BACKGROUND: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions.
OBJECTIVE: We hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism.
METHODS: A randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation.
RESULTS: Eleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: -46.6, -24.1) from 4.9% [2.4-11.0] (median interquartile range) to 2.9% [1.4-6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged.
CONCLUSIONS: Reduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.

OBJECTIVE: Aging and excessive fat intake may additively induce dysbiosis of the gut microbiota and intestinal inflammatory damage. Here, we analyzed microbiota dysbiosis and intestinal injury in high-fat diet-loaded senescence-accelerated mice (SAMP8). Additionally, we examined whether treatment with molecular hydrogen could improve the intestinal environment.
METHODS: SAMP8 and SAMR1 (control) mice were first fed a normal diet (ND) or high-fat diet (HFD) for 10 wk (n = 10 each group). Subsequently, HFD was supplemented with a placebo jelly or hydrogen-rich jelly (HRJ) for 4 wk. After treatment, isolated small intestinal tissues were used for hematoxylin and eosin staining, immunofluorescence staining, and thiobarbituric acid reactive substances (TBARS) assay. Furthermore, we analyzed alterations in the microbiota composition in cecal feces using 16S rRNA gene analysis for microbiota profiling. Statistical analyses were performed using unpaired Student\'s t tests or one-way analysis of variance and Tukey\'s post hoc test for multiple comparisons.
RESULTS: HFD feeding reduced the expression of caudal-related homeobox transcription factor 2 (CDX2) and 5-bromo-2\'-deoxyuridine (BrdU) and enhanced malondialdehyde (MDA) levels in the small intestine of SAMP8. HRJ treatment improved the reduction in CDX2 and BrdU and enhanced MDA levels. We performed a sequence analysis of the gut microbiota at the genus level and identified 283 different bacterial genera from the 30 samples analyzed in the study. Among them, Parvibacter positively correlated with both HFD intake and aging, whereas 10 bacteria, including Anaerofustis, Anaerosporobacter, Butyricicoccus, and Ruminococcus were negatively correlated with both HFD and aging. HRJ treatment increased Lactinobactor and decreased Akkermansia, Gracilibacter, and Marvinbryantia abundance.
CONCLUSIONS: Our findings suggest that treatment with molecular hydrogen may affect microbiota profiling and suppress intestinal injury in HFD-loaded SAMP8.

BACKGROUND: Although there are numerous animal models of polycystic ovary syndrome (PCOS), they often fail to accurately replicate the reproductive and metabolic phenotypes associated with PCOS. The objective of this study is to assess oxidative status and inflammatory levels in a rat model of PCOS subjected to a new high-fat diet (HFD) in combination with letrozole.
METHODS: In this experimental study, mature, six-week-old female Sprague-Dawley rats (n=20) were divided into four groups: control (standard diet); letrozole (letrozole plus a standard diet); HFD; and letrozole+HFD. After 16 weeks, the rats underwent vaginal smear analysis, measurement of hormonal and lipid profiles, and an oral glucose tolerance test (OGTT). Ovarian tissue morphology, oxidative parameters, and inflammatory status were evaluated.
RESULTS: The experimental groups exhibited anoestrus profiles in the vaginal smears and abnormal ovarian morphology, which was not observed in the control group. Steroid hormone levels were significantly higher in the letrozole+HFD group compared to the other groups (P=0.00). The experimental groups also showed abnormal glucose levels and lipid metabolism. The relative expression levels of inflammatory genes were significantly elevated in the experimental groups compared to the control group (P=0.00), and the letrozole+HFD group exhibited the highest expression level (P=0.00). The HFD, letrozole, and letrozole+HFD groups demonstrated significantly increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS), while the levels of enzymatic antioxidants were significantly reduced compared to the control group (P=0.00).
CONCLUSIONS: The combination of a new HFD and letrozole treatment induces inflammation and oxidative stress (OS) in a rat model of PCOS. This model accurately exhibits abnormal metabolic phenotypes and disruptions in hormonal profiles associated with PCOS.

AD16 is a Class 1.1 new drug candidate for Alzheimer\'s disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults.
Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed.
Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred.
The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD.
ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.

Platelet activation and proprotein convertase subtilisin kexin 9 (PCSK9) play pivotal roles in the progression of atherosclerosis to cardiovascular events. It has been reported that hyperlipidemia, a well-documented risk factors for cardiovascular diseases, tends increase platelet activation and PCSK9 expression. However, little is known about this specific mechanism, particularly how nutrition affects platelet activation and PCSK9 levels in hyperlipidemia conditions. This study aimed to assess how a high-fat diet influences platelet activation, its association with PCSK9, and the effects on blood pressure in an animal model. Here, male Wistar rats were divided into four groups, subjected to different high-fat diets for ten weeks with varying nutrient components. The results showed that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia significantly increased the plasma levels of β-thromboglobulin (β-TG), p-selectin, and platelet factor 4 (PF-4). The blood pressure readings were also elevated post high-fat diet induction. Interestingly, the group with the highest percentage of saturated fatty acid and trans-fat exhibited the highest PCSK9 levels, along with the highest increase in plasma cholesterol, triglycerides, and platelet activation parameters. These findings confirm that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia stimulate platelet activity and PCSK9 levels. Moreover, our results suggest that PCSK9, implicated in hypercholesterolemia and hypertriglyceridemia, may synergistically mediate platelet hyperactivity, aligning with clinical studies. Notably, our results highlight the association between a high-fat diet and PCSK9, providing insights for drug discovery targeting platelet activation in atherosclerosis-induced cardiovascular diseases.

