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Multiomic analyses in an individual with severe, early-onset obesity, followed by targeted screening in additional patients identifies a tandem duplication at the ASIP gene (encoding agouti-signalling protein) as a novel cause of monogenic obesity, with implications for genetic diagnosis of obesity.
mTORC1 integrates environmental signals to promote anabolism and repress catabolism. In this issue of Nature Metabolism, Hosios et al. identify a role for mTORC1 in controlling endosomal trafficking and degradation of membrane phospholipids in the lysosome, revealing a novel process used by cells to adapt to poor growth conditions.
The physiological role of aerobic glycolysis (also known as the Warburg effect), which is observed in many tumours, is still not fully understood. The finding that lactate dehydrogenase A (LDHA) activates RAC1 in breast cancer sheds new light on this persistently enigmatic aspect of cancer metabolism.
Sustained weight loss and weight maintenance are key challenges for the treatment of obesity. Here, the authors show that a high-protein diet following weight loss can protect against weight regain, through a process dependent on the gut microbiome.
BCAA homeostasis is crucial to human health. A new study demonstrates that a mitochondrial metabolon assembled by BCAT2 and BCKDH controls BCAA metabolism in vivo, providing opportunities to develop strategies for repairing dysfunctional BCAA homeostasis.
Adipose tissue is a specialized connective tissue and a major endocrine organ. Brown adipose tissue (BAT) secretes factors that modulate whole-body metabolic homeostasis and can affect distant organs. The discovery that BAT-secreted neuregulin 4 influences atherosclerotic progression opens new opportunities for treating atherosclerosis.
The human gut microbiome metabolizes hundreds of drugs, but the clinical relevance of these biotransformations remains unclear. Chen and colleagues show that gut bacterial nicotine metabolism protects against liver disease.
Scherer and colleagues demonstrate that manipulation of iron concentrations in the mitochondrial matrix of macrophages has profound effects on their polarization, leading to concomitant changes in adipocyte iron concentrations and, ultimately, systemic metabolic effects.
The core metabolic pathways are tightly intertwined, creating challenges for metabolic engineering. Yu et al. present a synthetic decarboxylation cycle that substitutes the TCA cycle in energy metabolism, gaining high yields in the production of reduced compounds such as fatty acids.
An explosion of recent work has harnessed the power of single-cell biology to reveal the transcriptomic diversity of cell types in the mouse hypothalamus. Steuernagel, Lam and co-authors present HypoMap, a comprehensive single-cell transcriptomic atlas of the mouse hypothalamus.
Biotransformation of xenobiotics by gut microbiota can impact bioactivity and toxicity. A new study shows how hydrogen sulfide generated by gut microbes reduces azo compounds extracellularly and non-enzymatically.
Gut commensal bacteria and their metabolites can contribute to metabolic diseases. Qiao, Liu et al. reveal that expansion of Parabacteroides merdae attenuates experimental atherosclerosis.
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.
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.
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.
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.
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.
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.
Mass spectrometry imaging holds promise for mapping the intricate organization of metabolism in complex tissues. Wang et al. combine this exciting technique with metabolic tracing ex vivo to uncover metabolic specialization and adaptation in the mouse kidney.
