Gene expression and ultra-structural evidence for metabolic derangement in the primary mitral regurgitation heart.

Aims: Chronic neurohormonal activation and haemodynamic load cause derangement in the utilization of the myocardial substrate. In this study, we test the hypothesis that the primary mitral regurgitation (PMR) heart shows an altered metabolic gene profile and cardiac ultra-structure consistent with decreased fatty acid and glucose metabolism despite a left ventricular ejection fraction (LVEF) > 60%. Methods and results: Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate-to-severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT4), GLUT1, and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase, and O-linked N-acetylglucosaminyl transferase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of neuropeptide Y were four-fold higher than simultaneous plasma, indicative of increased sympathetic drive. Quantitative transmission electron microscopy showed glycogen accumulation, glycophagy, increased lipid droplets (LDs), and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3ß, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance and positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma haemoglobin A1C, free fatty acids, and mitochondrial damage-associated molecular patterns in a separate cohort of patients with stable moderate PMR with an LVEF > 60% (n = 8) vs. normal controls (n = 8). Conclusion: The PMR heart has a global ultra-structural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and LDs. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.

Berberine directly targets AKR1B10 protein to modulate lipid and glucose metabolism disorders in NAFLD.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine (BBR) is the main active component from Coptidis rhizome, a well-known Chinese herbal medicine used for metabolic diseases, especially diabetes for thousands of years. BBR has been reported to cure various metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD). However, the direct proteomic targets and underlying molecular mechanism of BBR against NAFLD remain less understood. AIM OF THE STUDY: To investigate the direct target and corresponding molecular mechanism of BBR on NAFLD is the aim of the current study. MATERIALS AND METHODS: High-fat diet (HFD)-fed mice and oleic acid (OA) stimulated HepG2 cells were utilized to verify the beneficial impacts of BBR on glycolipid metabolism profiles. The click chemistry in proteomics, DARTS, CETSA, SPR and fluorescence co-localization analysis were conducted to identify the targets of BBR for NAFLD. RNA-seq and shRNA/siRNA were used to investigate the downstream pathways of the target. RESULTS: BBR improved hepatic steatosis, ameliorated insulin resistance, and reduced TG levels in the NAFLD models. Importantly, Aldo-keto reductase 1B10 (AKR1B10) was first proved as the target of BBR for NAFLD. The gene expression of AKR1B10 increased significantly in the NAFLD patients' liver tissue. We further demonstrated that HFD and OA increased AKR1B10 expression in the C57BL/6 mice's liver and HepG2 cells, respectively, whereas BBR decreased the expression and activities of AKR1B10. Moreover, the knockdown of AKR1B10 by applying shRNA/siRNA profoundly impacted the beneficial effects on the pathogenesis of NAFLD by BBR. Meanwhile, the changes in various proteins (ACC1, CPT-1, GLUT2, etc.) are responsible for hepatic lipogenesis, fatty acid oxidation, glucose uptake, etc. by BBR were reversed by the knockdown of AKR1B10. Additionally, RNA-seq was used to identify the downstream pathway of AKR1B10 by examining the gene expression of liver tissues from HFD-fed mice. Our findings revealed that BBR markedly increased the protein levels of PPARα while downregulating the expression of PPARγ. However, various proteins of PPAR signaling pathways remained unaffected post the knockdown of AKR1B10. CONCLUSIONS: BBR alleviated NAFLD via mediating PPAR signaling pathways through targeting AKR1B10. This study proved that AKR1B10 is a novel target of BBR for NAFLD treatment and helps to find new targets for the treatment of NAFLD by using active natural compounds isolated from traditional herbal medicines as the probe.

Impact of visceral adipose tissue on longevity and metabolic health: a comparative study of gene expression in perirenal and epididymal fat of Ames dwarf mice.

