Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator.

5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.

Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging.

Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.

Stomach clusterin as a gut-derived feeding regulator.

The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomachspecific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis.

Regulation of psoriasis, colitis, and the intestinal microbiota by clusterin.

Psoriasis, a chronic and systemic inflammatory disorder characterized by activation of the interleukin (IL)-23/IL-17 axis, may be associated with the intestinal microbiota through the so-called "gut-skin axis." Clusterin is a glycoprotein ubiquitously distributed in mammalian tissues; however, its role in psoriasis is unclear. Therefore, we evaluated the role of clusterin in psoriatic skin inflammation, systemic inflammation, and colitis using a murine model of IMQ-induced psoriasis. In IMQ-treated clusterin-knockout (clusterin-/-) mice, the expressions of inflammatory cytokines in clusterin-silenced human keratinocytes and intestinal microbial composition were analyzed. We also examined clusterin expression in the skin tissues of patients with psoriasis. IMQ-induced psoriatic skin inflammation is suppressed in clusterin-/- mice. Long-term administration of IMQ induced systemic inflammation and colitis; however, both were alleviated by the genetic deletion of clusterin. Genetic silencing of clusterin in human keratinocytes inhibited the production of inflammatory cytokines involved in the initiation and progression of psoriasis. The composition of the intestinal microbiota in IMQ-treated clusterin-/- and wild-type mice was different. Genetic deletion of clusterin suppressed the increase in the Firmicutes/Bacteroidetes (F/B) ratio. Skin tissues of patients with psoriasis showed high clusterin expression. In conclusion, inhibition of clusterin decreased psoriatic skin inflammation, systemic inflammation, colitis, and altered the F/B ratio in an IMQ-induced murine psoriasis model.

LRP1 mediates leptin transport by coupling with the short-form leptin receptor in the choroid plexus.

Adipocyte-derived leptin enters the brain to exert its anorexigenic action, yet its transport mechanism is poorly understood. Here we report that LRP1 (low-density lipoprotein receptor-related protein-1) mediates the transport of leptin across the blood-CSF barrier in Foxj1 expressing cells highly enriched at the choroid plexus (ChP), coupled with the short-form leptin receptor, and LRP1 deletion from ependymocytes and ChP cells leads to leptin resistance and hyperphagia, causing obesity. Thus, LRP1 in epithelial cells is a principal regulator of leptin transport in the brain.

A Single-Scan Ultraselective Heteronuclear Polarization Transfer Method for Unambiguous Complex Structure Assignment.

Complex nuclear magnetic resonance (NMR) signals of organic compounds containing multiple analogous substructures or mixtures pose a significant challenge to structural identification, thus resulting in frequent misassignment of structures. The GEMSTONE method, a single-scan technique that selectively excites a specific proton signal among the crowded NMR signals, was recently proposed as a solution. However, its extension to the polarization transfer method for heteronuclear spin systems was unsuccessful. Herein, we present an extension method that addresses the altered heteronuclear polarization transfer efficiency and enables the acquisition of ultraselective 13 C and 1 H-13 C correlation NMR subspectra with hertz-level signal selectivity in both dimensions. We demonstrate the effectiveness of this technique in the structural analysis of a chromopeptide pharmaceutical and a diastereomeric mixture of a fungicide.

Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+-SIRT-FOXO1-melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT-hypothalamic NAD+-FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.

Side-Chain-Assisted Transition of Conjugated Polymers from a Semiconductor to Conductor and Comparison of Their NO2 Sensing Characteristics.

To investigate the effect of a side chain on the electrical properties of a conjugated polymer (CP), we designed two different CPs containing alkyl and ethylene glycol (EG) derivatives as side chains on the same conjugated backbone with an electron donor-acceptor (D-A) type chain configuration. PTQ-T with an alkyl side chain showed typical p-type semiconducting properties, whereas PTQ-TEG with an EG-based side chain exhibited electrically conductive behavior. Both CPs generated radical species owing to their strong D-A type conjugated structure; however, the spin density was much greater in PTQ-TEG. X-ray photoelectron spectroscopy analysis revealed that the O atoms of the EG-based side chains in PTQ-TEG were intercalated with the conjugated backbone and increased the carrier density. Upon application to a field-effect transistor sensor for PTQ-T and resistive sensor for PTQ-TEG, PTQ-TEG exhibited a better NO2 detection capability with faster signal recovery characteristics than PTQ-T. Compared with the relatively rigid alkyl side chains of PTQ-T, the flexible EG-based side chains in PTQ-TEG have a higher potential to enlarge the free volume as well as improve NO2-affinity, which promotes the diffusion of NO2 in and out of the PTQ-TEG film, and ultimately resulting in better NO2 detection capabilities.

