Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression.

Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic leptin resistance and obesity.

Long-term exercise training down-regulates m6A RNA demethylase FTO expression in the hippocampus and hypothalamus: an effective intervention for epigenetic modification.

BACKGROUND: Exercise boosts the health of some brain parts, such as the hippocampus and hypothalamus. Several studies show that long-term exercise improves spatial learning and memory, enhances hypothalamic leptin sensitivity, and regulates energy balance. However, the effect of exercise on the hippocampus and hypothalamus is not fully understood. The study aimed to find epigenetic modifications or changes in gene expression of the hippocampus and hypothalamus due to exercise. METHODS: Male C57BL/6 mice were randomly divided into sedentary and exercise groups. All mice in the exercise group were subjected to treadmill exercise 5 days per week for 1 h each day. After the 12-week exercise intervention, the hippocampus and hypothalamus tissue were used for RNA-sequencing or molecular biology experiments. RESULTS: In both groups, numerous differentially expressed genes of the hippocampus (up-regulated: 53, down-regulated: 49) and hypothalamus (up-regulated: 24, down-regulated: 40) were observed. In the exercise group, increased level of N6-methyladenosine (m6A) was observed in the hippocampus and hypothalamus (p < 0.05). Furthermore, the fat mass and obesity-associated gene (FTO) of the hippocampus and hypothalamus were down-regulated in the exercise group (p < 0.001). In addition, the Fto co-expression genes of the mouse brain were studied and analyzed using database to determine the potential roles of exercise-downregulated FTO in the brain. CONCLUSION: The findings demonstrate that long-term exercise might elevates the levels of m6A-tagged transcripts in the hippocampus and hypothalamus via down-regulation of FTO. Hence, exercise might be an effective intervention for epigenetic modification.

Spinal arachnoiditis followed by intrathecal tigecycline therapy for central nervous system infection by extremely drug-resistant Acinetobacter baumannii.

In prior research, intrathecal tigecycline was successfully used to treat central nervous system infection by extensively drug-resistant Acinetobacter baumannii. However, little is known about its safe dose and adverse reactions. This study reports the case of a 28-year-old male patient who was diagnosed with central nervous system infection by extensively drug-resistant A. baumannii after the removal of a ventriculoperitoneal shunt. Intravenous and intrathecal tigecycline were administrated simultaneously. Spinal arachnoiditis was discovered after nine doses of intrathecal tigecycline. Spinal arachnoiditis was resolved after discontinuation of the antibiotic. This is the first report of an adverse reaction to intrathecal tigecycline. The case was complicated by spinal arachnoiditis, which obstructed the assessment of cerebrospinal fluid. The appropriate dose and administration schedule of intrathecal tigecycline remain to be determined.

[Effect of xiaokeling concentration fluid on mRNA expression of insulin-like growth factor-1 in sciatic nerve of Streptozotocin-induced diabetic rats].

OBJECTIVE: To investigate the effect of xiaokeling concentration fluid on insulin-like growth factor-1 (IGF-1) mRNA expression in sciatic nerve of Streptozotocin-induced diabetic rats. METHODS: Thirty diabetic rats were randomly divided into model group, mecobalamin tablets group, and xiaokeling concentration fluid group. The IGF-1 mRNA level in sciatic nerve of each group was determined after 8 weeks by relative quantity RT-PCR. RESULTS: The IGF-1 mRNA level in sciatic nerve of diabetic rats between xiaokeling concentration fluid group, mecobalamin tablets group and normal group showed no significant difference ( P = 0.213, P = 0.822, P = 0.304 ), while was significantly higher than that of the model group ( P < 0.05 ). IGF-1 mRNA level was negatively correlated with the level of blood sugar (P < 0.05). CONCLUSION: IGF-1 mRNA level decreased in sciatic nerve of diabetic rats. Xiaokeling concentration fluid can increase the IGF-1 mRNA level in sciatic nerve of diabetic rats. Xiaokeling concentration fluid is involved in the regulation of IGF-1 expression, and probably prevents diabetic peripheral neuropathy from deteriorating.