Emerging research underscores the pivotal role of adipose tissue in regulating systemic aging processes, particularly when viewed through the lens of the endocrine hypotheses of aging. This study delves into the unique adipose characteristics in an important animal model of aging - the long-lived Ames dwarf (df/df) mice. Characterized by a Prop1df gene mutation, these mice exhibit a deficiency in growth hormone (GH), prolactin, and TSH, alongside extremely low circulating IGF-1 levels. Intriguingly, while surgical removal of visceral fat (VFR) enhances insulin sensitivity in normal mice, it paradoxically increases insulin resistance in Ames dwarfs. This suggests an altered profile of factors produced in visceral fat in the absence of GH, indicating a unique interplay between adipose tissue function and hormonal influences in these models. Our aim was to analyze the gene expression related to lipid and glucose metabolism, insulin pathways, inflammation, thermoregulation, mitochondrial biogenesis, and epigenetic regulation in the visceral (perirenal and epididymal) adipose tissue of Ames dwarf and normal mice. Our findings reveal an upregulation in the expression of key genes such as Lpl, Adrß3, Rstn, Foxo1, Foxo3a, Irs1, Cfd, Aldh2, Il6, Tnfα, Pgc1α, Ucp2, and Ezh2 in perirenal and Akt1, Foxo3a, PI3k, Ir, Acly, Il6, Ring1a, and Ring 1b in epididymal fat in df/df mice. These results suggest that the longevity phenotype in Ames dwarfs, which is determined by peripubertal GH/IGF-1 levels, may also involve epigenetic reprogramming of adipose tissue influenced by hormonal changes. The increased expression of genes involved in metabolic regulation, tumor suppression, mitochondrial biogenesis, and insulin pathways in Ames dwarf mice highlights potentially beneficial aspects of this model, opening new avenues for understanding the molecular underpinnings of longevity and aging.

Spontaneous nonsense mutation in the tuftelin 1 gene is associated with abnormal hair appearance and amelioration of glucose and lipid metabolism in the rat.

Recently, we have identified a recessive mutation, an abnormal coat appearance in the BXH6 strain, a member of the HXB/BXH set of recombinant inbred (RI) strains. The RI strains were derived from the spontaneously hypertensive rat (SHR) and Brown Norway rat (BN-Lx) progenitors. Whole genome sequencing of the mutant rats identified the 195875980 G/A mutation in the tuftelin 1 (Tuft1) gene on chromosome 2, which resulted in a premature stop codon. Compared with wild-type BXH6 rats, BXH6-Tuft1 mutant rats exhibited lower body weight due to reduced visceral fat and ectopic fat accumulation in the liver and heart. Reduced adiposity was associated with decreased serum glucose and insulin and increased insulin-stimulated glycogenesis in skeletal muscle. In addition, mutant rats had lower serum monocyte chemoattractant protein-1 and leptin levels, indicative of reduced inflammation. Analysis of the liver proteome identified differentially expressed proteins from fatty acid metabolism and ß-oxidation, peroxisomes, carbohydrate metabolism, inflammation, and proteasome pathways. These results provide evidence for the important role of the Tuft1 gene in the regulation of lipid and glucose metabolism and suggest underlying molecular mechanisms.NEW & NOTEWORTHY A new spontaneous mutation, abnormal hair appearance in the rat, has been identified as a nonfunctional tuftelin 1 (Tuft1) gene. The pleiotropic effects of this mutation regulate glucose and lipid metabolism. Analysis of the liver proteome revealed possible molecular mechanisms for the metabolic effects of the Tuft1 gene.

Adipocyte commitment of 3T3-L1 cells is required to support human adenovirus 36 productive replication concurrent with altered lipid and glucose metabolism.

Human adenovirus 36 (HAdV-D36) can cause obesity in animal models, induces an adipogenic effect and increased adipocyte differentiation in cell culture. HAdV-D36 infection alters gene expression and the metabolism of the infected cells resulting in increased glucose internalization and triglyceride accumulation. Although HAdV-D36 prevalence correlates with obesity in humans, whether human preadipocytes may be targeted in vivo has not been determined and metabolic reprogramming of preadipocytes has not been explored in the context of the viral replication cycle. HAdV-D36 infection of the mouse fibroblasts, 3T3-L1 cells, which can differentiate into adipocytes, promotes proliferation and differentiation, but replication of the virus in these cells is abortive as indicated by short-lived transient expression of viral mRNA and a progressive loss of viral DNA. Therefore, we have evaluated whether a productive viral replication cycle can be established in the 3T3-L1 preadipocyte model under conditions that drive the cell differentiation process. For this purpose, viral mRNA levels and viral DNA replication were measured by RT-qPCR and qPCR, respectively, and viral progeny production was determined by plaque assay. The lipogenic effect of infection was evaluated with Oil Red O (ORO) staining, and expression of genes that control lipid and glucose metabolism was measured by RT-qPCR. In the context of a viral productive cycle, HAdV-D36 modulated the expression of the adipogenic genes, C/EBPα, C/EBPß and PPARγ, as well as intracellular lipid accumulation, and the infection was accompanied by altered expression of glucolytic genes. The results show that only adipocyte-committed 3T3-L1 cells are permissive for the expression of early and late viral mRNAs, as well as viral DNA replication and progeny production, supporting productive HAdV-D36 viral replication, indicating that a greater effect on adipogenesis occurs in adipocytes that support productive viral replication.

Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease.

The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2-/- mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2-/- mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2-/- mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.

Assessment of sex differences in associations between sleep duration and lipid/glucose metabolism in urban Japan: a cross-sectional study.

Inadequate sleep durations (short or long) are related to worsening of lipid/glucose metabolism, leading to atherosclerotic cardiovascular diseases (ASCVD). Few data exist on sex differences in this relationship that, to date, has been scarcely reported. This cross-sectional study included 6678 men and 4700 women at the Health Planning Center of Nihon University Hospital, located in the center of Tokyo, between September 2015 and October 2016. The prevalence of diabetes and dyslipidemia in the participants was 3.3% and 6.5%, respectively. Sleep duration was divided into five categories: < 5 h, 5-6 h, 6-7 h, 7-8 h, and ≥ 8 h. We examined the odds ratio (OR) and 95% confidence interval (CI) of lipid/glucose metabolism-related markers for the reference value defined in each guideline with 6-7 h as the reference of comparison. In men, a sleep duration of < 5 h was associated with ORs of 1.32 and 1.33 (95% CI, 1.01-1.73 and 1.02-1.74) for LDL-C level ≥ 120 mg/dL and non-HDL-C level of ≥ 150 mg/dL (defined as "borderline hyper" by the Japan Atherosclerosis Society Guidelines for Prevention of ASCVD 2017), respectively. Moreover, a sleep duration of < 5 h was associated with an OR of 1.77 (1.33-2.35) for fasting blood glucose of ≥ 100 mg/dL (defined as "high" by a specialized lifestyle checkup program in Japan). In women, sleep duration of < 5 h was associated with an OR of 1.70 (1.24-2.33) for HbA1c level of ≥ 5.6% (defined as "high" by a specialized life style checkup program in Japan). However, there was no association between sleep duration and serum lipid profile. Inadequate short sleep duration was as a potential risk factor of adverse lipid and/or glucose metabolism in both sexes. However, there were sex differences in associations between sleep duration and lipid/glucose metabolism in urban Japan. To further reduce risks of ASCVD, it is of particular importance to emphasize adequate sleep duration in both sexes.Trial registration UMIN ( http://www.umin.ac.jp/ ) Study ID: UMIN000037643 retrospectively registered on August 9, 2019.

The role of REV-ERB in NASH.

REV-ERBs are atypical nuclear receptors as they function as ligand-regulated transcriptional repressors. The natural ligand for the REV-ERBs (REV-ERBα and REV-ERBß) is heme, and heme-binding results in recruitment of transcriptional corepressor proteins such as N-CoR that mediates repression of REV-ERB target genes. These two receptors regulate a large range of physiological processes including several important in the pathophysiology of non-alcoholic steatohepatitis (NASH). These include carbohydrate and lipid metabolism as well as inflammatory pathways. A number of synthetic REV-ERB agonists have been developed as chemical tools and they show efficacy in animal models of NASH. Here, we will review the functions of REV-ERB with regard to their relevance to NASH as well as the potential to target REV-ERB for treatment of this disease.

Emodin palliates high-fat diet-induced nonalcoholic fatty liver disease in mice via activating the farnesoid X receptor pathway.

