Miki Watanabe-Chailland

Processes that promote white adipocyte inflammatory function remain incompletely defined. Here, we demonstrated that type I interferon–dependent (IFN-I–dependent) skewing of adipocyte glycolysis, nicotinamide adenine dinucleotide (NAD ⁺ ) utilization, and pyruvate kinase isozyme M2 (PKM2) function may contribute to increased systemic and tissue inflammation and disease severity in obesity. Notably, chemical and/or genetic inhibition of glycolysis, the NAD ⁺ salvage pathway, or PKM2 restricted IFN-I–dependent increase in adipocyte inflammatory cytokine production. Further, genetic or small molecule targeting of PKM2 function in vivo was sufficient to reduce systemic and tissue inflammation and metabolic disease severity in obese mice, in an adipocyte PKM2-dependent manner. Further, white adipose tissue of individuals living with obesity and metabolic disease, compared with metabolically healthy individuals with obesity, showed an increase in expression of inflammatory and metabolic genes, while small molecule targeting of PKM2 function contributed to reduced IFN-I–driven inflammatory cytokine production by primary human adipocytes. Together, our findings invoke the IFN-I/PKM2 axis as a potential target for modulating adipocyte dysregulated inflammation.

Spina bifida, known more commonly as myelomeningocele, is a neural tube defect that results in herniation of the cerebellum through the foramen magnum into the central canal as part of the Chiari II malformation. Effects stemming from the herniated cerebellum and its metabolic profile have not been extensively studied. The objective of this study is to examine the metabolic effects of this disease on the cerebellum in utero through the utilization of a retinoid acid-induced Spina bifida rat model. Analysis of this model at mid-late (day 15) and term (day 20) of gestation in comparison to both non-exposed and retinoic acid-exposed non-myelomeningocele controls, the observed metabolic changes suggest that mechanisms of oxidative stress and energy depletion are at play in this neuro tissue. These notable mechanisms are likely to result in further damage to neural tissue as the fetus grows and the compressed cerebellum develops and herniates more due to myelomeningocele.

Purpose Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development. Methods To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1. Results The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase. Conclusion Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

Oncogenic kinase inhibitors show short-lived responses in the clinic due to high rate of acquired resistance. We previously showed that pharmacologically exploiting oncogene-induced proteotoxic stress can be a viable alternative to oncogene-targeted therapy. Here, we performed extensive analyses of the transcriptomic, metabolomic and proteostatic perturbations during the course of treatment of Her2+ breast cancer cells with a Her2 inhibitor covering the drug response, resistance, relapse and drug withdrawal phases. We found that acute Her2 inhibition, in addition to blocking mitogenic signaling, leads to significant decline in the glucose uptake, and shutdown of glycolysis and of global protein synthesis. During prolonged therapy, compensatory overexpression of Her3 allows for the reactivation of mitogenic signaling pathways, but fails to re-engage the glucose uptake and glycolysis, resulting in proteotoxic ER stress, which maintains the protein synthesis block and growth inhibition. Her3-mediated cell proliferation under ER stress during prolonged Her2 inhibition is enabled due to the overexpression of the eIF2 phosphatase GADD34, which uncouples protein synthesis block from the ER stress response to allow for active cell growth. We show that this imbalance in the mitogenic and proteostatic signaling created during the acquired resistance to anti-Her2 therapy imposes a specific vulnerability to the inhibition of the endoplasmic reticulum quality control machinery. The latter is more pronounced in the drug withdrawal phase, where the de-inhibition of Her2 creates an acute surge in the downstream signaling pathways and exacerbates the proteostatic imbalance. Therefore, the acquired resistance mechanisms to oncogenic kinase inhibitors may create secondary vulnerabilities that could be exploited in the clinic.

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Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms of CDH pathogenesis are yet to be understood. Acknowledgment of the lung metabolism during the in-utero CDH development can help to discern the CDH pathophysiology changes. Timed-pregnant dams received nitrofen or vehicle (olive oil) on E9.5 day of gestation. All fetal lungs exposed to nitrofen or vehicle control were harvested at day E21.5 by C-section and processed for metabolomics analysis using nuclear magnetic resonance (NMR) spectroscopy. The three groups analyzed were nitrofen-CDH (NCDH), nitrofen-control (NC), and vehicle control (VC). A total of 64 metabolites were quantified and subjected to statistical analysis. The multivariate analysis identified forty-four metabolites that were statistically different between the three groups. The highest Variable importance in projection (VIP) score (>2) metabolites were lactate, glutamate, and adenosine 5′-triphosphate (ATP). Fetal CDH lungs have changes related to oxidative stress, nucleotide synthesis, amino acid metabolism, glycerophospholipid metabolism, and glucose metabolism. This work provides new insights into the molecular mechanisms behind the CDH pathophysiology and can explore potential novel treatment targets for CDH patients.

A variety of wildlife species maintained in captivity are susceptible to iron storage disease (ISD), or hemochromatosis, a disease resulting from the deposition of excess iron into insoluble iron clusters in soft tissue. Sumatran rhinoceros (Dicerorhinus sumatrensis) is one of the rhinoceros species that has evolutionarily adapted to a low-iron diet and is susceptible to iron overload. Hemosiderosis is reported at necropsy in many African black and Sumatran rhinoceroses but only a small number of animals reportedly die from hemochromatosis. The underlying cause and reasons for differences in susceptibility to hemochromatosis within the taxon remains unclear. Although serum ferritin concentrations have been useful in monitoring the progression of ISD in many species, there is some question regarding their value in diagnosing hemochromatosis in the Sumatran rhino. To investigate the metabolic changes during the development of hemochromatosis and possibly increase our understanding of its progression and individual susceptibility differences, the serum metabolome from a Sumatran rhinoceros was investigated by nuclear magnetic resonance (NMR)-based metabolomics. The study involved samples from female rhinoceros at the Cincinnati Zoo (n = 3), including two animals that died from liver failure caused by ISD, and the Sungai Dusun Rhinoceros Conservation Centre in Peninsular Malaysia (n = 4). Principal component analysis was performed to visually and statistically compare the metabolic profiles of the healthy animals. The results indicated that significant differences were present between the animals at the zoo and the animals in the conservation center. A comparison of the 43 serum metabolomes of three zoo rhinoceros showed two distinct groupings, healthy (n = 30) and unhealthy (n = 13). A total of eighteen altered metabolites were identified in healthy versus unhealthy samples. Results strongly suggest that NMR-based metabolomics is a valuable tool for animal health monitoring and may provide insight into the progression of this and other insidious diseases.