Hesperidin (HSP) has multiple beneficial effects in verities of clinical situations including type 2 diabetes mellitus (T2DM).
OBJECTIVE: Determination of curative effects of HSP on the liver in T2DM rats through biochemical and histopathological studies.
METHODS: Animals. Fifty rats were enrolled. 10 rats were fed a normal diet (control group), and the remaining 40 rats received a high-fat diet (HFD) for 8 weeks. The HFD-fed rats were grouped into Group II: 10 rats, and Group III: 10 rats received HSP 100 mg/kg. Group IV: 10 rats received a single dose of streptozotocin (STZ), 30 mg/kg, and Group V: 10 rats received STZ and HSP. Body weight, Blood glucose, insulin level, liver enzymes, lipid profile, oxidative stress, TNF-α, NF-κB, and liver biopsy were estimated.
RESULTS: there is improvement in the histological profile of the steatosis in HFD-fed rats treated with HSP either in group III or in group V (received STZ) along with amelioration in blood glucose, insulin, liver enzymes, lipid profile, oxidative profile, TNF-α, and NF-κB.
CONCLUSIONS: HSP in this STZ model revealed an improvement in steatosis, biochemical markers, and histologic findings. By studying these factors, we expected to identify the prospective targets for intervention that could help improve outcomes for individuals with obesity and diabetes-related liver diseases.

Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated.
Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m3. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice.
These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

Obesity is a serious health issue. As regard, the central nervous system, obesity induces neuronal damage. Vitamin D has well-known anti-inflammatory and neuroprotective effects. To detect if vitamin D protects against damage in the arcuate nucleus induced by a high fat-high fructose diet. Forty adult rats were used, and four groups were formed. Group I (negative control) kept on a standard chow diet for six weeks, Group II (positive control) received vitamin D orally once every other day for six weeks, Group III (high fat-high fructose treated group) was given high fat-high fructose diets for six weeks and Group IV (high fat-high fructose and vitamin D treated group) were given high fat-high fructose diets concomitantly with vitamin D for six weeks. High fat-high fructose diet markedly caused histological changes in arcuate neurons as nuclei appeared darkly stained and shrunken with condensed chromatin, and the nucleolus became less prominent. The cytoplasm appeared rarefied with loss of most of the organelles. An increase in neuroglial cells was noticed. The synaptic area showed sparse degenerated mitochondria and a disrupted presynaptic membrane. A high-fat diet has a damaging effect on arcuate neurons and vitamin D alleviates these effects.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, and there is still no effective treatment for its advanced stage, nonalcoholic steatohepatitis (NASH). An ideal animal model of NAFLD/NASH is urgently needed for preclinical studies. However, the models reported previously are quite heterogeneous owing to differences in animal strains, feed formulations, and evaluation indicators, among others. In this study, we report 5 NAFLD mouse models we developed in previous studies and comprehensively compared their characteristics. The high-fat diet (HFD) model was time-consuming and characterized by early insulin resistance and slight liver steatosis at 12 weeks. However, inflammation and fibrosis were rare, even at 22 weeks. The high-fat, high-fructose, and high-cholesterol diet (FFC) exacerbates glucose and lipid metabolism disorders, showing distinct hypercholesterolemia, steatosis, and mild inflammation at 12 weeks. An FFC diet combined with streptozotocin (STZ) was a novel model that speeds up the process of lobular inflammation and fibrosis. The STAM model also used a combination of FFC and STZ but used newborn mice and showed the fastest formation of fibrosis nodules. The HFD model was appropriate for the study of early NAFLD. FFC combined with STZ accelerated the pathologic process of NASH and might be the most promising model for NASH research and drug development.

Drug metabolism genes are involved in the in vivo metabolic processing of drugs. In previous research, we found that a high-fat diet affected the transcript levels of mouse hepatic genes responsible for drug metabolism.
Our research intends to discover the drug metabolism genes that are dysregulated at the transcriptome level in nonalcoholic fatty liver disease (NAFLD).
We analyzed the transcriptome for drug metabolism genes of 35 human liver tissues obtained during laparoscopic cholecystectomy. Additionally, we imported transcriptome data from mice fed a high-fat diet in previous research and two open-access Gene Expression Omnibus (GEO) datasets (GSE63067 and GSE89632). Then, using quantitative real-time polymerase chain reaction (qRT-PCR), we cross-linked the differentially expressed genes (DEGs) in clinical and animal samples and validated the common genes.
In this study, we identified 35 DEGs, of which 33 were up-regulated and two were down-regulated. Moreover, we found 71 DEGs (39 up- and 32 down-regulated), 276 DEGs (157 up- and 119 down-regulated), and 158 DEGs (117 up- and 41 down-regulated) in the GSE63067, GSE89632, and high-fat diet mice, respectively. Of the 35 DEGs, nine co-regulated DEGs were found in the Venn diagram (CYP20A1, CYP2U1, SLC9A6, SLC26A6, SLC31A1, SLC46A1, SLC46A3, SULT1B1, and UGT2A3).
Nine significant drug metabolism genes were identified in NAFLD. Future research should investigate the impacts of these genes on drug dose adjustment in patients with NAFLD.
http://www.chictr.org.cn, identifier ChiCTR2100041714.