Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of rare diabetes with low incidence of vascular complications caused by GCK gene inactivation. This study aimed to investigate the effects of GCK inactivation on hepatic lipid metabolism and inflammation, providing evidence for the cardioprotective mechanism in GCK-MODY. We enrolled GCK-MODY, type 1 and 2 diabetes patients to analyze their lipid profiles, and found that GCK-MODY individuals exhibited cardioprotective lipid profile with lower triacylglycerol and elevated HDL-c. To further explore the effects of GCK inactivation on hepatic lipid metabolism, GCK knockdown HepG2 and AML-12 cell models were established, and in vitro studies showed that GCK knockdown alleviated lipid accumulation and decreased the expression of inflammation-related genes under fatty acid treatment. Lipidomic analysis indicated that the partial inhibition of GCK altered the levels of several lipid species with decreased saturated fatty acids and glycerolipids including triacylglycerol and diacylglycerol, and increased phosphatidylcholine in HepG2 cells. The hepatic lipid metabolism altered by GCK inactivation was regulated by the enzymes involved in de novo lipogenesis, lipolysis, fatty acid β-oxidation and the Kennedy pathway. Finally, we concluded that partial inactivation of GCK exhibited beneficial effects in hepatic lipid metabolism and inflammation, which potentially underlies the protective lipid profile and low cardiovascular risks in GCK-MODY patients.

Neuroblastoma (NB) is an extracranial solid tumor in children with poor prognosis in high-risk patients and its pathogenesis and prognostic markers urgently need to be explored. This study aimed to explore potential biomarkers related to NB from the aspect of lipid metabolism. Fifty-eight lipid metabolism-related differentially expressed genes between high-risk NB and non-high-risk NB in the GSE49710 dataset were analyzed using bioinformatics, including 45 down-regulated genes and 13 up-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified steroid hormone biosynthesis as an abnormal metabolic pathway in high-risk NB. Survival analysis established a three-gene prognostic model, including ACHE, GDPD5 and PIK3R1. In the test data, the AUCs of the established prognostic models used to predict patient survival at 1, 3 and 5 years were 0.84, 0.90 and 0.91, respectively. Finally, in the SH-SY5Y cell line, it was verified that overexpression of GDPD5 can inhibit cell proliferation and migration, as well as affect the lipid metabolism of SH-SY5Y, but not the sugar metabolism. hsa-miR-592 was predicted to be a potential target miRNA of GDPD5 by bioinformatics. In conclusion, this study develops a lipid-metabolism-related gene-based prognostic model for NB and demonstrates that GDPD5 inhibits SH-SY5Y proliferation and migration and may be targeted by hsa-miR-592 and inhibit SH-SY5Y fat synthesis.

Detrimental exposures in mothers are recognized as risk factors for the development of metabolic dysfunction in offspring. In contrast, maternal exercise has been reported to be an effective strategy to maintain offspring health. However, the mechanisms underlying the protective effects of maternal exercise on adult offspring metabolic homeostasis are largely unclear. This study aims to investigate whether maternal exercise before and during pregnancy could combat the adverse effects of maternal high-fat diet (HFD) on metabolism in 24-week-old male offspring and to explore the role of miRNAs in mediating the effects. Female C57BL/6 mice were fed with either control diet or HFD 3-week prior to breeding and throughout pregnancy and lactation, among whom half of the HFD-fed mice were submitted to voluntary wheel running training 3-week before and during pregnancy. Male offspring were sedentary and fed with a control diet from weaning to 24 weeks. Body weight, the content of inguinal subcutaneous adipose tissue and perirenal visceral adipose tissue, glucose tolerance, and serum insulin and lipids in offspring were analyzed. Hepatic tissues were collected for transcriptome and miRNA sequencing and reverse transcription-quantitative polymerase chain reaction validation. The results showed that maternal HFD resulted in significant glucose intolerance, insulin resistance, and dyslipidemia in adult offspring, which were negated by maternal exercise. Transcriptome sequencing showed that maternal exercise reversed perinatal HFD-regulated genes in adult offspring, which were enriched in glucose and lipid metabolic-related signaling pathways. At the same time, maternal exercise significantly rescued the changes in the expression levels of 3 hepatic miRNAs in adult offspring, and their target genes were involved in the regulation of cholesterol biosynthesis and epigenetic modification, which may play an important role in mediating the intergenerational metabolic regulation of exercise. Overall, our research pioneered the role of miRNAs in mediating the programming effects of maternal exercise on adult offspring metabolism, which might provide novel insight into the prevention and treatment of metabolic disorders in early life.