BACKGROUND: Cassia mimosoides Linn (CMD) is a traditional Chinese herb that clears liver heat and dampness. It has been widely administered in clinical practice to treat jaundice associated with damp-heat pathogen and obesity. Emodin (EMO) is a major bioactive constituent of CMD that has apparent therapeutic efficacy against obesity and fatty liver. Here, we investigated the protective effects and underlying mechanisms of EMO against high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: We aimed to investigate whether EMO activates farnesoid X receptor (FXR) signaling to alleviate HFD-induced NAFLD. MATERIALS AND METHODS: In vivo assays included serum biochemical indices tests, histopathology, western blotting, and qRT-PCR to evaluate the effects of EMO on glucose and lipid metabolism disorders in wild type (WT) and FXR knockout mice maintained on an HFD. In vitro experiments included intracellular triglyceride (TG) level measurement and Oil Red O staining to assess the capacity of EMO to remove lipids induced by oleic acid and palmitic acid in WT and FXR knockout mouse primary hepatocytes (MPHs). We also detected mRNA expression of FXR signaling genes in MPHs. RESULTS: After HFD administration, body weight and serum lipid and inflammation levels were dramatically increased in the WT mice. The animals also presented with impaired glucose tolerance, insulin resistance, and antioxidant capacity, liver tissue attenuation, and pathological injury. EMO remarkably reversed the foregoing changes in HFD-induced mice. EMO improved HFD-induced lipid accumulation, insulin resistance, inflammation, and oxidative stress in a dose-dependent manner in WT mice by inhibiting FXR expression. EMO also significantly repressed TG hyperaccumulation by upregulating FXR expression in MPHs. However, it did not improve lipid accumulation, insulin sensitivity, or glucose tolerance in HFD-fed FXR knockout mice. CONCLUSIONS: The present study demonstrated that EMO alleviates HFD-induced NAFLD by activating FXR signaling which improves lipid accumulation, insulin resistance, inflammation, and oxidative stress.

From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates.

Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to "hit the mark".

The protective effect of hydrogen-rich water on rats with type 2 diabetes mellitus.

The hydrogen-rich water (HW) has been reported to possess a beneficial role in patients with diabetes. However, a systemic evaluation with an appropriate animal model is necessary to reveal its mechanisms and efficacy. Herein, the protective effects of drinking HW on lipid and glucose metabolism, oxidative stress, and inflammation in type 2 diabetes mellitus (T2DM) rats were investigated. The well-modeled T2DM rats (induced by high-fat diet combined with low-dose streptozotocin (STZ) injection) were divided into two groups (n ≥ 15 of each): fed a high-fat diet and drinking distilled water or HW at a constant concentration above 1.0 ppm; normal rats were used as control group (n ≥ 10): fed a regular diet and drinking distilled water. Several biomarkers of lipid and glucose metabolism, oxidative stress ,and inflammation were evaluated after drinking distilled water or HW for 3 weeks. The effect of HW on liver, kidney, and spleen of T2DM rats was also analyzed by HE and Oil Red O staining. The results showed that drinking HW suppressed the increase in glucose, total cholesterol, oxidative stress, and inflammation. Moreover, HW also ameliorates hyperglycemia-induced liver, kidney, and spleen dysfunction. Overall, this study indicates that patients with T2DM may be able to improve their condition by supplementing HW as daily drinking water.

Testosterone deficiency caused by castration increases adiposity in male rats in a tissue-specific and diet-dependent manner.

BACKGROUND: Testosterone deficiency in men is clinically associated with the development of metabolic syndrome, which manifests as obesity, hepatic steatosis, and type-2 diabetes. We investigated the effects of castration-induced testosterone deficiency on body adiposity and the expression of genes related to lipid metabolism and glucose uptake and androgen signaling in male rats fed a normal diet (ND) or a high-fat diet (HFD). METHODS: Changes in lipid and glucose metabolism and androgen signaling were investigated at physiological and molecular levels in the muscle, liver, and adipose tissues of non-castrated and castrated rats under ND or HFD feeding. RESULTS: Castration-induced testosterone deficiency predisposed animals on ND to early development of fatty liver by activating fatty acid (FA) synthesis, whereas HFD activated hepatic FA uptake CD36 expression, leading to the development of hepatic steatosis. In rats fed ND, castration induced muscle fat accumulation by activating CD36 expression. In the subcutaneous fat of ND-fed rats, castration increased adiposity and the expression of FA synthesis-related genes, but it decreased glucose transporter gene expression. In the abdominal fat of rats fed ND, castration increased adiposity by upregulating FA synthesis-related genes, and HFD promoted adiposity by inducing FA uptake, glucose transporter, and FA synthesis-related gene expression. In rats fed ND, castration decreased body growth and muscle weight and downregulated the expression of genes androgen signaling in the longissimus dorsi muscle. CONCLUSIONS: Testosterone deficiency increases adiposity in a tissue-specific and diet-dependent manner. Testosterone deficiency decreases body and muscle weights and downregulates androgen signaling.

Nutrients and Porphyria: An Intriguing Crosstalk.

