Iuteolin对糖尿病大鼠心脏功能的保护作用及其可能机制

目的：研究Iuteolin对链脲佐菌素诱导的Ⅰ型糖尿病大鼠心功能及心肌线粒体氧化应激的影响。方法：雄性SD大鼠,随机分成正常对照组,Iuteolin对照纽,糖尿病模型组,低剂量Iuteolin（10ms／（kg·d））灌胃治疗组,高剂量Iuteolin（100ms／（kg·d））灌胃治疗组。各组大鼠饲养8周后,测体重、血糖、心功能、左心室重量、心肌胶原含量及活性氧自由基（ROS）水平,分离心肌线粒体检测ROS水平、超氧化物歧化酶（SOD）活性及线粒体肿胀程度。结果：Iuteolin处理对糖尿病大鼠血糖无明显影响,但可减少糖尿病引起的体重下降。高剂量Iuteolin可显著减小糖尿病大鼠心室与体重比值,提高左室发展压,降低左室舒张末压。高剂量Iuteolin治疗后,糖尿病大鼠心肌ROS及胶原含量。心肌线粒体ROS水平与肿胀程度均明显下降,心肌线粒体SOD活性明显增加。结论：Iuteolin处理可显著改善糖尿病大鼠心功能．其机制可能与减轻心肌线粒体氧化应激及抑制线粒体肿胀有关。     

Impact of obesity on left ventricular mass and function in subjects with chronic volume overload

Objective: Previous studies evaluated the effect of obesity on left ventricular (LV) mass and systolic function in healthy subjects and in patients with coexistent chronic LV pressure overload due to hypertension, but no data exist regarding subjects with underlying volume overload. This study assessed the impact of overweight‐obesity on LV mass and systolic function in patients with coexistent chronic LV volume overload. Research Methods and Procedures: In 885 subjects with degenerative aortic regurgitation, a common cause of LV volume overload, LV mass, ejection fraction, and myocardial contractility were determined by echocardiography. Results: LV mass was greater in overweight (193.5 ± 54.2 g) and further increased in obese subjects (208.4 ± 63.6 g) in comparison with normal‐weight patients (177.7 ± 54.9 g) (p < 0.0001), and these differences were still evident after adjustment for LV workload, gender, and body size. Despite no differences in ejection fraction, LV myocardial contractility was lower in overweight (92.6 ± 14.8%) and obese subjects (91.7 ± 14.4%) than normal‐weight individuals (95.6 ± 16.0%) (p = 0.0058). The magnitudes of these effects were not different from those found in age‐, gender‐, and body size‐matched controls, suggesting additive interaction, rather than synergistic, between overweight‐obesity and the underlying condition of volume overload. Multivariate analysis showed that BMI independently predicted LV mass and that the negative effect on LV myocardial contractility was mediated by LV hypertrophy. Discussion: Overweight and obesity are associated with LV hypertrophy and contractile impairment in patients with underlying chronic LV volume overload.     

Alginate oligosaccharide alleviates D-galactose-induced cardiac ageing via regulating myocardial mitochondria function and integrity in mice

Ageing is a crucial risk factor for the development of age-related cardiovascular diseases. Therefore, the molecular mechanisms of ageing and novel anti-ageing interventions need to be deeply studied. Alginate oligosaccharide (AOS) possesses high pharmacological activities and beneficial effects. Our study was undertaken to investigate whether AOS could be used as an anti-ageing drug to alleviate cardiac ageing. D-galactose (D-gal)-induced C57BL/6J ageing mice were established by subcutaneous injection of D-gal (200 mg·kg^-1·d^-1) for 8 weeks. AOS (50, 100 and 150 mg·kg^-1·d^-1) were administrated intragastrically for the last 4 weeks. As a result, AOS prevented cardiac dysfunction in D-gal-induced ageing mice, including partially preserved ejection fraction (EF%) and fractional shortening (FS%). AOS inhibited D-gal-induced up-regulation of natriuretic peptides A (ANP), brain natriuretic peptide (BNP) and ageing markers p53 and p21 in a dose-dependent manner. To further explore the potential mechanisms contributing to the anti-ageing protective effect of AOS, the age-related mitochondrial compromise was analysed. Our data indicated that AOS alleviated D-gal-induced cardiac ageing by improving mitochondrial biogenesis, maintaining the mitochondrial integrity and enhancing the efficient removal of impaired mitochondria. AOS also decreased the ROS production and oxidative stress status, which, in turn, further inhibiting cardiac mitochondria from being destroyed. Together, these results demonstrate that AOS may be an effective therapeutic agent to alleviate cardiac ageing.     