Aim: Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated via PPARγ (peroxisome proliferator-activated receptor gamma) pathway both in vivo and in vitro. Materials and Methods: Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats. Twenty-eight days after treatment, hematoxylin-eosin (HE) staining was applied to visualize cardiomyocyte morphological changes. High performance liquid chromatography (HPLC) was performed to assess the contents of adenosine phosphates in heart. Positron emission tomography and computed tomography (PET-CT) was conducted to evaluate the cardiac glucose metabolism. Expressions of key molecules such as PPARγ, sterol carrier protein 2 (SCP2) and long chain acyl CoA dehydrogenase (ACADL) were measured by Western blotting (WB) and immunohistochemistry (IHC). Oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro. Results: Treatment with DQP rescued hearts from structural and functional damages as well as inflammatory infiltration. Levels of adenosine triphosphate (ATP) and energy charge (EC) in DQP group were also up-regulated compared to model group. Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compromised in model group compared to sham group. Intriguingly, DQP could up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously. Results on upstreaming signaling pathway demonstrated that DQP could dramatically increase the expressions of PPARγ. In vitro study suggested the efficacy of DQP could be blocked by T0070907, a selective PPARγ inhibitor. Conclusion: DQP has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism. The effects may be mediated by PPARγ pathway.

Lipid metabolism disorders are considerably involved in the pathology of atherosclerosis; nevertheless, the fundamental mechanism is still largely unclear. This research sought to examine the function of lipophagy in lipid metabolism disorder-induced atherosclerosis and its fundamental mechanisms. Previously, Sirt6 has been reported to stimulate plaque stability by promoting macrophage autophagy. However, its role in macrophage lipophagy and its relationship with Wnt1 remains to be established. In this study, ApoE-/-: Sirt6-/- and ApoE-/-: Sirt6Tg mice were used and lipid droplets were analysed via transmission electron microscopy and Bodipy 493/503 staining in vitro. Atherosclerotic plaques in ApoE-/-: Sirt6-/- mice showed greater necrotic cores and lower stability score. Reconstitution of Sirt6 in atherosclerotic mice improved lipid metabolism disorder and prevented the progression of atherosclerosis. Furthermore, macrophages with Ac-LDL intervention showed more lipid droplets and increased expression of adipophilin and PLIN2. Reconstitution of Sirt6 recruited using SNF2H suppressed Wnt1 expression and improved lipid metabolism disorder by promoting lipophagy. In addition, downregulation of Sirt6 expression in Ac-LDL-treated macrophages inhibited lipid droplet degradation and stimulated foam cell formation. Innovative discoveries in the research revealed that atherosclerosis is caused by lipid metabolism disorders due to downregulated Sirt6 expression. Thus, modulating Sirt6's function in lipid metabolism might be a useful therapeutic approach for treating atherosclerosis.

Maternal malnutrition leads to the incidence of metabolic diseases in offspring. The purpose of this project was to examine whether maternal low chromium could disturb normal lipid metabolism in offspring, altering adipose cell differentiation and leading to the incidence of lipid metabolism diseases, including metabolic syndrome and obesity. Female C57BL mice were given a control diet (CD) or a low chromium diet (LCD) during the gestational and lactation periods. After weaning, offspring was fed with CD or LCD. The female offspring were assessed at 32 weeks of age. Fresh adipose samples from CD-CD group and LCD-CD group were collected. Genome mRNA were analysed using Affymetrix GeneChip Mouse Gene 2.0 ST Whole Transcript-based array. Differentially expressed genes (DEGs) were analysed based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis database. Maternal low chromium irreversibly increased offspring body weight, fat-pad weight, serum triglyceride (TG) and TNF-α. Eighty five genes increased and 109 genes reduced in the offspring adipose of the maternal low chromium group. According to KEGG pathway and String analyses, the PPAR signalling pathway may be the key controlled pathway related to the effect of maternal low chromium on female offspring. Maternal chromium status have long-term effects of lipid metabolism in female mice offspring. Normalizing offspring diet can not reverse these effects. The potential underlying mechanisms are the disturbance of the PPAR signalling pathway in adipose tissue.

