From the Cover: Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth

Mothers with obesity or gestational diabetes mellitus have low circulating levels of adiponectin (ADN) and frequently deliver large babies with increased fat mass, who are susceptible to perinatal complications and to development of metabolic syndrome later in life. It is currently unknown if the inverse correlation between maternal ADN and fetal growth reflects a cause-and-effect relationship. We tested the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin/mechanistic target of rapamycin complex 1 (mTORC1) signaling and nutrient transport, and prevents fetal overgrowth. Compared with dams on a control diet, female C57BL/6J mice fed an obesogenic diet before mating and throughout gestation had increased fasting serum leptin, insulin, and C-peptide, and reduced high-molecular-weight ADN at embryonic day (E) 18.5. Placental insulin and mTORC1 signaling was activated, peroxisome proliferator-activated receptor-α (PPARα) phosphorylation was reduced, placental transport of glucose and amino acids in vivo was increased, and fetal weights were 29% higher in obese dams. Maternal ADN infusion in obese dams from E14.5 to E18.5 normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARα signaling, nutrient transport, and fetal growth without affecting maternal fat mass. Using a mouse model with striking similarities to obese pregnant women, we demonstrate that ADN functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function. Importantly, maternal ADN supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth. Improving maternal ADN levels may serve as an effective intervention strategy to prevent fetal overgrowth caused by maternal obesity.Obesity and the metabolic syndrome are major risk factors for a wide array of diseases, including type 2 diabetes mellitus, cardiovascular disease, and cancer (1, 2). Compelling evidence shows that metabolic syndrome is caused, in part, by a suboptimal intrauterine environment (3). The strong association between maternal obesity during pregnancy and metabolic syndrome in childhood is of particular concern because almost two-thirds of American women now enter pregnancy either overweight or obese (4). Obesity during pregnancy therefore creates a vicious, detrimental cycle of intrauterine transmission of metabolic disease from the mother to her children (5). Intervention strategies involving lifestyle changes or antiobesity drugs remain largely unsuccessful, and it is therefore urgent to explore the possibility of intervening in utero to prevent the development of obesity and metabolic syndrome.Obesity in pregnant women is associated with activation of placental insulin and mechanistic target of rapamycin complex 1 (mTORC1) signaling, up-regulation of specific placental amino acid transporters, and fetal overgrowth (6, 7). In addition, circulating levels of adiponectin (ADN) are decreased in obese pregnant women (8, 9). The ADN protein is synthesized in adipose tissue and undergoes tightly regulated multimerization involving chaperone proteins, including disulfide-bond A oxidoreductase-like protein (DsbA-L), resulting in the assembly of oligomeric ADN proteins of different molecular weight (10). Multimerization into the high-molecular-weight (HMW) form increases the t_1/2 of ADN (11), and the insulin-sensitizing effect of ADN can largely be attributed to the HMW form (12). Low circulating levels of HMW ADN strongly predict the development of gestational diabetes mellitus (GDM) independent of maternal adiposity (13, 14).We recently reported that ADN, in contrast to its well-known insulin-sensitizing effects in skeletal muscle and liver, inhibits insulin and mTORC1 signaling and amino acid transport in cultured primary human trophoblast (PHT) cells (15) and in pregnant mice in vivo (16). This effect is mediated by activation of trophoblast peroxisome proliferator-activated receptor-α (PPARα) signaling and increased ceramide synthesis, resulting in inhibition of IRS-1 (17). Thus, low circulating ADN in maternal obesity may be causally linked to changes in placental function and increased fetal growth. These findings, together with the recent discovery of an orally active ADN receptor agonist (AdipoRon) (18), provide the rationale for exploring the possibility that maternal ADN supplementation may prevent the adverse fetal outcomes in maternal obesity.We recently established a mouse model of obesity in pregnancy, which shows extensive similarities to the human condition, including low maternal ADN and glucose intolerance, increased placental nutrient transport, and fetal overgrowth (19). In this study, we used this model to test the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin signaling and nutrient transport, and prevents fetal overgrowth.     