Diabetes-induced metabolic abnormalities in myocardium: Effect of antioxidant therapy

Effects of hyperglycemia (both diabetes and experimental galactosemia) on cardiac metabolism have been determined. In addition, the effect of supplemental antioxidants on these hyperglycemia-induced abnormalities of cardiac metabolism has been investigated. Diabetes or experimental galactosemia of 2 months duration in rats significantly increased oxidative stress in myocardium, as demonstrated by elevation of thiobarbituric acid reactive substances (TBARS) and lipid fluorescent products in left ventricle. Activity of protein kinase C (PKC) was elevated in the myocardium, and the activities of (Na,K)-ATPase and calcium ATPases were subnormal. Administration of supplemental antioxidants containing a mixture of ascorbic acid, Trolox; α-tocopherol acetate, N-acetyl cysteine, β-carotene, and selenium prevented both the diabetes-induced and galactosemia-induced elevation of oxidative stress and PKC activity, and inhibited the decreases of myocardial (Na,K)-ATPase and calcium ATPases. The results show that these metabolic abnormalities are not unique to diabetes per se, but are secondary to elevated blood hexose levels, and supplemental antioxidants inhibit these metabolic abnormalities. Our findings suggest that antioxidants inhibit abnormal metabolic processes that may contribute to the development of cardiac disease in diabetes, and offer a potential clinical means to inhibit cardiac abnormalities in diabetes.     

Contrasting metabolic effects of medium- versus long-chain fatty acids in skeletal muscle

Dietary intake of long-chain fatty acids (LCFAs) plays a causative role in insulin resistance and risk of diabetes. Whereas LCFAs promote lipid accumulation and insulin resistance, diets rich in medium-chain fatty acids (MCFAs) have been associated with increased oxidative metabolism and reduced adiposity, with few deleterious effects on insulin action. The molecular mechanisms underlying these differences between dietary fat subtypes are poorly understood. To investigate this further, we treated C2C12 myotubes with various LCFAs (16:0, 18:1n9, and 18:2n6) and MCFAs (10:0 and 12:0), as well as fed mice diets rich in LCFAs or MCFAs, and investigated fatty acid-induced changes in mitochondrial metabolism and oxidative stress. MCFA-treated cells displayed less lipid accumulation, increased mitochondrial oxidative capacity, and less oxidative stress than LCFA-treated cells. These changes were associated with improved insulin action in MCFA-treated myotubes. MCFA-fed mice exhibited increased energy expenditure, reduced adiposity, and better glucose tolerance compared with LCFA-fed mice. Dietary MCFAs increased respiration in isolated mitochondria, with a simultaneous reduction in reactive oxygen species generation, and subsequently low oxidative damage. Collectively our findings indicate that in contrast to LCFAs, MCFAs increase the intrinsic respiratory capacity of mitochondria without increasing oxidative stress. These effects potentially contribute to the beneficial metabolic actions of dietary MCFAs.     

