Sex Difference is a Determinant of Gut Microbes and Their Metabolites SCFAs/MCFAs in High Fat Diet Fed Rats.

There are gender differences in obesity and related metabolic diseases, but the mechanism of these differences has not been elucidated. Gut microbiota has been recently recognized as a pivotal determinant of obesity and related diseases. The aim of the present study was to investigate sex differences in gut microbiota and its metabolites in an obesity rat model induced by prolonged high-fat-diet (HFD) feeding. In this study, male and female Sprague-Dawley rats were fed normal chow or HFD for 16 weeks (n = 8 for each group). We found that comparing with male rats on HFD (MHFD), female rats on HFD (FHFD) gained more body weight percentage, while had lower body weight gain efficiency and less severity of hepatic steatosis. HFD induced decreased taxon diversity and richness of gut microbiota, and FHFD group had even lower diversity than MHFD group. Among key genera, HFD induced increased Bilophila in male rats but not in female rats. Compared with the MHFD group, FHFD group possessed increases of Akkermansia and Murimonas, and decreases of Acetanaerobacterium, Bacteroides, Bilophila, Blautia and Romboutsia. The levels of total SCFAs in colon contents were increased in tendency in HFD-fed rats of both sexes. FHFD group had increased propionate and decreased ratio of acetate to propionate and butyrate than MHFD group. For MCFAs, HFD induced increases in undecanoic acid and lauric acid in female rats but not in males. In conclusion, HFD induced sex-related alterations in gut microbiome and short/medium-chain fatty acids in rats.

Effects of constant light exposure on sphingolipidomics and progression of NASH in high-fat-fed rats.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a growing public health concern worldwide. With the progression of urbanization, light pollution is becoming an inevitable risk factor for NAFLD. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. The present study explored effects of constant light exposure on NAFLD and elucidated its related mechanisms. METHODS: Thirty-two male Sprague Dawley rats were divided into four groups (n = 8 each): (i) rats on a normal diet exposed to standard light-dark cycle (ND-LD); (ii) rats on a normal diet exposed to constant light (ND-LL); (iii) rats on a high-fat diet exposed to standard light-dark cycle (HFD-LD); and (iv) and rats on a high-fat diet exposed to constant light (HFD-LL). After 12 weeks of treatment, rats were sacrificed and pathophysiological assessments were performed. Targeted lipidomics was used to measure sphingolipids, including ceramides, glucosylceramides, and lactosylceramides, sphingomyelins, and sphingosine-1-phosphates in plasma and liver tissues. RESULTS: In normal chow rats, constant light exposure led to glucose abnormalities and dyslipidemia. In high-fat-fed rats, constant light exposure exacerbated glucose abnormalities, dyslipidemia, insulin resistance, and inflammation and aggravated steatohepatitis. Compared with HFD-LD rats, HFD-LL had decreased plasma sphingosine-1-phosphate and elevated liver concentrations of total ceramide and specific ceramide species (ceramide d18:0/24:0, ceramide d18:1/22:0, ceramide d18:1/24:0, and ceramide d18:1/24:1), which were associated with increased hepatocyte apoptosis. CONCLUSIONS: Constant light exposure causes dysregulation of sphingolipids and promotes steatohepatitis in high-fat-fed rats.

[Subclinical hypothyroidism and endocrine metabolic characteristics in women with polycystic ovary syndrome].

OBJECTIVE: To explore associations of subclinical hypothyroidism (SCH) with endocrine metabolic characteristics in women with polycystic ovary syndrome (PCOS).
 Methods: A total of 321 women who were newly diagnosed as PCOS were recruited from two endocrine outpatient clinics. The diagnosis of PCOS was established according to the 2003 Rotterdam consensus criteria. Thyroid function was examined by chemiluminescent immunoassay. Patients who had normal free thyroxine (FT4) were divided into different SCH subgroups according to two thyroid stimulating hormone (TSH) cutoff points (4.2 and 2.5 mU/L). Endocrine metabolic characteristics in different subgroups were compared and analyzed.
 Results: In PCOS women with normal FT4, the patients with TSH≥4.2 mU/L had higher prolactin (PRL), luteinizing hormone-to-follicle stimulating hormone ratio, and visceral adipose index (all P<0.05). There were trends toward an increase in triglyceride (P=0.085) and a decrease in high-density lipoprotein cholesterol (HDL-C) (P=0.060) in the patients with TSH≥4.2 mU/L compared with that in the patients with TSH<4.2 mU/L. Also in PCOS women with normal FT4, the patients with TSH≥2.5 mU/L had higher body mass index, PRL, triglyceride, visceral adipose index and lower HDL-C in comparison of that in the patients with TSH<2.5 mU/L (all P<0.05).
 Conclusion: SCH is associated with more severe endocrine abnormality, dyslipidemia, and visceral obesity in PCOS women. PCOS women with normal FT4 and endocrine metabolic characteristics are more prone to be different between the SCH group and the euthyroid group when setting 2.5 mU/L as a TSH cutoff for SCH, indicating that 2.5 mU/L is a good TSH cutoff for SCH in PCOS women.