Porphyria refers to a group of fascinating diseases from a metabolic and nutritional standpoint as it provides an example of how metabolic manipulation can be used for therapeutic purposes. It is characterized by defects in heme synthesis, particularly in the erythrocytes and liver. Specific enzymes involved in heme biosynthesis directly depend on adequate levels of vitamins and minerals in the tissues. Moreover, micronutrients that are required for producing succinyl CoA and other intermediates in the Krebs (TCA) cycle are indirectly necessary for heme metabolism. This review summarizes articles that describe the nutritional status, supplements intake, and dietary practices of patients affected by porphyria, paying special attention to the therapeutic use of nutrients that may help or hinder this group of diseases.

A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that down-regulates hepatic low-density lipoprotein receptor (LDLR) by binding and shuttling LDLR to lysosomes for degradation. The development of therapy that inhibits PCSK9 has attracted considerable attention for the management of cardiovascular disease risk. However, only monoclonal antibodies of PCSK9 have reached the clinic use. Oral administration of small-molecule transcriptional inhibitors has the potential to become a therapeutic option. METHODS: Here, we developed a cell-based small molecule screening platform to identify transcriptional inhibitors of PCSK9. Through high-throughput screening and a series of evaluation, we found several active compounds. After detailed investigation on the pharmacological effect and molecular mechanistic characterization, 7030B-C5 was identified as a potential small-molecule PCSK9 inhibitor. FINDINGS: Our data showed that 7030B-C5 down-regulated PCSK9 expression and increased the total cellular LDLR protein and its mediated LDL-C uptake by HepG2 cells. In both C57BL/6 J and ApoE KO mice, oral administration of 7030B-C5 reduced hepatic and plasma PCSK9 level and increased hepatic LDLR expression. Most importantly, 7030B-C5 inhibited lesions in en face aortas and aortic root in ApoE KO mice with a slight amelioration of lipid profiles. We further provide evidences suggesting that transcriptional regulation of PCSK9 by 7030B-C5 mostly depend on the transcriptional factor HNF1α and FoxO3. Furthermore, FoxO1 was found to play an important role in 7030B-C5 mediated integration of hepatic glucose and lipid metabolism. INTERPRETATION: 7030B-C5 with potential suppressive effect of PCSK9 expression may serve as a promising lead compound for drug development of cholesterol/glucose homeostasis and cardiovascular disease therapy. FUND: This work was supported by grants from the National Natural Science Foundation of China (81473214, 81402929, and 81621064), the Drug Innovation Major Project of China (2018ZX09711001-003-006, 2018ZX09711001-007 and 2018ZX09735001-002), CAMS Innovation Fund for Medical Sciences (2016-I2M-2-002, 2016-I2M-1-011 and 2017-I2M-1-008), Beijing Natural Science Foundation (7162129).

A multi-omics investigation of the molecular characteristics and classification of six metabolic syndrome relevant diseases.

Metabolic syndrome (MTS) is a cluster of concurrent metabolic abnormal conditions. MTS and its component metabolic diseases are heterogeneous and closely related, making their relationships complicated, thus hindering precision treatment. Methods: We collected seven groups of samples (group a: healthy individuals; group b: obesity; group c: MTS; group d: hyperglycemia, group e: hypertension, group f: hyperlipidemia; group g: type II diabetes, n=7 for each group). We examined the molecular characteristics of each sample by metabolomic, proteomic and peptidomic profiling analysis. The differential molecules (including metabolites, proteins and peptides) between each disease group and the healthy group were recognized by statistical analyses. Furthermore, a two-step clustering workflow which combines multi-omics and clinical information was used to redefine molecularly and clinically differential groups. Meanwhile, molecular, clinical, network and pathway based analyses were used to identify the group-specific biological features. Results: Both shared and disease-specific molecular profiles among the six types of diseases were identified. Meanwhile, the patients were stratified into three distinct groups which were different from original disease definitions but presented significant differences in glucose and lipid metabolism (Group 1: relatively favorable metabolic conditions; Group 2: severe dyslipidemia; Group 3: dysregulated insulin and glucose). Group specific biological signatures were also systematically described. The dyslipidemia group showed higher levels in multiple lipid metabolites like phosphatidylserine and phosphatidylcholine, and showed significant up-regulations in lipid and amino acid metabolism pathways. The glucose dysregulated group showed higher levels in many polypeptides from proteins contributing to immune response. The another group, with better glucose/lipid metabolism ability, showed higher levels in lipid regulating enzymes like the lecithin cholesterol acyltransferase and proteins involved in complement and coagulation cascades. Conclusions: This multi-omics based study provides a general view of the complex relationships and an alternative classification for various metabolic diseases where the cross-talk or compensatory mechanism between the immune and metabolism systems plays a critical role.