The role of oxidative stress in the development of obesity and obesity-related metabolic disorders

Obesity is a serious medical condition, defined as excessive accumulation of fat. Abdominal fat is recognized as the major risk for obesity related diseases such as: hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, stroke, non-alcoholic fatty liver disease etc. Fat accumulation is also related to pro-oxidant and pro-inflammatory states. Recently published articles suggest that oxidative stress may be a link between obesity and related complications. Adiposity leads to increased oxidative stress via several multiple biochemical processes such as superoxide generation through the action of NADPH oxidase, glyceraldehyde auto-oxidation, oxidative phosphorylation, protein kinase C (PKC) activation, and polyol and hexosamine pathways. On the other hand, oxidative stress plays a causative role in the development of obesity, by stimulating the deposition of adipose tissue, including preadipocyte proliferation, adipocyte differentiation and growth. Exercise-induced weight loss can improve the redox state by modulating both oxidative stress and antioxidant promoters, which reduce endothelial dysfunction and inflammation.     

The association between cardiac autonomic neuropathy and heart function in type 2 diabetic patients

Abstract

Aim: Cardiac autonomic neuropathy (CAN) is a common and important chronic complication in diabetic patients. Heart failure resulting from cardiomyopathy is also a lethal complication in diabetic patients. However, data showing the exact association between CAN and heart failure in diabetic patients are relatively scarce. Therefore, our study aimed to determine the association between the parameters assessing CAN and heart function in diabetic patients.

Method: The medical records of type 2 diabetic patients who underwent an autonomic function test with heart rate variability (HRV) and echocardiography were reviewed from January 2018 to December 2018. A total of 100 type 2 diabetic patients were included, and the association between the parameters assessing CAN and heart function was analysed.

Results: Among the 100 analysed patients, 65 were diagnosed with CAN and 26 showed diastolic dysfunction. Moreover, 19 (73.1%) diabetic patients with diastolic dysfunction were complicated with CAN. The occurrence of diastolic dysfunction was higher in diabetic patients with CAN than in diabetic patients without CAN (29.2% vs 20.0%, p?<?0.05), and the occurrence of CAN was higher in diabetic patients with diastolic dysfunction than in patients without diastolic dysfunction (73.1% vs 62.2%, p?<?0.05). However, there were no significant associations between HRV parameters and heart function.

Conclusion: We demonstrated that diastolic dysfunction is more common in diabetic patients complicated with CAN than in diabetic patients without CAN, although several diabetic patients without diastolic dysfunction are also diagnosed with CAN. Moreover, further studies about the long-term serial monitoring of heart function according to the progression of CAN are required to confirm the exact association between CAN and heart function.     

力竭运动后不同时相大鼠心电图、心功能变化及Nrf2的作用

目的：研究大鼠力竭运动及运动结束后心电图、心功能的动态变化规律及转录因子E2相关因子（Nrf2）相关的氧化应激变化,为运动性心脏损伤防治提供依据。方法：SD大鼠随机分为5组（n=6）：对照组（Con）组、力竭组（EE）、力竭恢复6 h,12 h,24 h组（EER6、EER12、EER24组）。急性力竭游泳建立损伤模型。分别对各组动物进行心电图描记,压力容积导管检测心功能改变,ELISA法观测血清ROS,Nrf2,GPX及CAT变化。结果：① EE组心率（HR）,收缩末期压力（Pes）,发展压,动脉弹性,压力上升,下降最大速率（dP/dt_max、-dP/dt_min）降至最低。舒张末期压力容积、收缩末期容积、搏出量、Tau值增大。EER6、EER12、EER24组HR、Pes、dP/dt_max、-dP/dt_min与EE组相比均差异显著。②EE组、EER6、EER12、EER24组与Con组相比心率加快,QT间期延长,P波R波ST段数值增高,但恢复各组与EE组相比无统计学意义。③EE组大鼠血清ROS、Nrf2含量升高,GPX含量降低,CAT在EER6组降至最低。④血清Nrf2水平与ROS,-dP/dt_min呈正相关,与HR、Ea呈负相关。血清ROS水平与EF,-dP/dt_min呈正相关,与HR、Ea、dP/dt_max呈负相关。结论：力竭运动后心脏生物电改变,舒缩功能均受损,以舒张功能减退突出,随力竭恢复时间延长,心脏舒缩功能逐步恢复,这与Nrf2调节GPX,CAT降低氧化应激有关。     