Effective Model Update for Adaptive Classification of Text Streams in a Distributed Learning Environment.

In this study, we propose dynamic model update methods for the adaptive classification model of text streams in a distributed learning environment. In particular, we present two model update strategies: (1) the entire model update and (2) the partial model update. The former aims to maximize the model accuracy by periodically rebuilding the model based on the accumulated datasets including recent datasets. Its learning time incrementally increases as the datasets increase, but we alleviate the learning overhead by the distributed learning of the model. The latter fine-tunes the model only with a limited number of recent datasets, noting that the data streams are dependent on a recent event. Therefore, it accelerates the learning speed while maintaining a certain level of accuracy. To verify the proposed update strategies, we extensively apply them to not only fully trainable language models based on CNN, RNN, and Bi-LSTM, but also a pre-trained embedding model based on BERT. Through extensive experiments using two real tweet streaming datasets, we show that the entire model update improves the classification accuracy of the pre-trained offline model; the partial model update also improves it, which shows comparable accuracy with the entire model update, while significantly increasing the learning speed. We also validate the scalability of the proposed distributed learning architecture by showing that the model learning and inference time decrease as the number of worker nodes increases.

Interstitial lung abnormalities (ILA) on routine chest CT: Comparison of radiologists' visual evaluation and automated quantification.

PURPOSE: We aimed to evaluate the performance of a fully automated quantitative software in detecting interstitial lung abnormalities (ILA) according to the Fleischner Society guidelines on routine chest CT compared with radiologists' visual analysis. METHOD: This retrospective single-centre study included participants with ILA findings and 1:2 matched controls who underwent routine chest CT using various CT protocols for health screening. Two thoracic radiologists independently reviewed the CT images using the Fleischner Society guidelines. We developed a fully automated quantitative tool for detecting ILA by modifying deep learning-based quantification of interstitial lung disease and evaluated its performance using the radiologists' consensus for ILA as a reference standard. RESULTS: A total of 336 participants (mean age, 70.5 ± 6.1 years; M:F = 282:54) were included. Inter-reader agreements were substantial for the presence of ILA (weighted κ, 0.74) and fair for its subtypes (weighted κ, 0.38). The quantification system for identifying ILA using a threshold of 5 % in at least one zone showed 67.6 % sensitivity, 93.3 % specificity, and 90.5 % accuracy. Eight of 20 (40 %) false positives identified by the system were underestimated by readers for ILA extent. Contrast-enhancement in a certain vendor and suboptimal inspiration caused a true false-positive on the system (all P < 0.05). The best cut-off value of abnormality extent detecting ILA on the system was 3.6 % (sensitivity, 84.8 %; specificity 92.4 %). CONCLUSIONS: Inter-reader agreement was substantial for ILA but only fair for its subtypes. Applying an automated quantification system in routine clinical practice may aid the objective identification of ILA.

Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c).

Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPRmt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.

Mechanisms of Weight Control by Primary Cilia.

A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.

Mouse Model of Small for Gestational Age Offspring with Catch-up Growth Failure and Dysregulated Glucose Metabolism in Adulthood.

Background: We aimed to build mouse models of small for gestational age (SGA), recapitulating failure of catch-up growth and dysregulated metabolic outcomes in adulthood. Methods: Pregnant C57BL/6 mice were given a protein-restricted diet (PRD; 6% kcal from protein) during pregnancy without (model 1) or with cross-fostering (model 2). Model 3 extended the PRD to the end of the lactation period. Model 4 changed to a 9% PRD without cross-fostering. Results: Model 1 yielded a reduced size of offspring with a poor survival rate. Model 2 improved survival but offspring showed early catch-up growth. Model 3 maintained a reduced size of offspring after weaning with a higher body mass index and blood glucose levels in adult stages. Model 4 increased the survival of the offspring while maintaining a reduced size and dysregulated glucose metabolism. Conclusion: Models 3 and 4 are suitable for studying SGA accompanying adulthood short stature and metabolic disorders.

Homeostatic Regulation of Glucose Metabolism by the Central Nervous System.

Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.

Volume Doubling Times of Pulmonary Metastases in Patients With Bone and Soft-Tissue Sarcomas: Associations With Subsequent New Metastases and Survival After Metastasectomy.