Metabolic changes with degarelix vs leuprolide plus bicalutamide in patients with prostate cancer: a randomized clinical study.

PURPOSE: In a mouse model, degarelix generated the least metabolic consequences via low follicle-stimulating hormone (FSH) levels compared with orchiectomy and leuprolide after 4 months of androgen deprivation therapy (ADT). Here, we comparatively investigated the influence of ADT with degarelix or leuprolide on the development of metabolic syndrome in patients with prostate cancer (PCa). METHODS: Patients with hormone-naive PCa were recruited. Eligible patients were randomized (1:1) to monthly degarelix or monthly leuprolide for 6 months. Key trial variables were monitored monthly. The primary endpoint was changes in fasting blood sugar (FBS). Secondary endpoints were changes in body weight, abdominal circumference, lipid profiles, and hemoglobin A1c (HbA1c) and FSH levels. Computed tomography was performed to measure subcutaneous and visceral fat areas before and after 6 months of ADT. Data were analyzed using the χ2 test, Student's t test, and analysis of variance. RESULTS: From the 100 patients registered, 85 completed the trial (degarelix: 40 patients; leuprolide: 45 patients). Mean increases in FBS did not differ between the two arms. Similarly, there were no differences between the arms in mean increases in body weight, abdominal circumference, lipid profiles, HbA1c, or subcutaneous and visceral fat areas. Follicle-stimulating hormone levels were significantly lower in the degarelix arm than in the leuprolide arm (p < 0.05). CONCLUSIONS: Lipid and glucose metabolism did not differ significantly between the arms, while FSH levels were significantly lower in the degarelix arm.

Diiodothyronines regulate metabolic homeostasis in primary human hepatocytes by modulating mTORC1 and mTORC2 activity.

Until three decades, ago 3,5-diiodothyronine (3,5-T2) and 3,3'-diiodothyronine (3,3'-T2) were considered products of thyroid hormone catabolism without biological activity. Some metabolic effects have been described in rodents, but the physiological relevance in humans and the mechanisms of action are unknown. Aim of this work was to investigate the role and the mechanisms of action of 3,5-T2 and 3,3'-T2 in the regulation of metabolic homeostasis in human liver. We used primary human hepatocytes freshly isolated from donors and grown on Matrigel as the golden standard in vitro model to study human hepatic metabolism. Results show that diiodothyronines in the range of plasma physiological concentrations reduced hepatic lipid accumulation, by modulating the activity of the mTORC1/Raptor complex through an AMPK-mediated mechanism, and stimulated the mTORC2/Rictor complex-activated pathway, leading to the down regulation of the expression of key gluconeogenic genes. Hence, we propose that diiodothyronines act as key regulators of hepatic metabolic homeostasis in humans.

miRNA-Gene Regulatory Network in Gnotobiotic Mice Stimulated by Dysbiotic Gut Microbiota Transplanted From a Genetically Obese Child.

Gut microbiota (GM) dysbiosis has been considered a pathogenic origin of many chronic diseases. In our previous trial, a shift in GM structure caused by a complex fiber-rich diet was associated with the health improvement of obese Prader-Willi syndrome (PWS) children. The pre- and post-intervention GMs (pre- and post-group, respectively) from one child were then transplanted into gnotobiotic mice, which resulted in significantly different physiological phenotypes, each of which was similar to the phenotype of the corresponding GM donor. This study was designed to investigate the miRNA-gene regulatory networks involved in causing these phenotypic differences. Using the post-group as a reference, we systematically identified and annotated the differentially expressed (DE) miRNAs and genes in the colon and liver of the pre-group in the second and fourth weeks after GM inoculation. Most of the significantly enriched GO terms and KEGG pathways were observed in the liver and were in the second week after GM transplantation. We screened 23 key genes along with their 73 miRNA regulators relevant to the host phenotype changes and constructed a network. The network contained 92 miRNA-gene regulation relationships, 51 of which were positive, and 41 of which were negative. Both the colon and liver had upregulated pro-inflammatory genes, and genes involved in fatty acid oxidation, lipolysis, and plasma cholesterol clearance were downregulated in only the liver. These changes were consistent with lipid and cholesterol accumulation in the host and with a high inflammation level. In addition, the colon showed an impacted glucagon-like peptide 1 (GLP-1) signaling pathway, while the liver displayed decreased insulin receptor signaling pathway activity. These molecular changes were mainly found in the second week, 2 weeks before changes in body fat occurred. This time lag indicated that GM dysbiosis might initially induce cholesterol and lipid metabolism-related miRNA and gene expression disorder and then lead to lipid accumulation and obesity development, which implicates a causative role of GM dysbiosis in obesity development rather than a result of obesity. This study provides fundamental molecular information that elucidates how dysbiotic GM increases host inflammation and disturbs host lipid and glucose metabolism.