Baroreflex sensitivity in obesity: relationship with cardiac autonomic nervous system activity

Objective: The aim of this study was to test the hypothesis that baroreflex sensitivity (BRS), assessed by indirect measurement of aortic pressure, is blunted in obesity. Additionally, the potential effect of cardiac autonomic nervous system (ANS) activity, aortic compliance, and metabolic parameters on BRS of obese subjects was investigated. Research Methods and Procedures: A group of 30 women with BMI >30 kg/m² and a group of 30 controls with BMI <25 kg/m² were examined. BRS was estimated by the sequence technique, cardiac ANS activity by short‐term spectral analysis of heart rate variability (HRV), and aortic compliance by the method of applanation tonometry. Results: BRS was lower in obese women (9.18 ± 3.77 vs. 19.63 ± 9.16 ms/mm Hg, p < 0.001). The median values (interquartile range) of the power of both the high‐frequency and low‐frequency components of the HRV were higher in the lean than in the obese participants [1079.2 (202.7 to 1716.9) vs. 224.1 (72.7 to 539.6) msec², p = 0.001 and 411.8 (199.3 to 798.0) vs. 235.8 (99.4 to 424.5) msec², p = 0.01 respectively]. Low‐to‐high‐frequency ratio values were higher in the obese subjects [0.82 (0.47 to 2.1) vs. 0.57 (0.28 to 0.89), p = 0.02]. Aortic augmentation values were not significantly different between lean and obese subjects. Multivariate analysis demonstrated a significant and independent association between BRS and age (p = 0.003), BMI (p < 0.001), and high‐frequency power of HRV (p < 0.001). These variables explained 72% of the variation of BRS values. Discussion: BRS is severely reduced in obese subjects. BMI, age, and the parasympathetic nervous system activity are the main determinants of BRS. Baroreflex behavior is of clinical relevance because an attenuated BRS represents a negative prognostic factor in cardiovascular diseases, which are common in obesity.     

Comparative anatomical study of the autonomic cardiac nervous system in macaque monkeys

The main aim of this study was to clarify the general morphology of the autonomic cardiac nervous system in macaque monkeys. A submacroscopic comparative anatomical study of the autonomic cardiac nervous system was performed by examining 22 sides of 11 bodies of four species of macaque monkeys, including some previously unreported species (pig-tailed and stump-tailed monkeys), under a surgical stereomicroscope. The following results were obtained. 1) The basic arrangement of the autonomic cardiac nervous system is constant in all examined macaques. 2) A superior cardiac nerve originating from the superior cervical ganglion was not observed, whereas the thoracic cardiac nerve originating from the sympathetic trunk/ganglia under the cervicothoracic ganglion was rarely observed in all the examined macaques. 3) The main cardiac nerve is the middle cardiac nerve originating from the middle cervical ganglion, similar to the situation in humans. 4) Although the superior, inferior, and thoracic cardiac branches of the vagus nerve were consistently observed, the left thoracic cardiac branch is rarely absent because of its lower origin to the heart. 5) The cranial autonomic nerves tend to distribute into the heart medially (arterial porta), and the caudal autonomic nerves tend to distribute into the heart laterally (venous porta). To comprehend the comparative morphological and evolutionary changes more completely, these results were compared with our previous studies and some references. Consequently, differences in the sympathetic cardiac nerves of macaques and humans are recognized, in spite of the similar morphologies of the vagal cardiac branches. These differences include the composition of the cervicothoracic ganglion, the lower positions of the middle cervical and cervicothoracic ganglia, and the narrow range for the origin of the cardiac nerves in macaques compared to that in humans.     

Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification

Evidence suggests that aging, per se, is a major risk factor for cardiac dysfunction. Oxidative modification of cardiac proteins by non-enzymatic glycation, i.e. advanced glycation endproducts (AGEs), has been implicated as a causal factor in the aging process. This study was designed to examine the role of aging on cardiomyocyte contractile function, cardiac protein oxidation and oxidative modification. Mechanical properties were evaluated in ventricular myocytes from young (2-month) and aged (24-26-month) mice using a MyoCam system. The mechanical indices evaluated were peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Oxidative stress and protein damage were evaluated by glutathione and glutathione disulfide (GSH/GSSG) ratio and protein carbonyl content, respectively. Activation of NAD(P)H oxidase was determined by immunoblotting. Aged myocytes displayed a larger cell cross-sectional area, prolonged TR90, and normal PS, +/- dL/dt and TPS compared with young myocytes. Aged myocytes were less tolerant of high stimulus frequency (from 0.1 to 5 Hz) compared with young myocytes. Oxidative stress and protein oxidative damage were both elevated in the aging group associated with significantly enhanced p47phox but not gp91phox expression. In addition, level of cardiac AGEs was approximately 2.5-fold higher in aged hearts than young ones determined by AGEs-ELISA. A group of proteins with a molecular range between 50 and 75 kDa with pI of 4-7 was distinctively modified in aged heart using one- or two-dimension SDS gel electrophoresis analysis. These data demonstrate cardiac diastolic dysfunction and reduced stress tolerance in aged cardiac myocytes, which may be associated with enhanced cardiac oxidative damage, level of AGEs and protein modification by AGEs.     

Loperamide‐induced cardiotoxicity in rats: Evidence from cardiac and oxidative stress biomarkers

At therapeutic dose, loperamide is a safe over‐the‐counter antidiarrheal drug but could induce cardiotoxic effect at a supratherapeutic dose. In this study, we use cardiac and oxidative biomarkers to evaluate loperamide‐induced cardiotoxicity in rats. Rats were orally gavaged with 1.5, 3, or 6 mg/kg body weight (BW) of loperamide hydrochloride for 7 days. The results after 7 days administration of loperamide, revealed dose‐dependent increase (P < 0.05) in aspartate aminotransferase, lactate dehydrogenase, creatine kinase‐MB, and serum concentration of cardiac troponin I, total homocysteine, and nitric oxide. A 50% decrease in antioxidant enzymes activity was observed at 6 mg/kg BW. Furthermore, malondialdehyde and fragmented DNA also increased significantly in the heart of the treatment groups. Loperamide provoked cardiotoxicity through oxidative stress, lipid peroxidation, and DNA fragmentation in rats. This study has provided a possible biochemical explanation for the reported cardiotoxicity induced by loperamide overdose.     

Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway

Increase of myocardial oxidative stress is closely related to the occurrence and development of cardiac hypertrophy. Cordycepin, also known as 3'‐deoxyadenosine, is a natural bioactive substance extracted from Cordyceps militaris (which is widely cultivated for commercial use in functional foods and medicine). Since cordycepin suppresses oxidative stress both in vitro and in vivo, we hypothesized that cordycepin would inhibit cardiac hypertrophy by blocking oxidative stress‐dependent related signalling. In our study, a mouse model of cardiac hypertrophy was induced by aortic banding (AB) surgery. Mice were intraperitoneally injected with cordycepin (20 mg/kg/d) or the same volume of vehicle 3 days after‐surgery for 4 weeks. Our data demonstrated that cordycepin prevented cardiac hypertrophy induced by AB, as assessed by haemodynamic parameters analysis and echocardiographic, histological and molecular analyses. Oxidative stress was estimated by detecting superoxide generation, superoxide dismutase (SOD) activity and malondialdehyde levels, and by detecting the protein levels of gp91^phox and SOD. Mechanistically, we found that cordycepin activated activated protein kinase α (AMPKα) signalling and attenuated oxidative stress both in vivo in cordycepin‐treated mice and in vitro in cordycepin treated cardiomyocytes. Taken together, the results suggest that cordycepin protects against post‐AB cardiac hypertrophy through activation of the AMPKα pathway, which subsequently attenuates oxidative stress.     