It is now broadly accepted that the nutritional environment in early life is a key factor in susceptibility to metabolic diseases. In this study, we evaluated the effects of maternal chromium restriction in vivo on the modulation of lipid metabolism and the mechanisms involved in this process. Sixteen pregnant C57BL mice were randomly divided into two dietary treatments: a control (C) diet group and a low chromium (L) diet group. The diet treatment was maintained through gestation and lactation period. After weaning, some of the pups continued with either the control diet or low chromium diet (CC or LL), whereas other pups switched to another diet (CL or LC). At 32 weeks of age, serum lipid metabolism, proinflammatory indexes, oxidative stress and anti-oxidant markers, and DNA methylation status in adipose tissue were measured. The results indicated that the maternal low chromium diet increased body weight, fat pad weight, serum triglyceride (TG), low-density lipoprotein cholesterol (LDL), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and oxidized glutathione (GSSG). There was a decrease in serum reduced/oxidized glutathione (GSH/GSSG) ratio at 32 weeks of age in female offspring. From adipose tissue, we identified 1214 individual hypomethylated CpG sites and 411 individual hypermethylated CpG sites in the LC group when compared to the CC group. Pathway analysis of the differential methylation genes revealed a significant increase in hypomethylated genes in the mitogen-activated protein kinase (MAPK) signaling pathway in the LC group. Our study highlights the importance of the MAPK signaling pathway in epigenetic changes involved in the lipid metabolism of the offspring from chromium-restricted dams.

Genistein has beneficial effects on metabolic disorders. However, the specific mechanism is not clearly understood. In light of the significant role of the hypothalamus in energy and metabolic homeostasis, this study was designed to explore whether dietary genistein intake could mitigate the harmful effects of a high-fat diet on glucose and lipid metabolism and whether any alterations caused by dietary genistein were associated with hypothalamic gene expression profiles. C57BL/6 female mice were fed a high-fat diet without genistein (HF), a high-fat diet with genistein (HFG), or a normal control diet (CON) for 8 weeks. Body weight and energy intake were assessed. At the end of the study, glucose tolerance and serum levels of insulin and lipids were analyzed. Hypothalamic tissue was collected for whole transcriptome sequencing and reverse transcription quantitative PCR (RT-qPCR) validation. Energy intake and body weight were significantly reduced in the mice of the HFG group compared with those of the HF group. Mice fed the HFG diet had improved glucose tolerance and decreased serum triacylglycerol, free fatty acids, and low-density lipoprotein cholesterol compared with those fed the HF diet. The HFG diet also modulated gene expression in the hypothalamus; the most abundant genes were enriched in the circadian entrainment pathway. Dietary genistein intake could reduce body weight, improve glucose and lipid metabolism, and regulate hypothalamic circadian entrainment. The ability of genistein intake to influence regulation of the hypothalamic circadian rhythm is important since this could provide a novel target for the treatment of obesity and diabetes.

Maternal over-nutrition can lead to metabolic disorders in offspring, whereas maternal dietary genistein may have beneficial effects on the metabolic health of offspring. Our objective was to determine whether maternal dietary genistein could attenuate the detrimental effects of a maternal high-fat diet on their offspring's metabolism and to explore the role of the gut microbiota on their offspring's glucose and lipid metabolism. C57BL/6 female mice were fed either a high-fat diet without genistein (HF), high-fat diet with low-dose genistein (0.25 g/kg diet) (HF.LG), high-fat diet with high-dose genistein (0.6 g/kg diet) (HF.HG) or normal control diet (Control) for 3 weeks prior to breeding and throughout gestation and lactation. The female offspring in the HF group had lower birth weights and glucose intolerance and higher serum insulin, triacylglycerol (TG) and total cholesterol (TC) levels at weaning compared with the Control group. Offspring from HF.LG dams had increased birth weight, improved glucose tolerance, and decreased fasting insulin, whereas the serum TG and TC levels were decreased in HF.HG offspring in comparison with HF offspring. The significant enrichment of Bacteroides and Akkermansia in offspring from genistein-fed dams might play vital roles in improving glucose homeostasis and insulin sensitivity, and the significantly increased abundance of Rikenella and Rikenellaceae_RC9_ gut_group in the HF.HG group may be associated with the decreased serum levels of TG and TC. In conclusion, maternal dietary genistein negates the harmful effects of a maternal high-fat diet on glucose and lipid metabolism in female offspring, in which the altered gut microbiota plays crucial roles. The ability of maternal genistein intake to improve offspring metabolism is important since this intervention could fight the transmission of diabetes to subsequent generations.

