Triglyceride-Rich Lipoprotein-Mediated Polymer Dots for Multimodal Imaging Interscapular Brown Adipose Tissue Capillaries.

Brown adipose tissues (BATs) have been identified as a promising target of metabolism disorders. [18F]FDG-PET (FDG = fluorodeoxyglucose; PET = positron emission tomography) has been predominantly employed for BAT imaging, but its limitations drive the urgent need for novel functional probes combined with multimodal imaging approaches. It has been reported that polymer dots (Pdots) display rapid BAT imaging without additional cold stimulation. However, the mechanism by which Pdots image BAT remains unclear. Here, we made an intensive study of the imaging mechanism and found that Pdots can bind to triglyceride-rich lipoproteins (TRLs). By virtue of their high affinity to TRLs, Pdots selectively accumulate in capillary endothelial cells (ECs) in interscapular brown adipose tissues (iBATs). Compared to poly(styrene-co-maleic anhydride)cumene terminated (PSMAC)-Pdots with a short half-life and polyethylene glycol (PEG)-Pdots with low lipophilicity, naked-Pdots have good lipophilicity, with a half-life of about 30 min and up to 94% uptake in capillary ECs within 5 min, increasing rapidly after acute cold stimulation. These results suggested that the accumulation changes of Pdots in iBAT can reflect iBAT activity sensitively. Based on this mechanism, we further developed a strategy to detect iBAT activity and quantify the TRL uptake in vivo using multimodal Pdots.

Corrigendum: The correlation between collagen types and ultrasound feature score in evaluating the vulnerability of carotid artery plaque.

[This corrects the article DOI: 10.3389/fcvm.2021.756424.].

Effectiveness of olanzapine in the treatment of anorexia nervosa: A systematic review and meta-analysis.

OBJECTIVE: Anorexia nervosa (AN) is a severe psychiatric disorder characterized by starvation and malnutrition, a high incidence of coexisting psychiatric conditions, and treatment resistance. The effect of pharmacotherapy has been controversial. METHOD: A systematic review was conducted for evidence of an effect of olanzapine versus placebo in adults or its effect as adjuvant treatment of AN in adolescents. RESULTS: A total of seven articles (304 patients with AN) were identified. There were four double-blind, randomized studies examining the effect of olanzapine in the treatment of AN. The mean difference in body mass index (BMI) at the end of treatment between olanzapine and placebo was 0.67 kg/m2 (95% confidence interval (CI) 0.15-1.18 kg/m2 ; p = 0.01; I2  = 0%, p for heterogeneity < 0.79). The olanzapine groups showed a significant increase in BMI of 0.68 kg/m2 (95% CI 0.22-1.13 kg/m2 ; p < 0.001; I2  = 0%, p for heterogeneity = 0.74) compared to the placebo groups. Only two studies examined the effect of olanzapine as adjuvant treatment in adolescents and showed an increase in BMI of 0.66 kg/m2 (95% CI -0.36 to 1.67 kg/m2 ; p = 0.21; I2  = 11%, p for heterogeneity = 0.32). DISCUSSION: Olanzapine showed efficacy in the treatment of AN with an increased BMI at the end of treatment in adults. The effect of olanzapine as adjuvant treatment in adolescents remains unclear.

The Correlation Between Collagen Types and Ultrasound Feature Score in Evaluating the Vulnerability of Carotid Artery Plaque.