Spondias mombin supplementation attenuated cardiac remodelling process induced by tobacco smoke

The objective of this study was to investigate the influence of Spondias mombin (SM) supplementation on the cardiac remodelling process induced by exposure to tobacco smoke (ETS) in rats. Male Wistar rats were divided into 4 groups: group C (control, n = 20) comprised animals not exposed to cigarette smoke and received standard chow; group ETS (n = 20) comprised animals exposed to cigarette smoke and received standard chow; group ETS100 (n = 20) received standard chow supplemented with 100 mg/kg body weight/d of SM; and group ETS250 (n = 20) received standard chow supplemented with 250 mg/kg body weight/d of SM. The observation period was 2 months. The ETS animals had higher values of left cardiac chamber diameters and of left ventricular mass index. SM supplementation attenuated these changes. In addition, the myocyte cross‐sectional area (CSA) was lower in group C compared with the ETS groups; however, the ETS250 group had lower values of CSA compared with the ETS group. The ETS group also showed higher cardiac levels of lipid hydroperoxide (LH) compared with group C; and, groups ETS100 and ETS250 had lower concentrations of LH compared with the ETS group. Regarding energy metabolism, SM supplementation decreased glycolysis and increased the β‐oxidation and the oxidative phosphorylation. There were no differences in the expression of Nrf‐2, SIRT‐1, NF‐κB, interferon‐gamma and interleukin 10. In conclusion, our results suggest that ETS induced the cardiac remodelling process. In addition, SM supplementation attenuated this process, along with oxidative stress reduction and energy metabolism modulation.     

Visfatin aggravates transverse aortic constriction-induced cardiac remodelling by enhancing macrophage-mediated oxidative stress in mice

Previous studies have reported that visfatin can regulate macrophage polarisation, which has been demonstrated to participate in cardiac remodelling. The aims of this study were to investigate whether visfatin participates in transverse aortic constriction (TAC)-induced cardiac remodelling by regulating macrophage polarisation. First, TAC surgery and angiotensin II (Ang II) infusion were used to establish a mouse cardiac remodelling model, visfatin expression was measured, and the results showed that TAC surgery or Ang II infusion increased visfatin expression in the serum and heart in mice, and phenylephrine or hydrogen peroxide promoted the release of visfatin from macrophages in vitro. All these effects were dose-dependently reduced by superoxide dismutase. Second, visfatin was administered to TAC mice to observe the effects of visfatin on cardiac remodelling. We found that visfatin increased the cross-sectional area of cardiomyocytes, aggravated cardiac fibrosis, exacerbated cardiac dysfunction, further regulated macrophage polarisation and aggravated oxidative stress in TAC mice. Finally, macrophages were depleted in TAC mice to investigate whether macrophages mediate the regulatory effect of visfatin on cardiac remodelling, and the results showed that the aggravating effects of visfatin on oxidative stress and cardiac remodelling were abrogated. Our study suggests that visfatin enhances cardiac remodelling by promoting macrophage polarisation and enhancing oxidative stress. Visfatin may be a potential target for the prevention and treatment of clinical cardiac remodelling.     

Dietary interaction of high fat and marginal copper deficiency on cardiac contractile function