Adverse early-life exposures program increased risk of chronic metabolic diseases in adulthood. However, the effects of genistein supplementation in early life on metabolic health in later life are largely unclear. Our objective was to investigate whether maternal genistein intake could mitigate the deleterious influence of a maternal high-fat diet on glucose and lipid metabolism in offspring and to explore the role of gut microbiota in mediating the transgenerational effects. C57BL/6 female mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.6 g/kg diet) (HFG) or normal control diet (C) for 3 weeks before pregnancy and throughout pregnancy and lactation. The male offspring had ad libitum access to normal chow diet from weaning to 24 weeks of age. Then the content of inguinal subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were weighed. Glucose tolerance test (GTT), the level of serum insulin and lipid profiles were analyzed. The caecal contents were collected for 16S rDNA sequencing. The results showed that maternal genistein intake could significantly reduce blood glucose levels during GTT, fasting insulin levels, VAT mass and serum triglyceride levels as well as increase high-density lipoprotein cholesterol in adult male offspring. Significant decrease of germs from the Tenericutes phylum and enrichment of Rikenella as well as SCFA (short-chain fatty acid)-producing bacteria, including Alloprevotella, Odoribacter, and Clostridium XlVa, in offspring of genistein fed dams might play crucial roles in the improvement of glucose and lipid metabolism. Overall, early-life genistein intake attenuated the harmful effects of maternal HF on metabolism in adult offspring and the protective effects were associated with the alterations in gut microbiota, which provides new evidence and targets for mitigate the poor effects of adverse early-life exposures on metabolic health in later life.

Supplementation with Selenium (Se) has been shown to lower blood cholesterol and increase tissue concentrations of the antioxidant glutathione (GSH); however, the effects of Se supplementation, in combination with supplemental magnesium, on high fat-induced hyperlipidemia have not been studied. This study was designed to elucidate the effects of oral selenium and magnesium co-supplementation on antihyperlipidemic and hepatoprotective, antioxidative activities, and related gene expression in a hyperlipidemic rat model.

Great attention has been paid to 1,3-dichloro-2-propanol (1,3-DCP) due to its presence in food and concerns about toxic potential as carcinogens. In our previous study, we found that long-term low-dose 1,3-DCP exposure induced lipid accumulation in mouse liver. Recent studies have demonstrated that autophagy plays an important role in regulating lipid metabolism. So, we speculated that 1,3-DCP induced lipid accumulation by regulating autophagy in hepatocytes. In this study, we first studied the effect of 100 μM 1,3-DCP on autophagy flux in HepG2 cells. The data showed that 1,3-DCP (100 μM) impaired autophagy flux mainly through the attenuation of autophagosomes via AKT/mTOR signaling pathway and inhibition of lysosomes biosynthesis. Furthermore, we demonstrated that treatment with 100 μM 1,3-DCP for 24 h affected lipid metabolism through the colocalization of LC3 and Bodipy. We used an autophagy activator or an autophagy inhibitor to test the effect of 1,3-DCP on lipid accumulation through detecting lipid droplets staining, triglyceride (TG) and total cholesterol (TC). The data showed that 1,3-DCP-induced lipid accumulation was alleviated in the presence of Rapamycin (an autophagy activator). On the contrary, 1,3-DCP-induced lipid accumulation was significantly exacerbated in the presence of an autophagy inhibitor (3-methyladenine or chloroquine). These results suggested that 1,3-DCP might induce lipid accumulation by the impairment of autophagy flux in HepG2 cells.

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.

Berberine is known to improve glucose and lipid metabolism disorders, but it poorly absorbed into the blood stream from the gut. Therefore, the exact underlying mechanism for berberine is still unknown. In this study, we investigated the effect of berberine on glucose metabolism in diabetic rats and tested the hypothesis that berberine acts directly in the terminal ileums.

