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A small-molecule aldolase inhibitor, aldolazin is reported and shown to selectively activate the lysosomal pool of AMPK, which has glucose-lowering effects in rodents.
Microglia require a large amount of energy to clear plaques in the brains of people with Alzheimer’s disease. Leng et al. found that increased activity of the glycolytic enzyme hexokinase 2 (HK2) blocks microglial phagocytosis in Alzheimer’s disease. Inhibition of HK2 results in increased microglial energy production by a compensatory lipid metabolism response, restores phagocytosis and improves cognitive function.
Accumulation of β-amyloid plaques contributes to neuronal cell death in Alzheimer’s disease. In this study, Leng et al. describe a role for hexokinase 2 in metabolic reconfiguration in microglia that promotes phagocytosis and supports amyloid plaque clearance.
Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer mortality. Modulation of tumour metabolism may represent a novel therapeutic strategy. Hexokinase 1, secreted into extracellular vesicles by activated hepatic stellate cells, is shown to be taken up by tumour cells, where it accelerates glycolysis and HCC growth.
Hexokinase 1 is found to be secreted from hepatic stellate cells in large extracellular vesicles in response to TGF-β, and is subsequently taken up by hepatocellular carcinoma cells, where it promotes tumor progression and metastasis.
Kang et al. reveal that GAB, classically known as a neurotransmitter, can control pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation in a cell-autonomous manner, thus modulating T cell-mediated inflammation.
SARS-CoV-2-induced anorexia triggers systemic metabolic alterations. In a study published in Nature, Karagiannis et al. show that the ketone body β-hydroxybutyrate (BHB) improves COVID-19 disease outcomes. Further, BHB metabolically and functionally reprograms CD4+ T cells, highlighting immunometabolic tuning of immunity in COVID-19.
Nature Metabolism is launching an online collection with articles highlighting best practices in experimental design, analysis and reporting to support the metabolic research community and increase the reproducibility of research in the life sciences.
Decreased insulin action and insulin receptor signalling contribute to the pathology of diabetes. Liu et al. uncover a role for the Ephrin type-B receptor 4 in insulin receptor degradation regulating liver and systemic insulin sensitivity.
The tyrosine kinase receptor EphB4 is shown to interact with the insulin receptor to facilitate its endocytosis and degradation, thereby decreasing insulin signaling and promoting insulin resistance.
This Review summarizes emerging concepts for diabetes therapy aimed at specifically altering β cell biology and function, such as β cell insulin signalling, proliferation, differentiation, apoptosis, as well as the selective killing of senescent β cells.
Achreja et al. develop a framework to identify collateral lethalities in cancer, uncovering MTHFD2 as a collateral lethal gene in UQCR11-deficient ovarian tumours.
Chen et al. show that the endoplasmic reticulum stress sensor IRE1α acts in white and beige adipocytes to restrain beige adipocyte activation, through regulation of lipolysis and Pgc1α messenger RNA levels, respectively.
Synergistic toxicity of alcohol and cannabinoid exposure in mice leads to impairments on motor coordination by affecting the activity of presynaptic cannabinoid type 1 receptors and extrasynaptic glycine receptors in cerebellar Purkinje cells.
It has long been recognized that some phenotypic variation in mammals cannot be explained by known genetic or environmental variables. Here, the authors show that the absence of Nnat expression is associated with polyphenism in mice with the same genotype. Broadly consistent effects are also found in humans.
Yang et al. show that neuronatin (NNAT) can explain part of the phenotypic variation of complex traits, independently of genetics or the environment. Such NNAT-dependent variations can stratify human cohorts into four metabolic sub-types, including two distinct types of obesity.
PRDM16 is a key mediator of thermogenic fat, counteracting adipose fibrosis and inflammation. Kajimura and co-authors demonstrate that a CUL2–APPBP2 ubiquitin E3 ligase complex destabilizes the PRDM16 protein, resulting in declined metabolic activity in an age-dependent manner.