Objectives: To investigate whether ultrasound score has clinical value in identifying carotid artery-vulnerable plaque and the impacts of collagen distribution on the stability of plaque. Materials and Methods: Standard carotid artery ultrasound examinations were performed in 51 patients with carotid artery plaques before carotid endarterectomy. Hematoxylin-eosin staining and Sirius red-picric acid staining of plaque sections were performed to analyze the pathological features and collagen distribution. All plaques were classified into vulnerable and stable groups by pathological features. Ultrasound scores, cap thickness, and the ratios of different collagen types were recorded and analyzed between two groups and different parts of plaques. Results: Ultrasound scores of the vulnerable group were higher than those of the stable group (4.35 ± 1.23 vs. 2.09 ± 1.04, P = 0.001). AUC was 0.894 (best cutoff point three) in differentiating vulnerable and stable plaques. Compared with the stable group, the fibrous caps of the vulnerable group were thinner (P = 0.012); the area ratios of collagen type I to all collagen in the vulnerable group were lower (P = 0.033); however, the area ratios of collagen type IV to all collagen were higher (P = 0.026). Compared with downstream shoulders, the ultrasound scores of upstream shoulders of plaque were higher (P = 0.001), the fibrous caps of upstream shoulders were thinner (P = 0.001), and the area ratios of collagen type I to all collagen were lower (P = 0.022). Conclusion: Ultrasound score could have a clinical value in identifying vulnerable carotid artery plaque, and the collagen distribution could impact the stability of plaques, especially collagen type I and type IV. The results also prompted that the upstream shoulders were more vulnerable than the downstream shoulders.

Dithienocoronene diimide (DTCDI)-derived triads for high-performance air-stable, solution-processed balanced ambipolar organic field-effect transistors.

Developing ambipolar organic semiconducting materials is essential for use in complementary-like inverters and light-emitting transistors. In this study, three new dithienocoronenediimide (DTCDI)-derived triads, DTCDI-BT, DTCDI-BBT and DTCDI-BNT, were designed and synthesized, in which various sizes of terminal groups, i.e., thiophene (T), benzo[b]thiophene (BT) and naphtha[2,3-b]thiophene (NT) were substituted at the α-positions of the two thiophene rings of DTCDI, respectively. The DFT calculations reveal that the HOMO energy levels of the three triads when compared to that of the parent DTCDI-core (-5.99 eV) are significantly increased to -5.59, -5.59 and -5.45 eV for DTCDI-BT, DTCDI-BBT and DTCDI-BNT, respectively, whereas the LUMO energy levels (-3.07 eV ∼ -3.14 eV) are almost identical with that of the DTCDI-core (-3.10 eV). The results predict that the triads could possess ambipolar transport properties in organic field-effect transistor (OFET) applications. In fact, under an ambient atmosphere, solution-processed bottom-gate top-contact (BGTC) transistors exhibit ambipolar charge transport properties by tuning the HOMOs of the DTCDI-based triads so that they were suitable for hole injection, resulting in balanced maximum electron and hole mobilities of 1.66 × 10-3 and 1.02 × 10-3 cm2 V-1 s-1 for DTCDI-BT, 2.60 × 10-2 and 3.60 × 10-2 cm2 V-1 s-1 for DTCDI-BBT, and 2.43 × 10-3 and 4.15 × 10-3 cm2 V-1 s-1 for DTCDI-BNT, respectively. This is the first time that the DTCDI building block has been used to develop ambipolar small molecular semiconductors, and achieved a device performance comparable to that of the DTCDI-based polymeric semiconductors. In addition, DTCDI-BBT-based complementary-like inverters were made, and the inverter devices operated well in both p-mode and n-mode under ambient conditions. The results show that the DTCDI is a promising π-electron-deficient building block which could be further used to develop ambipolar semiconducting materials for OFET devices.

Diagnostic Efficacy of Ultrasound, Cytology, and BRAFV600E Mutation Analysis and Their Combined Use in Thyroid Nodule Screening for Papillary Thyroid Microcarcinoma.