Danqi pill (DQP) is one of the most widely prescribed formulas and has been shown to have remarkable protective effect on coronary heart disease (CHD). However, its regulatory effects on lipid metabolism disorders haven't been comprehensively studied so far. We aimed to explore the effects of DQP on Peroxisome Proliferator activated receptors α (PPARα), lipid uptake-transportation-metabolism pathway and arachidonic acid (AA)-mediated inflammation pathway in rats with CHD.

Circadian misalignment induced by a high-fat diet (HFD) increases the risk of metabolic diseases. Methionine restriction (MR) is known to have the potential of alleviating obesity by improving insulin sensitivity. However, the role of the circadian clock in mediating the effects of MR on obesity-related metabolic disorders remains unclear. Ten-week-old male C57BL/6 J mice were fed with a low-fat diet (LFD) or a HFD for 4 wk., followed with a full diet (0.86% methionine, w/w) or a methionine-restricted diet (0.17% methionine, w/w) for 8 wk. Our results showed that MR attenuated insulin resistance triggered by HFD, especially at ZT12. Moreover, MR led to a time-specific enhancement of the expression of FGF21 and activated the AMPK/PGC-1α signaling. Notably, MR upregulated the cyclical levels of cholic acid (CA) and chenodeoxycholic acid (CDCA), and downregulated the cyclical level of deoxycholic acid (DCA) in the dark phase. MR restored the HFD-disrupted cyclical fluctuations of lipidolysis genes and BAs synthetic genes and improved the circulating lipid profile. Also, MR improved the expressions of clock-controlled genes (CCGs) in the liver and the brown adipose tissue throughout one day. In conclusion, MR exhibited the lipid-lowering effects on HFD-induced obesity and restored the diurnal metabolism of lipids and BAs, which could be partly explained by improving the expression of CCGs. These findings suggested that MR could be a potential nutritional intervention for attenuating obesity-induced metabolic misalignment.

Scope: Maternal obesity leads to glucose intolerance in the offspring. Changes in the gut microbiota are being increasingly implicated in the pathogenesis of diabetes. We hypothesized that inulin intervention during gestation and lactation improves glucose metabolism disorders in mouse offspring from high-fat diet (HD)-fed dams. Procedures: Female C57BL mice were fed a control diet or HD for 4 weeks before mating. After mating, pregnant mice were randomly divided into three groups through gestation and lactation: control diet (CD) group, HD group, and HD treated with inulin (HD-inulin) group. At weaning, glucose metabolic status was assessed. Gut microbial DNA from offspring cecal contents was isolated and processed for metagenomic shotgun sequencing, and taxonomic and functional profiling were performed. Results: Offspring from dams in the HD-inulin groups demonstrated reduced fasting blood glucose, decreased blood glucose area under the curve during the oral glucose tolerance test, and reduced fasting serum insulin and HOMA-IR compared to offspring from dams in the HD group. Nineteen differentially abundant bacterial species were identified between the HD-inulin and HD groups. The HD-inulin group displayed significantly greater abundances of Bacteroides_acidifaciens, Eubacterium_sp_CAG_786, Clostridium_sp_CAG_343, and Bifidobacterium_breve species and lower abundances of Oscillibacter_sp_1_3, Ruminococcus_gnavus_CAG_126, and Bacteroides_massiliensis species. Differentially abundant bacterial species among the three groups were involved in 38 metabolic pathways, including several glucose and lipid metabolism pathways. Conclusion: Our results show that early inulin intervention in HD-fed mouse dams moderates offspring glucose metabolism and gut dysbiosis.