BACKGROUND. Pulmonary metastases of bone and soft-tissue sarcoma are common and have a high recurrence rate after metastasectomy. Factors associated with postmetastasectomy recurrence are not well studied. OBJECTIVE. The purpose of this study was to investigate the association of the volume doubling time (VDT) of pulmonary metastases with the subsequent development of new pulmonary nodules and survival after metastasectomy in patients with bone or soft-tissue sarcoma. METHODS. This retrospective study included patients with bone or soft-tissue sarcoma who, between January 2010 and December 2020, underwent first complete metastasectomy of pulmonary nodules visualized on two sequential preoperative CT scans. Semiautomatic volumetric segmentation of the pulmonary metastases was performed on the two CT scans, and VDTs were calculated. VDT was compared between patients with and without subsequent new metastases after metastasectomy. Cox proportional hazards regression analyses were performed to determine risk factors for recurrence-free survival (RFS) after metastasectomy and for postmetastasectomy overall survival (OS). RESULTS. Forty patients (21 women, 19 men; mean age, 51.1 ± 14.3 [SD] years) were included. Of these patients, 23 (57.5%) developed new metastatic nodules after metastasectomy, and 10 (25.0%) died during follow-up. Median VDT was shorter in patients with, versus those without, new metastases after metastasectomy (56 vs 140 days, p = .002). Only four of 23 patients with new metastases had VDT of 140 days or more. In multivariable analysis, older age (hazard ratio [HR], 1.06; p = .004), female sex (HR, 2.80; p = .03), and VDT less than 140 days (HR, 4.22; p = .01) were independent predictors of worse RFS. Also in multivariable analysis, only older age (HR, 1.17; p = .005) and VDT less than 50 days (HR, 8.60; p = .02) were independent predictors of worse OS. OS was significantly worse in patients with VDT less than 140 days (10 deaths among 27 patients) than in patients with VDT of 140 days or more (no deaths in 13 patients) (p = .01). CONCLUSION. In patients with bone and soft-tissue sarcoma, shorter VDT of pulmonary metastases is independently associated with subsequent new metastases after metastasectomy and worse OS. CLINICAL IMPACT. VDT of pulmonary nodules may be considered in patient selection for pulmonary metastasectomy and in postoperative patient management.

Luteolin-3'-O-Phosphate Inhibits Lipopolysaccharide-Induced Inflammatory Responses by Regulating NF-κB/MAPK Cascade Signaling in RAW 264.7 Cells.

Luteolin (LT), present in most plants, has potent anti-inflammatory properties both in vitro and in vivo. Furthermore, some of its derivatives, such as luteolin-7-O-glucoside, also exhibit anti-inflammatory activity. However, the molecular mechanisms underlying luteolin-3'-O-phosphate (LTP)-mediated immune regulation are not fully understood. In this paper, we compared the anti-inflammatory properties of LT and LTP and analyzed their molecular mechanisms of action; we obtained LTP via the biorenovation of LT. We investigated the anti-inflammatory activities of LT and LTP in macrophage RAW 264.7 cells. We confirmed from previously reported literature that LT inhibits the production of nitric oxide and prostaglandin E2, as well as the expression of inducible NO synthetase and cyclooxygenase-2. In addition, expressions of inflammatory genes and mediators, such as tumor necrosis factor-α, interleukin-6, and interleukin-1ß, were suppressed. LTP showed anti-inflammatory activity similar to LT, but better anti-inflammatory activity in all the experiments, while also inhibiting mitogen-activated protein kinase and nuclear factor-kappa B more effectively than LT. At a concentration of 10 µM, LTP showed differences of 2.1 to 44.5% in the activity compared to LT; it also showed higher anti-inflammatory activity. Our findings suggest that LTP has stronger anti-inflammatory activity than LT.

Prunetin 4'-O-Phosphate, a Novel Compound, in RAW 264.7 Macrophages Exerts Anti-Inflammatory Activity via Suppression of MAP Kinases and the NFκB Pathway.

Biorenovation, a microbial enzyme-assisted degradation process of precursor compounds, is an effective approach to unraveling the potential bioactive properties of the derived compounds. In this study, we obtained a new compound, prunetin 4'-O-phosphate (P4P), through the biorenovation of prunetin (PRN), and investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells. The anti-inflammatory effect of P4P was evaluated by measuring the production of prostaglandin-E2 (PGE2), nitric oxide (NO), which is an inflammation-inducing factor, and related cytokines such as tumor necrosis factor-α (TNFα), interleukin-1ß (IL1ß), and interleukin-6 (IL6). The findings demonstrated that P4P was non-toxic to cells, and its inhibition of the secretion of NO-as well as pro-inflammatory cytokines-was concentration-dependent. A simultaneous reduction in the protein expression level of pro-inflammatory proteins such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was observed. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), p38 MAPK (p38), and nuclear factor kappa B (NFκB) was downregulated. To conclude, we report that biorenovation-based phosphorylation of PRN improved its anti-inflammatory activity. Cell-based in vitro assays further confirmed that P4P could be applied in the development of anti-inflammatory therapeutics.