BACKGROUND: Ultrasound, cytology, and BRAFV600E mutation analysis were applied as valuable tools in the differential diagnosis of thyroid nodules. The aim of the present study was to evaluate the diagnostic efficiency of the three methods and their combined use in screening for papillary thyroid microcarcinoma (PTMC). METHODS: A total of 1,081 patients with 1,157 thyroid nodules (0.5-1 cm in maximum diameter) classified as thyroid imaging reporting and data system (TIRADS) 4-5 were recruited. All patients underwent ultrasound, fine-needle aspiration (FNA) examination, and an additional BRAFV600E mutation test. TIRADS and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) were adopted to judge the ultrasound and cytological results. The receiver operating characteristic (ROC) curve was established to assess the diagnostic values of different methods. RESULTS: Of the 1,157 nodules, 587 were benign and 570 were PTMCs. BRAFV600E mutation test had highest sensitivity (85.4%), specificity (97.1%), accuracy (91.4%), and area under the ROC curve (Az) value (0.913) among the three methods. The combination of BSRTC and BRAFV600E mutation analysis yielded a considerably high sensitivity (96.0%), accuracy (94.3%), and negative predictive value (95.9%) than either BSRTC or BRAFV600E mutation alone (P < 0.0001 for all comparisons). Of all the methods, the combined use of the three methods produced the best diagnostic performance (Az = 0.967), which was significantly higher than that (Az = 0.943) for the combination of BSRTC and BRAFV600E mutation (P < 0.0001). The diagnostic accuracy of the molecular method in the 121 nodules with indeterminate cytology was 90.1% (109/121), which was significantly higher than that of TIRADS classification, 74.4% (90/121) (P = 0.002). CONCLUSION: The combined use of ultrasound, cytology, and BRAFV600E mutation analysis is the most efficient and objective method for diagnosing PTMC. Both BRAFV600E mutation and TIRADS classification are potentially useful adjuncts to differentiate thyroid nodules, especially indeterminate samples classified as BSRTC III.

Two Isomeric Azulene-Decorated Naphthodithiophene Diimide-based Triads: Molecular Orbital Distribution Controls Polarity Change of OFETs Through Connection Position.

Altering the charge carrier transport polarities of organic semiconductors by molecular orbital distribution has gained great interest. Herein, we report two isomeric azulene-decorated naphthodithiophene diimide (NDTI)-based triads (e.g., NDTI-B2Az and NDTI-B6Az), in which two azulene units were connected with NDTI at the 2-position of the azulene ring in NDTI-B2Az, whereas two azulene units were incorporated with NDTI at the 6-position of the azulene ring in NDTI-B6Az. The two isomeric triads were excellently soluble in common organic solvents. Density functional theory calculations on the molecular orbital distributions of the triads reveal that the lowest unoccupied molecular orbitals are completely delocalized over the entire molecule for both NDTI-B2Az and NDTI-B6Az, indicating great potential for n-type transport behavior, whereas the highest occupied molecular orbitals are mainly delocalized over the entire molecule for NDTI-B2Az or only localized at the two terminal azulene units for NDTI-B6Az, implying great potential for p-type transport behavior for the former and a disadvantage of hole carrier transport for the latter. Under ambient conditions, solution-processed bottom-gate top-contact transistors based on NDTI-B2Az showed ambipolar field-effect transistor (FET) characteristics with high electron and hole mobilities of 0.32 (effective electron mobility ≈0.14 cm2 V-1 s-1 according to a reliability factor of 43%) and 0.03 cm2 V-1 s-1 (effective hole mobility ≈0.01 cm2 V-1 s-1 according to a reliability factor of 33%), respectively, whereas a typically unipolar n-channel behavior is found for a film of NDTI-B6Az with a high electron mobility up to 0.13 cm2 V-1 s-1 (effective electron mobility ≈0.06 cm2 V-1 s-1 according to a reliability factor of 43%). The results indicate that the polarity change of organic FETs based on the two isomeric triads could be controlled by the molecular orbital distributions through the connection position between the azulene unit and NDTI.

Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21.

Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). After having characterized the TLQP-21/C3aR1 lipolytic mechanism, a homology modeling and molecular dynamics simulation identified the TLQP-21 binding motif and C3aR1 binding site for the human (h) and mouse (m) molecules. mTLQP-21 showed enhanced binding affinity and potency for hC3aR1 compared with hTLQP-21. Consistently, mTLQP-21, but not hTLQP-21, potentiates lipolysis in human adipocytes. These findings led us to uncover five mutations in the C3aR1 binding pocket of the rodent Murinae subfamily that are causal for enhanced calculated affinity and measured potency of TLQP-21. Identifying functionally relevant peptide/receptor co-evolution mechanisms can facilitate the development of innovative pharmacotherapies for obesity and other diseases implicating GPCRs.

Comparisons and Combined Application of Two-Dimensional and Three-Dimensional Real-time Shear Wave Elastography in Diagnosis of Thyroid Nodules.

Purpose Two-dimensional and three-dimensional real-time shear wave elastography (2D+3D SWE) represents a new technology for the quantification of tissue elasticity. This study investigated whether they could be performed to differentiate between benign and malignant thyroid nodules. Methods Conventional B-mode ultrasound, 2D and 3D SWE were performed in 96 patients with 97 thyroid nodules with pathology results. Results All the elastography values of 2D&3D SWE in malignant thyroid nodules were higher than those in benign nodules. These two elastography methods alone could not improve diagnostic value comparing to B-mode ultrasound significantly. However, B-mode US + 2D SWE (TI-RADS ≥ 4c or S-Emean ≥ 23.75 kPa, suspicious), B-mode US + 3D SWE (TI-RADS ≥ 4c or 3D-T-Emean ≥ 20.75 kPa, suspicious), B-mode US + 2D + 3D SWE (TI-RADS ≥ 4c or S-Emean ≥ 23.75 kPa or 3D-T-Emean ≥ 20.75 kPa, suspicious) had higher sensitivity and accuracy values than those of 3 methods alone but lower specificity values. Among them, B-mode ultrasound + 2D SWE had the highest sensitivity, NPV, accuracy and Youden's index (0.881, 0.788, 0.804 and 0.57). Conclusions 2D SWE or 3D SWE alone could not improve the diagnostic value of differentiating malignant from benign thyroid nodules comparing to conventional B-mode ultrasound. But combination methods could improve the diagnostic value, especially B-mode US + 2D SWE.

The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis.

OBJECTIVES: Obesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases. The molecular mechanism is still largely uncharacterized. METHODS: We used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used for in vitro experiments. Chronic in vivo experiments were conducted on diet-induced obese wild type, ß1, ß2, ß3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acute in vivo lipolysis experiments were conducted on Sprague Dawley rats. RESULTS: We demonstrated that TLQP-21 does not possess lipolytic properties per se. Rather, it enhances ß-AR activation-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of Hormone Sensitive Lipase (HSL). TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. Finally, chronic peripheral TLQP-21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism involving ß-adrenergic and C3a receptor activation without associated adverse metabolic effects. CONCLUSIONS: In conclusion, our data identify an alternative pathway modulating lipolysis that could be targeted to diminish fat mass in obesity without the side effects typically observed when using potent pro-lipolytic molecules.

[Development of multiplex oligonucleotide ligation-PCR-universal DNA microarrays for detection of foodborne pathogens].

OBJECTIVE: To develop a multiplex oligonucleotide ligation-polymerase chain reaction( MOL-PCR) based universal microarray assay for multiplexed detection of foodborne pathogens. METHODS: Eight common foodborne pathogens causing bacterial food poisoning were selected as detection models. An upstream and downstream adjacent detection probes were designed within specific primer pair for each of eight pathogens. Target fragments of the eight pathogens were enriched by multiplex PCR and used as ligation templates. Abundant fluorescently labeled single-stranded amplicons containing anti-tag sequences were gained by multiplex ligase detection reaction and asymmetric PCR labeling with universal primers. The products could be detected by hybridization with corresponding tag sequences immobilized on DNA microarrays. RESULTS: The results indicated that the assay could specifically identify all eight pathogens in single and multiple infections. The detection limits were( 1. 1- 8. 5) × 10~2 CFU /mL of pure bacterial cultures. The microarray results for 96 food poisoning and clinical diarrheal samples were consistent with that of traditional culture, biochemical identification and real-time PCR. CONCLUSION: The assay provides a novel platform for rapid, accurate, sensitive and high-throughput detection of pathogenic bacteria of foodborne diseases.

