at second and third trimesters of pregnancy in pre‐eclamptic compared to healthy pregnancies (p < 0.05). In addition, FLI was significantly higher in the luteal phase compared with the follicular phase of the menstrual cycle in eumenorrheic women (p < 0.05). Receiver operating characteristic (ROC) curve analysis revealed the ability of leptin (AUC = 0.72) and FLI (AUC = 0.67) as a reliable predictor for mild pre‐eclampsia during the second trimester of pregnancy. In conclusion, our findings show that FLI were significantly increased in mild pre‐eclamptic pregnancies and allowed us to hypothesize that this rise might alter leptin bioavailability and bioactivity which might lead to the sympathetic hyperactivity and the hypertensive disorders during pregnancy.

This study investigated the effect of decaffeinated green tea extract (dGTE), with or without antioxidant nutrients, on fat oxidation, body composition and cardio-metabolic health measures in overweight individuals engaged in regular exercise. Twenty-seven participants (20 females, 7 males; body mass: 77.5 ± 10.5 kg; body mass index: 27.4 ± 3.0 kg·m2; peak oxygen uptake (V.O2peak): 30.2 ± 5.8 mL·kg−1·min−1) were randomly assigned, in a double-blinded manner, either: dGTE (400 mg·d−1 (−)-epigallocatechin−3-gallate (EGCG), n = 9); a novel dGTE+ (400 mg·d−1 EGCG, quercetin (50 mg·d−1) and α-lipoic acid (LA, 150 mg·d−1), n = 9); or placebo (PL, n = 9) for 8 weeks, whilst maintaining standardised, aerobic exercise. Fat oxidation (‘FATMAX’ and steady state exercise protocols), body composition, cardio-metabolic and blood measures (serum glucose, insulin, leptin, adiponectin, glycerol, free fatty acids, total cholesterol, high [HDL-c] and low-density lipoprotein cholesterol [LDL-c], triglycerides, liver enzymes and bilirubin) were assessed at baseline, week 4 and 8. Following 8 weeks of dGTE+, maximal fat oxidation (MFO) significantly improved from 154.4 ± 20.6 to 224.6 ± 23.2 mg·min−1 (p = 0.009), along with a 22.5% increase in the exercise intensity at which fat oxidation was deemed negligible (FATMIN; 67.6 ± 3.6% V.O2peak, p = 0.003). Steady state exercise substrate utilisation also improved for dGTE+ only, with respiratory exchange ratio reducing from 0.94 ± 0.01 at week 4, to 0.89 ± 0.01 at week 8 (p = 0.004). This corresponded with a significant increase in the contribution of fat to energy expenditure for dGTE+ from 21.0 ± 4.1% at week 4, to 34.6 ± 4.7% at week 8 (p = 0.006). LDL-c was also lower (normalised fold change of −0.09 ± 0.06) for dGTE+ by week 8 (p = 0.038). No other significant effects were found in any group. Eight weeks of dGTE+ improved MFO and substrate utilisation during exercise, and lowered LDL-c. However, body composition and cardio-metabolic markers in healthy, overweight individuals who maintained regular physical activity were largely unaffected by dGTE.

Berberine, a major pharmacological component of the Chinese herb Coptis chinensis, which was originally used to treat bacterial diarrhea, has recently been demonstrated to be clinically effective in alleviating type 2 diabetes. In this study, we revealed that berberine effectively prevented the development of obesity and insulin resistance in high-fat diet (HFD)-fed rats, which showed decreased food intake. Increases in the levels of serum lipopolysaccharide-binding protein, monocyte chemoattractant protein-1, and leptin and decrease in the serum level of adiponectin corrected for body fat in HFD-fed rats were also significantly retarded by the co-administration of berberine at 100 mg/kg body weight. Bar-coded pyrosequencing of the V3 region of 16S rRNA genes revealed a significant reduction in the gut microbiota diversity of berberine-treated rats. UniFrac principal coordinates analysis revealed a marked shift of the gut microbiota structure in berberine-treated rats away from that of the controls. Redundancy analysis identified 268 berberine-responding operational taxonomic units (OTUs), most of which were essentially eliminated, whereas a few putative short-chain fatty acid (SCFA)-producing bacteria, including Blautia and Allobaculum, were selectively enriched, along with elevations of fecal SCFA concentrations. Partial least square regression models based on these 268 OTUs were established (Q(2)>0.6) for predicting the adiposity index, body weight, leptin and adiponectin corrected for body fat, indicating that these discrete phylotypes might have a close association with the host metabolic phenotypes. Taken together, our findings suggest that the prevention of obesity and insulin resistance by berberine in HFD-fed rats is at least partially mediated by structural modulation of the gut microbiota, which may help to alleviate inflammation by reducing the exogenous antigen load in the host and elevating SCFA levels in the intestine.