[Association of NLRP3 gene single nucleotide polymorphisms with metabolic syndrome].

OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of NLRP3 gene with metabolic syndrome (MetS). METHODS: A total of 885 subjects including 410 MetS patients and 475 healthy controls were recruited. MetS was defined based on the National Cholesterol Education Program in Adult Treatment Panel III criteria. Two common SNPs of the NLRP3 gene, rs10754558 and rs4612666, were detected using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequencies of G allele and GG genotype of the NLRP3 rs10754558 in the MetS group were significantly higher than those of the control group. Logistic regression analysis showed that the GG genotype (OR=2.223, 95%CI: 1.296-6.924, P=0.00034) and G allele (OR=1.440, 95%CI: 1.189-4.063, P=0.00028) were associated with increased risk of MetS. NLRP3 rs10754558 GG genotype was associated with higher level of insulin resistance and visceral adiposity index. No association of NLRP3 rs4612666 SNPs with susceptibility to MetS was identified in this population. CONCLUSION: NLRP3 gene rs10754558 polymorphisms are associated with increased risk of MetS. The G allele and genotype GG are risk factors for MetS.

Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD.

Metformin prevents progression of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanism is not entirely understood. Ferroptosis, a recently recognized nonapoptotic form of regulated cell death, has been reported to be involved in the pathogenesis of NAFLD. Here, we investigated the effects of metformin on ferroptosis and its potential mechanism in NAFLD. We found that metformin prevented the progression of NAFLD, and alleviated hepatic iron overload (HIO), ferroptosis and upregulated ferroportin (FPN) expression in vivo and in vitro. Mechanically, metformin reduced the lysosomal degradation pathway of FPN through activation AMPK, thus upregulated the expression of FPN protein, alleviated HIO and ferroptosis, and prevented progression of NAFLD. These findings discover a mechanism of metformin, suggesting that targeting FPN may have the therapeutic potential for treating NAFLD and related disorders.

Chronic constant light exposure aggravates high fat diet-induced renal injury in rats.

Obesity-related kidney disease is now recognized as a global health issue, with a substantial number of patients developing progressive renal failure and end-stage renal disease. Interestingly, recent studies indicate light pollution is a novel environmental risk factor for chronic kidney disease. However, the impact of light pollution on obesity-related kidney disease remains largely unknown, with its underlying mechanism insufficiently explained. Renal hypoxia induced factor 1α (HIF1α) is critical in the development of glomerulosclerosis and renal fibrosis. The present study explored effects of constant light exposure on high fat diet (HFD) -induced renal injury and its association with HIF1α signal pathway. Thirty-two male Sprague Dawley rats were divided into four groups according to diet (HFD or normal chow diet) and light cycles (light/dark or constant light). After 16 weeks treatment, rats were sacrificed and pathophysiological assessments were performed. In normal chow fed rats, constant light exposure led to glucose abnormalities and dyslipidemia. In HFD fed rats, constant light exposure exacerbated obesity, glucose abnormalities, insulin resistance, dyslipidemia, renal functional decline, proteinuria, glomerulomegaly, renal inflammation and fibrosis. And, constant light exposure caused an increase in HIF1α and a decrease in prolyl hydroxylase domain 1 (PHD1) and PHD2 expression in kidneys of HFD-fed rats. Then, we demonstrated that BMAL1 bound directly to the promoters of PHD1 in mouse podocyte clone 5 cell line (MPC5) by ChIP assays. In conclusion, chronic constant light exposure aggravates HFD-induced renal injuries in rats, and it is associated with activation of HIF1α signal pathway.

Constant light exposure alters gut microbiota and short-/medium-chain fatty acids and aggravates PCOS-like traits in HFD-fed rats.

OBJECTIVE: This study investigated the effects of constant light exposure on polycystic ovary syndrome (PCOS)-like endocrine and metabolic changes in high-fat diet (HFD)-fed rats and to elucidate the related microbiotic mechanisms. METHODS: A total of 32 female Sprague-Dawley rats were divided into four groups (n = 8 each): rats on a normal chow diet with standard light-dark cycle, rats on a normal chow diet with constant light exposure, rats on an HFD with standard light-dark cycle, and rats on an HFD with constant light exposure. After 16 weeks of treatment, changes in anthropometric parameters, estrous cycle, hormone profiles, ovarian pathology, and gut microbiota and short-/medium-chain fatty acids in colon contents were assessed. RESULTS: Constant light exposure aggravated PCOS-like phenotypes in HFD-fed rats, such as hyperandrogenism, disrupted estrous cycle, and polycystic ovaries. Additionally, constant light exposure and an HFD synergized to decrease α-diversity of gut microbiota, create a reduced abundance of Ruminococcus genus, and create an increased abundance of Firmicutes and the Firmicutes/Bacteroidetes ratio. In HFD-fed rats, the group with constant light exposure had an increase in propionate acid and a decrease in total medium-chain fatty acids in colon contents compared with the standard light-dark cycle group. CONCLUSIONS: Constant light exposure causes gut dysbiosis, alters production of short- and medium-chain fatty acids, and aggravates PCOS-like traits in HFD-fed rats.

Constant Light Exposure Alters Gut Microbiota and Promotes the Progression of Steatohepatitis in High Fat Diet Rats.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) poses a significant health concern worldwide. With the progression of urbanization, light pollution may be a previously unrecognized risk factor for NAFLD/NASH development. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. Interestingly, recent studies indicate the gut microbiota affects NAFLD/NASH development. Therefore, the present study explored effects of constant light exposure on NAFLD and its related microbiotic mechanisms. MATERIALS AND METHODS: Twenty-eight SD male rats were divided into four groups (n = 7 each): rats fed a normal chow diet, and exposed to standard light-dark cycle (ND-LD); rats fed a normal chow diet, and exposed to constant light (ND-LL); rats fed a high fat diet, and exposed to standard light-dark cycle (HFD-LD); and rats on a high fat diet, and exposed to constant light (HFD-LL). Body weight, hepatic pathophysiology, gut microbiota, and short/medium chain fatty acids in colon contents, serum lipopolysaccharide (LPS), and liver LPS-binding protein (LBP) mRNA expression were documented post intervention and compared among groups. RESULT: In normal chow fed groups, rats exposed to constant light displayed glucose abnormalities and dyslipidemia. In HFD-fed rats, constant light exposure exacerbated glucose abnormalities, insulin resistance, inflammation, and liver steatohepatitis. Constant light exposure altered composition of gut microbiota in both normal chow and HFD fed rats. Compared with HFD-LD group, HFD-LL rats displayed less Butyricicoccus, Clostridium, and Turicibacter, butyrate levels in colon contents, decreased colon expression of occludin-1 and zonula occluden-1 (ZO-1), and increased serum LPS and liver LBP mRNA expression. CONCLUSION: Constant light exposure impacts gut microbiota and its metabolic products, impairs gut barrier function and gut-liver axis, promotes NAFLD/NASH progression in HFD rats.

Serum zonulin is elevated in women with polycystic ovary syndrome and correlates with insulin resistance and severity of anovulation.

OBJECTIVE: Evidence suggests that increased gut permeability may be associated with polycystic ovary syndrome (PCOS). Human zonulin is currently the only physiological mediator known to reversibly regulate gut permeability by disassembling intestinal tight junctions. So far, no data on serum zonulin levels in patients with PCOS are available. This study aimed to determine circulating serum zonulin levels in women with PCOS and discuss the relationship between zonulin, insulin resistance, and menstrual disorders in this group. DESIGN: A case-control study. METHODS: The study includes 78 women recently diagnosed with PCOS and 63 age-matched healthy controls recruited. Serum zonulin levels were determined by ELISA. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda and DeFronzo's insulin sensitivity index (ISI). RESULTS: PCOS women had higher serum zonulin levels (P=0.022). After adjustment for age and BMI, zonulin levels significantly correlated with HOMA-IR and ISI. Furthermore, PCOS women with more severe menstrual disorders had significantly higher zonulin levels and displayed an inverse correlation between zonulin and the number of menstrual cycles per year (r=-0.398, P<0.001). CONCLUSIONS: Serum zonulin, a biomarker for gut permeability, is increased in PCOS women and correlates with insulin resistance and severity of menstrual disorders. It suggests that alterations in gut permeability may play a role in the pathophysiology of PCOS, and serum zonulin might be used as a biomarker for both risk stratification and therapeutic outcomes in PCOS women.