Renal Denervation Normalizes Arterial Pressure With No Effect on Glucose Metabolism or Renal Inflammation in Obese Hypertensive Mice.

Hypertension often occurs in concurrence with obesity and diabetes mellitus, commonly referred to as metabolic syndrome. Renal denervation (RDNx) lowers arterial pressure (AP) and improves glucose metabolism in drug-resistant hypertensive patients with high body mass index. In addition, RDNx has been shown to reduce renal inflammation in the mouse model of angiotensin II hypertension. The present study tested the hypothesis that RDNx reduces AP and renal inflammation and improves glucose metabolism in obesity-induced hypertension. Eight-week-old C57BL/6J mice were fed either a low-fat diet (10 kcal%) or a high-fat diet (45 kcal%) for 10 weeks. Body weight, food intake, fasting blood glucose, and glucose metabolism (glucose tolerance test) were measured. In a parallel study, radiotelemeters were implanted in mice for AP measurement. High fat-fed C57BL/6J mice exhibited an inflammatory and metabolic syndrome phenotype, including increased fat mass, increased AP, and hyperglycemia compared with low-fat diet mice. RDNx, but not Sham surgery, normalized AP in high-fat diet mice (115.8±1.5 mm Hg in sham versus 96.6±6.7 mm Hg in RDNx). RDNx had no significant effect on AP in low-fat diet mice. Also, RDNx had no significant effect on glucose metabolism or renal inflammation as measured by the number of CD8, CD4, and T helper cells or levels of inflammatory cytokines in the kidneys. These results indicate that although renal nerves play a role in obesity-induced hypertension, they do not contribute to impaired glucose metabolism or renal inflammation in this model.

Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation.

Adipocytes are the primary cells in adipose tissue, and adipocyte dysfunction causes lipodystrophy, obesity and diabetes. The dipeptidyl peptidase (DPP) 4 family includes four enzymes, DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). DPP4 family inhibitors have been used for the treatment of type 2 diabetes patients, but their role in adipocyte formation are poorly understood. Here we demonstrate that the DPP8/9 selective inhibitor 1G244 blocks adipogenesis in preadipocyte 3T3-L1 and 3T3-F422A, while DPP4 and FAP inhibitors have no effect. In addition, knockdown of DPP8 or DPP9 significantly impairs adipocyte differentiation in preadipocytes. We further uncovered that blocking the expression or activities of DPP8 and DPP9 attenuates PPARγ2 induction during preadipocyte differentiation. Addition of PPARγ agonist thiazolidinediones (TZDs), or ectopic expression of PPARγ2, is able to rescue the adipogenic defect caused by DPP8/9 inhibition in preadipocytes. These results indicate the importance of DPP8 and DPP9 on adipogenesis.

Direct Detection of Erythromycin-Resistant Bordetella pertussis in Clinical Specimens by PCR.

Resistance of Bordetella pertussis to erythromycin has been increasingly reported. We developed an allele-specific PCR method for rapid detection of erythromycin-resistant B. pertussis directly from nasopharyngeal (NP) swab samples submitted for diagnostic PCR. Based on the proven association of erythromycin resistance with the A2047G mutation in the 23S rRNA of B. pertussis, four primers, two of which were designed to be specific for either the wild-type or the mutant allele, were used in two different versions of the allele-specific PCR assay. The methods were verified with results obtained by PCR-based sequencing of 16 recent B. pertussis isolates and 100 NP swab samples submitted for diagnostic PCR. The detection limits of the two PCR assays ranged from 10 to 100 fg per reaction for both erythromycin-susceptible and -resistant B. pertussis. Two amplified fragments of each PCR, of 286 and 112 bp, respectively, were obtained from a mutant allele of the isolates and/or NP swab samples containing B. pertussis DNAs. For the wild-type allele, only a 286-bp fragment was visible when the allele-specific PCR assay 1 was performed. No amplification was found when a number of non-Bordetella bacterial pathogens and NP swab samples that did not contain the DNAs of B. pertussis were examined. This assay can serve as an alternative for PCR-based sequencing, especially for local laboratories in resource-poor countries.

