Cauda equina syndrome by extrusion of lumbar disc after lumbar sympathetic neurolysis.

A 56-year-old woman experienced persistent excruciating pain with peroneal nerve injury in the anterior aspect of the lower leg after knee surgery. In our pain clinic, we diagnosed the patient with complex regional pain syndrome and performed lumbar sympathetic neurolysis (LSN) with absolute alcohol at the 3rd lumbar vertebra (L3). After the next follow-up, she complained of continuous dull low back pain, anal dysregulation, and fecal incontinence. We performed magnetic resonance imaging (MRI) to rule out other existing pathologies of back pain. On MRI, the nucleus pulposus was moderately extruded to the central zone with inferior sequestration at L2/3, and moderate central canal stenosis was observed at L2/3. She underwent partial laminectomy with discectomy at L2 level. We were not sure of the cause of disc herniation, but we strongly suspected that LSN at the L3 vertebral level was related to the pathology. Therefore, we discuss this unusual case.

Anti-Oxidant and Anti-Inflammatory Effects of Astaxanthin on Gastrointestinal Diseases.

A moderate amount of reactive oxygen species (ROS) is produced under normal conditions, where they play an important role in cell signaling and are involved in many aspects of the immune response to pathogens. On the other hand, the excessive production of ROS destructs macromolecules, cell membranes, and DNA, and activates pro-inflammatory signaling pathways, which may lead to various pathologic conditions. Gastrointestinal (GI) mucosa is constantly exposed to ROS due to the presence of bacteria and other infectious pathogens in food, as well as alcohol consumption, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAID). Prolonged excessive oxidative stress and inflammation are two major risk factors for GI disorders such as ulcers and cancers. Bioactive food compounds with potent anti-oxidant and anti-inflammatory activity have been tested in experimental GI disease models to evaluate their therapeutic potential. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid that is naturally present in algae, yeast, salmon, shrimp, and krill. It has been shown that AST exhibits protective effects against GI diseases via multiple mechanisms. Residing at the surface and inside of cell membranes, AST directly neutralizes ROS and lipid peroxyl radicals, enhances the activity of anti-oxidant enzymes, and suppresses pro-inflammatory transcription factors and cytokines. In addition, AST has been shown to inhibit cancer cell growth and metastasis via modulating cell proliferation-related pathways, apoptosis, and autophagy. Considering the potential benefits of AST in GI diseases, this review paper aims to summarize recent advances in AST research, focusing on its anti-oxidant and anti-inflammatory effects against gastric and intestinal ulcers and cancers.

Adapted Physical Education Teachers' Job Satisfaction.

Grounded in occupational socialization theory, the authors examined adapted physical education (APE) teachers' job satisfaction. Twelve (nine female and three male) APE teachers who had 3-43 years of teaching experience participated in the study. A semistructured interview was employed. The interviews focused on the participants' roles and responsibilities. The following questions guided this study: (a) What social agents positively impact APE teachers' job satisfaction? (b) what APE teachers' roles and responsibilities are related to job satisfaction? and (c) what type of working conditions are linked to APE teachers' job satisfaction? Thematic analysis was employed to analyze the data. The following four themes emerged from the analysis: (a) support from administrators, physical education teachers, and colleagues; (b) relevant and meaningful professional development; (c) itinerant working conditions; and (d) seeing students' progress and achievement. The results of this study provide several implications to enhance APE teachers' job satisfaction.

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress.

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14-/- (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.

Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity.

Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases.

Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin Receptor Trafficking and Glucose Metabolism.

Zinc influences signaling pathways through controlled targeted zinc transport. Zinc transporter Zip14 KO mice display a phenotype that includes impaired intestinal barrier function with low grade chronic inflammation, hyperinsulinemia, and increased body fat, which are signatures of diet-induced diabetes (type 2 diabetes) and obesity in humans. Hyperglycemia in type 2 diabetes and obesity is caused by insulin resistance. Insulin resistance results in inhibition of glucose uptake by liver and other peripheral tissues, principally adipose and muscle and with concurrently higher hepatic glucose production. Therefore, modulation of hepatic glucose metabolism is an important target for antidiabetic treatment approaches. We demonstrate that during glucose uptake, cell surface abundance of zinc transporter ZIP14 and mediated zinc transport increases. Zinc is distributed to multiple sites in hepatocytes through sequential translocation of ZIP14 from plasma membrane to early and late endosomes. Endosomes from Zip14 KO mice were zinc-deficient because activities of the zinc-dependent insulin-degrading proteases insulin-degrading enzyme and cathepsin D were impaired; hence insulin receptor activity increased. Transient increases in cytosolic zinc levels are concurrent with glucose uptake and suppression of glycogen synthesis. In contrast, Zip14 KO mice exhibited greater hepatic glycogen synthesis and impaired gluconeogenesis and glycolysis related to low cytosolic zinc levels. We can conclude that ZIP14-mediated zinc transport contributes to regulation of endosomal insulin receptor activity and glucose homeostasis in hepatocytes. Therefore, modulation of ZIP14 transport activity presents a new target for management of diabetes and other glucose-related disorders.