Salusin‑α and adiponectin, are vasoactive peptides with numerous similar biological effects related to lipid metabolism. Adiponectin has been shown to reduce fatty acid oxidation and to inhibit lipid synthesis of liver cells through its receptor, adiponectin receptor 2 (AdipoR2), but whether salusin‑α is able to interact with AdipoR2, was not previously reported. To investigate this, in vitro experiments were carried out. The overexpression and interference recombinant plasmids were constructed with salusin‑α. The lentiviral expression systems of salusin‑α overexpression and interference were respectively synthesized in 293T cells, and 293T cells were infected with the lentivirus. Finally, the association between salusin‑α and AdipoR2 was analyzed by semi‑quantitative PCR. Subsequently, HepG2 cells were also infected with these viruses. The expression levels of AdipoR2, peroxisome proliferator‑activated receptor‑α (PPARα), apolipoprotein A5 (ApoA5) and sterol regulatory element‑binding transcription factor 1 (SREBP‑1c) were detected by western blotting, and AdipoR2 inhibitor (thapsigargin) and agonist [4‑phenyl butyric acid (PBA)] were used to observe the resultant changes in the aforementioned molecules. The results obtained revealed that the overexpression of salusin‑α increased the level of AdipoR2 in 293T and HepG2 cells, led to an upregulation of the levels of PPARα and ApoA5, and inhibited the expression of SREBP‑1c, whereas the salusin‑α interference lentivirus exerted the opposite effects. Notably, thapsigargin inhibited the expression of AdipoR2, PPARα and ApoA5 in HepG2 cells of pHAGE‑Salusin‑α group, and caused an increase in the level of SREBP‑1c, whereas the opposite effects were observed in pLKO.1‑shSalusin‑α#1 group upon treatment with PBA. Taken together, these data demonstrated that overexpression of salusin‑α upregulated AdipoR2, which in turn activated the PPARα/ApoA5/SREBP‑1c signaling pathway to inhibit lipid synthesis in HepG2 cells, thereby providing theoretical data on which to base the clinical application of salusin‑α as a novel peptide for molecular intervention in fatty liver disease.

Bioactive food components have gained growing attention in recent years. Multiple studies demonstrated that genistein had beneficial effects on metabolism. However, the exact mechanism by which genistein improves metabolism remains unclear, especially the central regulation. This study was designed to evaluate whether addition of genistein to the high-fat diet could counter metabolic disorders and whether these alterations were associated with gene expression in hypothalamus. C57BL/6 mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.25 g/kg diet) (HFG) or a normal control diet (CON) for 8 weeks. Body weight was assessed during the study. After 8-week intervention, content of inguinal subcutaneous adipose tissue (SAT), perirenal visceral adipose tissue (VAT) and brown adipose tissue (BAT) were weighed. Glucose tolerance test, the serum levels of insulin and lipid were assessed. The mRNA of browning marker was detected in the white fat. The hypothalamus was collected for whole transcriptome sequencing and reverse transcription quantitative PCR validation. The results demonstrated that mice fed HFG diet had lower body weight and SAT mass, decrease levels of low-density lipoprotein cholesterol and free fatty acids, higher browning marker of Ucp1 and Cidea in WAT and an improvement in glucose tolerance and insulin sensitivity compared with those in HF group. Transcriptome sequencing showed that there were three differentially expressed genes in hypothalamus among the three groups, including Ucn3, Depp, and Stc1, which were significantly correlated with the browning markers in WAT and insulin sensitivity. Thus, regulating gene expressions in hypothalamus is a potential mechanism for genistein improving metabolism and inducing WAT browning, which may provide a novel target for the precaution and treatment of T2DM.

Maternal dietary modifications determine the susceptibility to metabolic diseases in adult life. However, whether maternal high-fat feeding can modulate glucose and lipid metabolism in the early life of offspring is less understood. Furthermore, we explored the underlying mechanisms that influence the phenotype. Using C57BL/6J mice, we examined the effects on the offspring at weaning from dams fed with a high-fat diet or normal chow diet throughout pregnancy and lactation. Gene array experiments and quantitative real-time PCR were performed in the liver tissues of the offspring mice. The offspring of the dams fed the high-fat diet had a heavier body weight, impaired glucose tolerance, decreased insulin sensitivity, increased serum cholesterol and hepatic steatosis at weaning. Bioinformatic analyses indicated that all differentially expressed genes of the offspring between the two groups were mapped to nine pathways. Genes in the peroxisome proliferator-activated receptor (PPAR) signaling pathway were verified by quantitative real-time PCR and these genes were significantly up-regulated in the high-fat diet offspring. A maternal high-fat diet during pregnancy and lactation can modulate hepatic glucose, lipid homeostasis, and gene expression in the PPAR signaling in the early life of offspring, and our results suggested that potential mechanisms that influences this phenotype may be related partially to up-regulate some gene expression in the PPAR signalling pathway.