Virtual touch tissue quantification (VTQ) in the diagnosis of thyroid nodules with coexistent chronic autoimmune Hashimoto's thyroiditis: a preliminary study.

OBJECTIVES: This study aimed at detecting whether Virtual Touch Tissue Quantification (VTQ) could be applied to differentiate between benign and malignant thyroid nodules with chronic autoimmune Hashimoto's thyroiditis (HT). METHODS: Convenient ultrasound and Virtual Touch Tissue Quantification were performed in 118 patients with 140 thyroid nodules with histology results. The HT group consisted of 46 patients with 58 nodules. The non-HT group consisted of 72 patients with 82 nodules. RESULTS: The stiffness of extra-nodular thyroid tissue could be significantly affected by the severity of chronic autoimmune thyroiditis. The shear wave velocity of thyroid benign nodules and malignant nodules did not significantly differ in the HT group as compared with the non-HT group (benign nodules: 2.13±0.32m/s vs 1.98±0.48m/s, P=0.122; malignant nodules: 3.32±0.77m/s vs 3.30±0.74m/s, P=0.894). In two groups, the shear wave velocity of malignant nodules is significantly higher than that of benign nodules (HT group: 3.32±0.77m/s vs 2.13±0.32m/s; non-HT group: 3.30±0.74m/s vs 1.98±0.48m/s, P<0.001). The best cutoff point for shear wave velocity between malignant and benign thyroid nodules was 2.75m/s. CONCLUSIONS: Virtual Touch Tissue Quantification technology could be performed in the differential diagnosis between malignant thyroid nodules and benign thyroid nodules independently from the coexistence of chronic autoimmune thyroiditis.

Stress hormone epinephrine enhances adipogenesis in murine embryonic stem cells by up-regulating the neuropeptide Y system.

Prenatal stress, psychologically and metabolically, increases the risk of obesity and diabetes in the progeny. However, the mechanisms of the pathogenesis remain unknown. In adult mice, stress activates NPY and its Y2R in a glucocorticoid-dependent manner in the abdominal fat. This increased adipogenesis and angiogenesis, leading to abdominal obesity and metabolic syndrome which were inhibited by intra-fat Y2R inactivation. To determine whether stress elevates NPY system and accelerates adipogenic potential of embryo, here we "stressed" murine embryonic stem cells (mESCs) in vitro with epinephrine (EPI) during their adipogenic differentiation. EPI was added during the commitment stage together with insulin, and followed by dexamethasone in the standard adipogenic differentiation medium. Undifferentiated embryonic bodies (EBs) showed no detectable expression of NPY. EPI markedly up-regulated the expression NPY and the Y1R at the commitment stage, followed by increased Y2R mRNA at the late of the commitment stage and the differentiation stage. EPI significantly increased EB cells proliferation and expression of the preadipocyte marker Pref-1 at the commitment stage. EPI also accelerated and amplified adipogenic differentiation detected by increasing the adipocyte markers FABP4 and PPARγ mRNAs and Oil-red O-staining at the end of the differentiation stage. EPI-induced adipogenesis was completely prevented by antagonists of the NPY receptors (Y1R+Y2R+Y5R), indicating that it was mediated by the NPY system in mESC's. Taken together, these data suggest that stress may play an important role in programming ESCs for accelerated adipogenesis by altering the stress induced hormonal regulation of the NPY system.