Objective: High‐fat and marginally copper‐deficient diets impair heart function, leading to cardiac hypertrophy, increased lipid droplet volume, and compromised contractile function, resembling lipotoxic cardiac dysfunction. However, the combined effect of the two on cardiac function is unknown. This study was designed to examine the interaction between high‐fat and marginally copper‐deficient diets on cardiomyocyte contractile function. Research Methods and Procedures: Weanling male rats were fed diets incorporating a low‐ or high‐fat diet (10% or 45% of kcal from fat, respectively) with adequate (6 mg/kg) or marginally deficient (1.5 mg/kg) copper content for 12 weeks. Contractile function was determined with an IonOptix system including peak shortening (PS), time‐to‐PS, time‐to‐90% relengthening, maximal velocity of shortening/relengthening, and intracellular Ca²⁺ ([Ca²⁺]_I) rise and decay. Results: Neither dietary treatment affected blood pressure or glucose levels, although the high‐fat diet elicited obesity and glucose intolerance. Both diets depressed PS, maximal velocity of shortening/relengthening, and intracellular Ca²⁺ ([Ca²⁺]_I) rise and prolonged time‐to‐90% relengthening and Ca²⁺ decay without an additive effect between the two. Ca²⁺ sensitivity, apoptosis, lipid peroxidation, nitrosative damage, tissue ceramide, and triglyceride levels were unaffected by either diet or in combination. Phospholamban (PLB) but not sarco(endo)plasmic reticulum Ca²⁺‐ATPase was increased by both diets. Endothelial NO synthase was depressed with concurrent treatments. The electron transport chain was unaffected, although mitochondrial aconitase activity was inhibited by the high‐fat diet. Discussion: These data suggest that high‐fat and marginally copper deficient diets impaired cardiomyocyte contractile function and [Ca²⁺]_i homeostasis, possibly through a similar mechanism, without obvious lipotoxicity, nitrosative damage, and apoptosis.     

Relationships of Plasma Leptin Levels to Changes in Plasma Free Fatty Acids in Women Who Are Lean and Women Who Are Abdominally Obese

HENNES, MAGDA MI, ARNAVAZ DUA, DIANA L MAAS, GABRIELE E SONNENBERG, GLENN R KRAKOWER, AHMED H KISSEBAH. Relationships of plasma leptin levels to changes in plasma free fatty acids in women who are lean and women who are abdominally obese. Regulation of leptin production by the hormonal and metabolic milieu is poorly understood. Because abdominal obesity is commonly associated with elevated plasma free fatty acid (FFA) flux, we examined the effects of augmenting FFA on plasma leptin levels in women who were lean and of suppressing FFA in women with abdominal obesity. In study 1, nine subjects who were lean, after a 12-hour overnight fast, received either intravenous saline or Intralipid plus heparin to increase the plasma FFA concentration to approximately 1000 μmol/ L. After 3 hours of additional fasting, subjects underwent 3-hour hyperglycemic clamps. In study 2, seven subjects with abdominal obesity were evaluated by a similar protocol, but lipolysis and plasma FFA flux were instead maximally suppressed by acipimox. In the individuals who were lean, leptin levels were unchanged during clamping. Increasing plasma FFA reduced plasma leptin from 7.66 ± 0.66 to 7.05 ±0 0.66 (p=0.03), but 3 hours of hyperglycemia plus hyperinsulinemia had no additional effect on leptin levels (7.15 ± 0.71). Basal leptin levels, 4-fold higher in the subjects with obesity, were reduced from 34.6 ± 2.4 μg/L to 32.3 ± 1.1 μg/L (p=0.004) during the clamp period. When plasma FFA flux was suppressed, however, plasma leptin levels after clamped hyperglycemia/hyperinsulinemia were increased to 38.9 ± 1.2 μg/L (p=0.014 vs. time 0 and 0.001 vs. saline protocol). Changes in leptin concentrations are not correlated with changes in FFA. These results suggest that plasma FFA concentration does not regulate plasma leptin levels in basal, extended fasting, or hyperglycemic/hyperinsulinemic states.     

Gender‐dependent progression of systemic metabolic states in early childhood

Little is known about the human intra‐individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on a series of samples selected from a large birth cohort study. We found multiple previously unknown age‐ and gender‐related metabolome changes of potential medical significance. Specifically, we found that the major developmental state differences between girls and boys are attributed to sphingolipids. In addition, we demonstrated the feasibility of state‐based alignment of personal metabolic trajectories. We show that children have different development rates at the level of metabolome and thus the state‐based approach may be advantageous when applying metabolome profiling in search of markers for subtle (patho)physiological changes.