Therapy of empagliflozin plus metformin on T2DM mice shows no higher amelioration for glucose and lipid metabolism than empagliflozin monotherapy.

AIMS: This study was designed to compare the effects of empagliflozin monotherapy and its combination with metformin on glucose and lipid modulations in T2DM mice. MAIN METHODS: Nine-week-old male C57BLKS/J db/db mice (n = 32) were used as T2DM model, and their age-matched C57BLKS/J db/m mice (n = 8) were used as normal control. A total of 32 db/db mice were randomly divided into four groups (n = 8/group): the DMT1 group, treated with metformin (250 mg/kg/day); the DMT2 group, treated with metformin (250 mg/kg/day) plus empagliflozin (10 mg/kg/day); the DMT3 group, treated with empagliflozin (10 mg/kg/day); the T2DM control group (DM), received 0.5% Natrosol. The db/m mice received same administration as DM group. KEY FINDINGS: After four-week treatments, compared with T2DM control (DM), the empagliflozin or its combination with metformin dramatically increased the levels of plasma HDL-C (139.6% and 154.9%, respectively), with significant decrease in plasma TC (22.9% and 13.7%, respectively) and plasma TG (26% and 19.7%, respectively) and in hepatic TG (30.3% and 28.6%, respectively). The protein expressions of SREBP1c (75.3% and 54.0%, respectively) and APOC-III (51.2% and 50.2%, respectively) were reduced, while CPT1A (304.0% and 221.4%, respectively) and ApoA1 levels (90.0% and 85.3%, respectively) were enhanced. Although both interventions improve above-mentioned lipid homeostasis, there were no statistic differences between two groups (p > 0.05). SIGNIFICANCE: Our study demonstrated that current dose of combination therapy may have no higher amelioration than empagliflozin monotherapy for glucose and lipid metabolism in male T2DM mice when it followed a treatment shorter than that expected during clinical treatment.

Astaxanthin as a Peroxisome Proliferator-Activated Receptor (PPAR) Modulator: Its Therapeutic Implications.

Peroxisome proliferator-activated receptors (PPARs) are part of the nuclear hormone receptors superfamily that plays a pivotal role in functions such as glucose and lipid homeostasis. Astaxanthin (ASX) is a lipid-soluble xanthophyll carotenoid synthesized by many microorganisms and various types of marine life that is known to possess antioxidant, anti-inflammatory, antidiabetic, anti-atherosclerotic, and anticancer activities. As such, it is a promising nutraceutical resource. ASX-mediated modulation of PPARs and its therapeutic implications in various pathophysiological conditions are described in this review. ASX primarily enhances the action of PPARα and suppresses that of PPARß/δ and PPARγ, but it has also been confirmed that ASX displays the opposite effects on PPARs, depending on the cell context. Anti-inflammatory effects of ASX are mediated by PPARγ activation, which induces the expression of pro-inflammatory cytokines in macrophages and gastric epithelial cells. The PPARγ-agonistic effect of ASX treatment results in the inhibition of cellular growth and apoptosis in tumor cells. Simultaneous and differential regulation of PPARα and PPARγ activity by ASX has demonstrated a hepatoprotective effect, maintaining hepatic lipid homeostasis and preventing related hepatic problems. Considering additional therapeutic benefits of ASX such as anti-gastric, cardioprotective, immuno-modulatory, neuroprotective, retinoprotective, and osteogenic effects, more studies on the association between ASX-mediated PPAR regulation and its therapeutic outcomes in various pathophysiological conditions are needed to further elucidate the role of ASX as a novel nutraceutical PPAR modulator.