Maternal low-protein diet up-regulates the neuropeptide Y system in visceral fat and leads to abdominal obesity and glucose intolerance in a sex- and time-specific manner.

Neuropeptide Y (NPY) mediates stress-induced obesity in adult male mice by activating its Y2 receptor (Y2R) in visceral adipose tissue (VAT). Here, we studied whether the NPY-Y2R system is also activated by maternal low-protein diet (LPD) and linked to obesity in offspring. Prenatal LPD offspring had lower birth weights compared to normal-protein diet (NPD) offspring. Female prenatal and lactation stress (PLS) offspring from mothers fed an LPD developed abdominal adiposity and glucose intolerance associated with a 5-fold up-regulation of NPY mRNA and a 6-fold up-regulation of Y2R mRNA specifically in VAT, in addition to elevated platelet-rich-plasma (PRP) NPY, compared to control females fed a high-fat diet (HFD). Conversely, PLS male offspring showed lower NPY in PRP, a 10-fold decrease of Y2R mRNA in VAT, lower adiposity, and improved glucose tolerance compared to control males. Interestingly, prenatal LPD offspring cross-fostered to control lactating mothers had completely inverse metabolic and NPY phenotypes. Taken together, these findings suggested that maternal LPD activates the VAT NPY-Y2R system and increases abdominal adiposity and glucose intolerance in a sex- and time-specific fashion, suggesting that the peripheral NPY system is a potential mediator of programming for the offspring's vulnerability to obesity and metabolic syndrome.

Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice.

Both genetic variations and diet-disrupted gut microbiota can predispose animals to metabolic syndromes (MS). This study assessed the relative contributions of host genetics and diet in shaping the gut microbiota and modulating MS-relevant phenotypes in mice. Together with its wild-type (Wt) counterpart, the Apoa-I knockout mouse, which has impaired glucose tolerance (IGT) and increased body fat, was fed a high-fat diet (HFD) or normal chow (NC) diet for 25 weeks. DNA fingerprinting and bar-coded pyrosequencing of 16S rRNA genes were used to profile gut microbiota structures and to identify the key population changes relevant to MS development by Partial Least Square Discriminate Analysis. Diet changes explained 57% of the total structural variation in gut microbiota, whereas genetic mutation accounted for no more than 12%. All three groups with IGT had significantly different gut microbiota relative to healthy Wt/NC-fed animals. In all, 65 species-level phylotypes were identified as key members with differential responses to changes in diet, genotype and MS phenotype. Most notably, gut barrier-protecting Bifidobacterium spp. were nearly absent in all animals on HFD, regardless of genotype. Sulphate-reducing, endotoxin-producing bacteria of the family, Desulfovibrionaceae, were enhanced in all animals with IGT, most significantly in the Wt/HFD group, which had the highest calorie intake and the most serious MS phenotypes. Thus, diet has a dominating role in shaping gut microbiota and changes of some key populations may transform the gut microbiota of Wt animals into a pathogen-like entity relevant to development of MS, despite a complete host genome.

Negative regulation of adiponectin receptor 1 promoter by insulin via a repressive nuclear inhibitory protein element.

Adiponectin is an adipose-derived hormone that has anti-diabetic and anti-atherogenic effects through interaction with adiponectin receptors AdipoR1 and AdipoR2. We analyzed the transcriptional regulation of AdipoR1 by insulin. Insulin repressed the promoter activity of AdipoR1 in C2C12 myoblasts via PI3K and Foxo1. Deletion studies demonstrated the presence of a putative insulin-responsive region which is composed of a nuclear inhibitory protein (NIP) binding element. Mutation of the NIP element abrogated the negative regulation of AdipoR1 promoter by insulin. Insulin treatment could induce formation of a protein complex that bound the NIP element. Collectively, our data suggest that a repressive NIP element is involved in the negative regulation of AdipoR1 promoter by insulin.