肥胖结肠癌患者血清脂肪因子与细胞因子水平的相关性分析

目的：探讨肥胖结肠癌患者血清脂肪因子与细胞因子水平相关性分析。方法选择2011年1至2013年6月收治的肥胖结肠癌患者53例为观察组,同时选择非肥胖的结肠癌患者51例为对照组,采用 Duke 分期标准对患者进行分期。对两组患者的 TNF-α、IGF-1、VEGF 及脂肪因子水平进行测定。结果观察组 A～B 期及 C～D 期与对照组同期相比,IGF-1较对照组同期均出现显著性升高（P ＜0．05）。观察组内 C～D 期较 A～B 期 TNF-α、IGF-1、VEGF 显著升高（P ＜0．05）,对照组 C～D 期较A～B 期 TNF-α、VEGF 显著升高（P ＜0．05）。观察组 A～B 期与对照组同期相比,内脂素、瘦素较对照组同期均出现显著性升高（P ＜0．05）,C～D 期与对照组同期相比,内脂素、抵抗素、瘦素较对照组同期均出现显著性升高（P ＜0．05）。内脂素与 IGF-1、VEGF 呈显著正相关（P ＜0．05）,抵抗素与 IGF-1呈显著正相关（P ＜0．05）,瘦素与 TNF-α、IGF-1、VEGF 呈显著正相关（P ＜0．05）。结论肥胖结肠癌存在明显的脂代谢及细胞因子紊乱,其水平紊乱可能促进结肠癌进展。     

Cardiometabolic-Based Chronic Disease,Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.     

Benefit of a low-fat over high-fat diet on vascular health during alternate day fasting

Background:

Alternate day fasting (ADF) with a low-fat (LF) diet improves brachial artery flow-mediated dilation (FMD). Whether these beneficial effects can be reproduced with a high-fat (HF) diet remains unclear.

Objective:

This study compared the effects of ADF-HF to ADF-LF regimens on FMD. The role that adipokines have in mediating this effect was also investigated.

Methods:

Thirty-two obese subjects were randomized to an ADF-HF (45% fat) or ADF-LF diet (25% fat), consisting of two phases: (1) a 2-week baseline weight maintenance period and (2) an 8-week ADF weight loss period. Food was provided throughout the study.

Results:

Body weight was reduced (P<0.0001) in the ADF-HF (4.4±1.0 kg) and ADF-LF group (3.7±0.7 kg). FMD decreased (P<0.05) by ADF-HF relative to baseline (7±1 to 5±2%) and increased (P<0.05) by ADF-LF (5±1 to 7±2%). Blood pressure remained unchanged in both groups. Adiponectin increased (P<0.05) in the ADF-HF (43±7%) and ADF-LF group (51±7%). Leptin and resistin decreased (P<0.05) in the ADF-HF (32±5% 23±5%) and ADF-LF group (30±3% 27±4%). Increases in adiponectin were associated with augmented FMD in the ADF-LF group only (r=0.34, P=0.03).

Conclusion:

Thus, improvements in FMD with ADF may only occur with LF diets and not with HF diets, and adipokines may not have a significant role in mediating this effect.     

ORIGINAL ARTICLE: Maternal Plasma Concentration of the Pro‐Inflammatory Adipokine Pre‐B‐Cell‐Enhancing Factor (PBEF)/Visfatin Is Elevated In Pregnant Patients with Acute Pyelonephritis

Citation Mazaki‐Tovi S, Vaisbuch E, Romero R, Kusanovic JP, Chaiworapongsa T, Kim SK, Nhan‐Chang C‐L, Gomez R, Yoon BH, Yeo L, Mittal P, Ogge G, Gonzalez JM, Hassan SS. Maternal plasma concentration of the pro‐inflammatory adipokine pre‐B‐cell‐enhancing factor (PBEF)/visfatin is elevated in pregnant patients with acute pyelonephritis. Am J Reprod Immunol 2010; 63: 252–262 Problem Visfatin/pre‐B‐cell‐enhancing factor (PBEF) has been implicated in the regulation of the innate immune system, as well as in glucose metabolism. Specifically, visfatin plays a requisite role in delayed neutrophil apoptosis in patients with sepsis. The aim of this study was to determine whether pyelonephritis during pregnancy is associated with changes in maternal plasma visfatin concentration in normal weight and overweight/obese patients. Method of study This cross‐sectional study included the following groups: (1) normal pregnant women (n = 200) and (2) pregnant women with pyelonephritis (n = 40). Maternal plasma visfatin concentrations were determined by ELISA. Non‐parametric statistics was used for analyses. Results (1) The median maternal plasma visfatin concentration was significantly higher in patients with pyelonephritis than in those with a normal pregnancy; (2) among overweight/obese pregnant women, those with pyelonephritis had a significantly higher median plasma visfatin concentration than women with a normal pregnancy; and (3) pyelonephritis was independently associated with higher maternal plasma visfatin concentrations after adjustment for maternal age, pre‐gestational body mass index, smoking status, gestational age at sampling, and birthweight. Conclusion Acute pyelonephritis during pregnancy is associated with a high circulating maternal visfatin concentration. These findings suggest that visfatin/PBEF may play a role in the regulation of the complex and dynamic crosstalk between inflammation and metabolism during pregnancy.     