Due to the low bioavailability of resveratrol, determining whether its metabolites exert any beneficial effect is an interesting issue. 3T3-L1 maturing pre-adipocytes were treated during differentiation with 25 µM of resveratrol or with its metabolites and 3T3-L1 mature adipocytes were treated for 24 hours with 10 µM resveratrol or its metabolites. The gene expression of adiponectin, leptin, visfatin and apelin was assessed by Real Time RT-PCR and their concentration in the incubation medium was quantified by ELISA. Resveratrol reduced mRNA levels of leptin and increased those of adiponectin. It induced the same changes in leptin secretion. Trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide increased apelin and visfatin mRNA levels. Trans-resveratrol-3-O-sulfate reduced leptin mRNA levels and increased those of apelin and visfatin. The present study shows for the first time that resveratrol metabolites have a regulatory effect on adipokine expression and secretion. Since resveratrol has been reported to reduce body-fat accumulation and to improve insulin sensitivity, and considering that these effects are mediated in part by changes in the analyzed adipokines, it may be proposed that resveratrol metabolites play a part in these beneficial effects of resveratrol.

Aged black garlic (ABG) is a functional food with antioxidant and anti-inflammatory properties. Recent studies also report its beneficial metabolic effects in a context of obesity or diabetes, although the mechanisms involved are poorly understood. The aim of this work was to analyze the effects of an ABG extract in the vascular and metabolic alterations induced by a high-fat/sucrose diet in rats. For this purpose, male Sprague–Dawley rats were fed either a standard chow (controls; n = 12) or a high-fat/sucrose diet (HFD; n = 24) for 16 weeks. From week 8 on, half of the HFD rats were treated with a commercial ABG extract concentrated in S-allyl cysteine and melanoidins (ABG10+®; 250 mg/kg daily by gavage; 5 mL/kg). ABG10+®-treated rats showed lower mean caloric intake, body weight, triglycerides, low density lipoprotein cholesterol (LDL-c), insulin and leptin serum concentrations and higher high density lipoprotein cholesterol (HDL-c) and adiponectin serum concentrations than non-treated rats. In the hypothalamus, ABG10+® treatment induced an increase in the gene expression of proopiomelanocortin (POMC) and a decrease in leptin receptor (ObR) mRNA levels. No significant changes were found in visceral adipose tissue except for an overexpression of β3-adrenergic receptor (β3-ADR) in ABG-treated rats. In subcutaneous adipose tissue, ABG10+® treatment decreased adipose weight and downregulated the gene expression of PPAR-γ, LPL, ObR and HSL. In brown adipose tissue, an overexpression of InsR, GLUT-4, UCP-1 and β3-ADR in ABG10+®-treated rats was found, whereas PPAR-γ mRNA levels were significantly decreased. Regarding vascular function, ABG10+® treatment attenuated the obesity-induced vasoconstriction in response to potassium chloride both in presence/absence of perivascular adipose tissue (PVAT). On the contrary, aorta segments from ABG-treated rats showed and improved relaxation in response to acetylcholine only when PVAT was present, with this fact possible being related to the decreased gene expression of proinflammatory cytokines in this tissue. In conclusion, ABG10+® administration partially improves the metabolic and vascular alterations induced by a high-fat/high-sucrose diet in rats through modifications in the gene expression of proteins and neuropeptides involved in inflammation, fat metabolism and food intake regulation. Further studies are required to assess the bioavailability of ABG between rats and humans.