The Roles of Glutamine in the Intestine and Its Implication in Intestinal Diseases.

Glutamine, the most abundant free amino acid in the human body, is a major substrate utilized by intestinal cells. The roles of glutamine in intestinal physiology and management of multiple intestinal diseases have been reported. In gut physiology, glutamine promotes enterocyte proliferation, regulates tight junction proteins, suppresses pro-inflammatory signaling pathways, and protects cells against apoptosis and cellular stresses during normal and pathologic conditions. As glutamine stores are depleted during severe metabolic stress including trauma, sepsis, and inflammatory bowel diseases, glutamine supplementation has been examined in patients to improve their clinical outcomes. In this review, we discuss the physiological roles of glutamine for intestinal health and its underlying mechanisms. In addition, we discuss the current evidence for the efficacy of glutamine supplementation in intestinal diseases.

Dietary Zinc Regulates Apoptosis through the Phosphorylated Eukaryotic Initiation Factor 2α/Activating Transcription Factor-4/C/EBP-Homologous Protein Pathway during Pharmacologically Induced Endoplasmic Reticulum Stress in Livers of Mice.

BACKGROUND: Several in vitro studies have shown that zinc deficiency could induce endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response. OBJECTIVE: We aimed to determine whether consumption of a zinc-deficient diet (ZnD) triggers ER stress and to understand the impact of dietary zinc intake on ER stress-induced apoptosis using a mouse model. METHODS: Young adult (8-16 wk of age) male mice of strain C57BL/6 were fed either a ZnD (<1 mg/kg diet), or a zinc-adequate diet (ZnA; 30 mg/kg diet). After 2 wk, liver, pancreas, and serum samples were collected and analyzed for indexes of ER stress. In another experiment, mice were fed either a ZnD, a ZnA, or a zinc-supplementation diet (ZnS; 180 mg/kg diet). After 2 wk, vehicle or tunicamycin (TM; 2 mg/kg body weight) was administered to mice to model ER stress. Liver and serum were analyzed for indexes of ER stress to evaluate the effects of zinc status. RESULTS: Mice fed a ZnD did not activate the apoptotic and ER stress markers in the liver or pancreas. During the TM challenge, mice fed a ZnD showed greater C/EBP-homologous protein expression in the liver (3.8-fold, P < 0.01) than did ZnA-fed mice. TM-treated mice fed a ZnD also had greater terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells in the liver (2.2-fold, P < 0.05), greater hepatic triglyceride accumulation (1.5-fold, P < 0.05), greater serum alanine aminotransferase activity (1.6-fold, P < 0.05), and greater protein-tyrosine phosphatase 1B activity (1.5-fold, P < 0.05), respectively, than did those fed a ZnA. No significant differences were observed in these parameters between mice fed ZnAs and ZnSs. CONCLUSIONS: Consumption of a ZnD per se is not a critical factor for induction of ER stress in mice; however, once ER stress is triggered, adequate dietary zinc intake is required for suppressing apoptotic cell death and further insults in the liver of mice.

Glutamine deprivation induces interleukin-8 expression in ataxia telangiectasia fibroblasts.

OBJECTIVE: To investigate whether glutamine deprivation induces expression of inflammatory cytokine interleukin-8 (IL-8) by determining NF-κB activity and levels of oxidative indices (ROS, reactive oxygen species; hydrogen peroxide; GSH, glutathione) in fibroblasts isolated from patients with ataxia telangiectasia (A-T). MATERIALS: We used A-T fibroblasts stably transfected with empty vector (Mock) or with human full-length ataxia telangiectasia mutated (ATM) cDNA (YZ5) and mouse embryonic fibroblasts (MEFs) transiently transfected with ATM small interfering RNA (siRNA) or with non-specific control siRNA. TREATMENT: The cells were cultured with or without glutamine or GSH. METHODS: ROS levels were determined using a fluorescence reader and confocal microscopy. IL-8 or murine IL-8 homolog, keratinocyte chemoattractant (KC), and hydrogen peroxide levels in the medium were determined by enzyme-linked immunosorbent assay and colorimetric assay. GSH level was assessed by enzymatic assay, while IL-8 (KC) mRNA level was measured by reverse transcription-polymerase chain reaction (RT-PCR) and/or quantitative real-time PCR. NF-κB DNA-binding activity was determined by electrophoretic mobility shift assay. Catalase activity and ATM protein levels were determined by O2 generation and Western blotting. RESULTS: While glutamine deprivation induced IL-8 expression and increased NF-κB DNA-binding activity in Mock cells, both processes were decreased by treatment of cells with glutamine or GSH or both glutamine and GSH. Glutamine deprivation had no effect on IL-8 expression or NF-κB DNA-binding activity in YZ5 cells. Glutamine-deprived Mock cells had higher oxidative stress indices (increases in ROS and hydrogen peroxide, reduction in GSH) than glutamine-deprived YZ5 cells. In Mock cells, glutamine deprivation-induced oxidative stress indices were suppressed by treatment with glutamine or GSH or both glutamine and GSH. GSH levels and catalase activity were lower in Mock cells than YZ5 cells. MEFs transfected with ATM siRNA and cultured without glutamine showed higher levels of ROS and IL-8 than those transfected with negative control siRNA; increased levels of ROS and IL-8 were suppressed by the treatment of glutamine. CONCLUSION: Glutamine deprivation induces ROS production, NF-κB activation, and IL-8 expression as well as a reduction in GSH in A-T fibroblasts, all of which are attenuated by glutamine supplementation.

Rapid discrimination of Panax ginseng powder adulterated with various root plants by FT-IR spectroscopy coupled with multivariate analysis.

Panax ginseng powder adulterated with other root plants (arrowroot, bellflower, and lance asiabell) was discriminated using Fourier transform infrared (FT-IR) spectroscopy, combined with multivariate analysis. Principal component analysis visually diagnosed the adulteration by showing two distinct clusters based on presence of adulteration. Wavenumber regions (1000 cm-1 and 3300 cm-1) selected from the loading plot associated with the vibration of OH and CH bond in ginsenoside and aromatic compounds. A quantitative model for the content of ginsenosides and specific aromatic compounds as indicators of pure ginseng powder, was developed based on partial least square regression analysis. The performance of the prediction model preprocessed with the Savizky-Golay 1st derivative was improved to R2 of 0.9650, 0.9635, and 0.9591 for Rb1, Rc, and ß-Panasinsene, respectively. Therefore, FT-IR technology makes it possible to rapidly authenticate pure ginseng product based on the ginsenoside contents and aroma compound.

SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.

SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic-onset or adult-onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN-projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN-projecting PVHSH2B1 neurons protects against diet-induced obesity. SH2B1 binds to TrkB and enhances brain-derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.

Dual-Photosensitizer Synergy Empowers Ambient Light Photoactivation of Indium Oxide for High-Performance NO2 Sensing.

Light-activated chemiresistors offer a powerful approach to achieving lower-temperature gas sensing with unprecedented sensitivities. However, an incomplete understanding of how photoexcited charge carriers enhance sensitivity obstructs the rational design of high-performance sensors, impeding the practical utilization under commonly accessible light sources instead of ultraviolet or higher-energy sources. Here, a rational approach is presented to modulate the electronic properties of the parent metal oxide phase, exemplified by this model system of Bi-doped In2O3 nanofibers decorated with Au nanoparticles (NPs) that exhibit superior NO2 sensing performance. Bi doping introduces mid-gap energy levels into In2O3, promoting photoactivation even under visible blue light. Additionally, green-absorbing plasmonic Au NPs facilitate electron transfer across the heterojunction, extending the photoactive region toward the green light. It is revealed that the direct involvement of photogenerated charge carriers in gas adsorption and desorption processes is pivotal for enhancing gas sensing performance. Owing to the synergistic interplay between the Bi dopants and the Au NPs, the Au-BixIn2-xO3 (x = 0.04) sensing layers attain impressive response values (Rg/Ra = 104 at 0.6 ppm NO2) under green light illumination and demonstrate practical viability through evaluation under simulated mixed-light conditions, all of which significantly outperforms previously reported visible light-activated NO2 sensors.

Cobalt-Doped Ceria Sensitizer Effects on Metal Oxide Nanofibers: Heightened Surface Reactivity for High-Performing Chemiresistive Sensors.

Chemiresistive gas sensors based on semiconducting metal oxides typically rely on noble metal catalysts to enhance their sensitivity and selectivity. However, noble metal catalysts have several drawbacks for practical utilization, including their high cost, their propensity for spontaneous agglomeration, and poisoning effects with certain types of gases. As such, in the interest of commercializing the chemiresistive gas sensor technology, we propose an alternative design for a noble-metal-free sensing material through the case study of Co-doped ceria (Co-CeO2) catalysts embedded in a SnO2 matrix. In this investigation, we utilized electrospinning and subsequent calcination to prepare Co-CeO2 catalyst nanoparticles integrated with SnO2 nanofibers (NFs) with uniform particle distribution and particle size regulation down to the sub-2 nm regime. The resulting Co-CeO2@SnO2 NFs exhibited superior gas sensing characteristics toward isoprene (C5H8) gas, a significant biomarker for monitoring the onset of various diseases through breath diagnostics. In particular, we identified that the Co-CeO2 catalysts, owing to the transition metal doping, facilitated the spillover of chemisorbed oxygen species to the SnO2 sensing body. This resulting in the sensor having a 27.4-fold higher response toward 5 ppm of C5H8 (compared to pristine SnO2), exceptionally high selectivity, and a low detection limit of 100 ppb. The sensor also exhibited high stability for prolonged response-recovery cycles, attesting to the strong anchoring of Co-CeO2 catalysts in the SnO2 matrix. Based on our findings, the transition metal-doped metal oxide catalysts, such as Co-CeO2, demonstrate strong potential to completely replace noble metal catalysts, thereby advancing the development of the commercially viable chemiresistive gas sensors free from noble metals, capable of detecting target gases at sub-ppm levels.

LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

Reverse Takotsubo cardiomyopathy with left bundle branch block after anesthesia induction in a patient with subarachnoid hemorrhage: a case report.

Cardiac dysfunction after subarachnoid hemorrhage (SAH) is described as Takotsubo or reverse Takotsubo cardiomyopathy that shows transient left ventricular wall motion abnormalities with electrocardiogram (ECG) changes. ST change followed by T inversion is a common ECG finding complicated with these disorders, left bundle branch block (LBBB) may be a potential ECG pattern which is seen. In this case, we describe the clinical profile and outcomes of a patient with LBBB and reverse Takotsubo cardiomyopathy after anesthetic induction, which was scheduled as an emergent external ventricular drainage after SAH. This is the first report of an LBBB pattern in reverse Takotsubo cardiomyopathy.

The Effects of Remifentanil and Fentanyl on Emergence Agitation in Pediatric Strabismus Surgery.

Emergence agitation (EA) is one of the main concerns in the field of pediatric anesthesia using sevoflurane. We investigated the effects of remifentanil and fentanyl on the incidence of EA in pediatric patients undergoing strabismus surgery. Ninety children were randomly allocated into two groups and received either remifentanil (group R: intraoperatively remifentanil 0.2 µg/kg/min) or fentanyl (group F: fentanyl 2 µg/kg at anesthetic induction) intraoperatively. After surgery, EA incidence was assessed using a four-point agitation scale and Pediatric Anesthesia Emergence Delirium (PAED) scale in the post-anesthesia care unit. Face, leg, activity, cry, and consolability (FLACC) scores for postoperative pain were also assessed. The incidence of EA using the four-point agitation scale (scores ≥ 3) was similar in both groups (remifentanil group, 28.89% vs. fentanyl group, 24.44%). Similar results were obtained using the PAED scale (scores > 12), with an incidence of 33.33% in the remifentanil group and 26.67% in the fentanyl group. Differences in FLACC scores were not found to be statistically significant. A single bolus administration of fentanyl during anesthetic induction and continuous infusion of remifentanil during surgery had similar effects on the EA incidence in these pediatric patients.

Role of Leptin in the Digestive System.

Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.

Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7.

Skeletal muscle represents the largest pool of body zinc, however, little is known about muscle zinc homeostasis or muscle-specific zinc functions. Zip14 (Slc39a14) was the most highly expressed zinc transporter in skeletal muscle of mice in response to LPS-induced inflammation. We compared metabolic parameters of skeletal muscle from global Zip14 knockout (KO) and wild-type mice (WT). At basal steady state Zip14 KO mice exhibited a phenotype that included muscle wasting and metabolic endotoxemia. Microarray and qPCR analysis of gastrocnemius muscle RNA revealed that ablation of Zip14 produced increased muscle p-Mef2c, Hspb7 and miR-675-5p expression and increased p38 activation. ChIP assays showed enhanced binding of NF-[Formula: see text] to the Mef2c promoter. In contrast, LPS-induced systemic inflammation enhanced Zip14-dependent zinc uptake by muscle, increased expression of Atrogin1 and MuRF1 and markedly reduced MyoD. These signatures of muscle atrophy and cachexia were not influenced by Zip14 ablation, however. LPS-induced miR-675-3p and -5p expression was Zip14-dependent. Collectively, these results with an integrative model are consistent with a Zip14 function in skeletal muscle at steady state that supports myogenesis through suppression of metabolic endotoxemia and that Zip14 ablation coincides with sustained activity of phosphorylated components of signaling pathways including p-Mef2c, which causes Hspb7-dependent muscle wasting.

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.