中链脂肪酸对高脂肪饲料诱导的肥胖C57BL/6J小鼠脂肪组织中转录因子的影响

目的观察中链脂肪酸（medium chain fatty acid,MCFA）对高脂肪饲料诱导的肥胖C57BL/6J小鼠脂肪组织中转录因子的表达,探讨中链脂肪酸降低体重、体脂肪的可能机制。方法 30只C57BL/6J肥胖小鼠按空腹体重随机分为两组,每组15只,分别给予含2%MCFA和长链脂肪酸（long chain fatty acid,LCFA）的高脂饲料喂养12周,测定小鼠体重、体长,取小鼠肝脏、肠系膜周围脂肪垫、附睾周围脂肪垫及肾周脂肪垫并称重。采用BCA法测定附睾周围脂肪组织（white adiposetissue,WAT）蛋白浓度,采用ELISA法测定小鼠WAT中肿瘤坏死因子（tumor necrosis factor-α,TNF-α）和过氧化物酶体增殖物激活受体-γ（peroxisome proliferators-activated receptor-γ,PPAR-γ）水平,采用Real-time PCR法检测WAT中PPAR-γ、甾醇调控元件结合蛋白-1（sterol regulatory element-binding protein-1,SREBP-1）和CCAAT/增强子结合蛋白（CCAAT enhancer binding protein-α,C/EBP-α）的mRNA表达。结果 MCFA饲料组肥胖小鼠体质量、体长、肝脏质量、肾周脂肪质量、附睾周脂肪质量以及WAT中TNF-α水平、SREBP-1和C/EBP-α的mRNA表达量均显著低于LCFA饲料组（P〈0.05）。PPAR-γ水平及其mRNA表达量,两组之间无统计学差异（P〉0.05）。结论 MCFA可能通过下调脂肪组织中TNF-α、SREBP-1及C/EBP-α水平和mRNA表达,抑制脂肪细胞分化。     

Novel factors as therapeutic targets to treat diabetes. Focus on leptin and ghrelin

Background: Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain. Objective/methods: To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes. Results/conclusions: A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.     

Powerful rare variant association testing in a copula-based joint analysis of multiple phenotypes

In genetic association studies of rare variants, the low power of association tests is one of the main challenges. In this study, we propose a new single-marker association test called C-JAMP (Copula-based Joint Analysis of Multiple Phenotypes), which is based on a joint model of multiple phenotypes given genetic markers and other covariates. We evaluated its performance and compared its empirical type I error and power with existing univariate and multivariate single-marker and multi-marker rare-variant tests in extensive simulation studies. C-JAMP yielded unbiased genetic effect estimates and valid type I errors with an adjusted test statistic. When strongly dependent traits were jointly analyzed, C-JAMP had the highest power in all scenarios except when a high percentage of variants were causal with moderate/small effect sizes. When traits with weak or moderate dependence were analyzed, whether C-JAMP or competing approaches had higher power depended on the effect size. When C-JAMP was applied with a misspecified copula function, it still achieved high power in some of the scenarios considered. In a real-data application, we analyzed sequencing data using C-JAMP and performed the first genome-wide association studies of high-molecular-weight and medium-molecular-weight adiponectin plasma concentrations. C-JAMP identified 20 rare variants with p-values smaller than 10⁻⁵, while all other tests resulted in the identification of fewer variants with higher p-values. In summary, the results indicate that C-JAMP is a powerful, flexible, and robust method for association studies, and we identified novel candidate markers for adiponectin. C-JAMP is implemented as an R package and freely available from https://cran.r-project.org/package=CJAMP .     

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels,glucose homeostasis and oxidative stress in male C57BL/6 mice

Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR.