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In this Perspective, the authors discuss the various mouse preclinical models that are available for the study of non-alcoholic steatohepatitis (NASH) and NASH-induced hepatocellular carcinoma, and provide advice on reporting practices and how to select the most appropriate model.
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.
Hu et al. study the role of hexokinase 2 in microglial metabolism and function, and show its dual role under physiological and pathological conditions in a mouse model of stroke-induced neuroinflammation
Paterson and Yu et al. demonstrate that loss of the RNA alternative splicing factor RBFOX2 in the liver during a lipogenic diet leads to dysregulation of liver lipid and cholesterol homeostasis through a specific alternative splicing programme, which includes a splice switch of the high-density lipoprotein receptor gene Scarb1.
Liu et al. identify a non-metabolic mechanism through which lactate dehydrogenase A (LDHA) promotes cancer progression. This study shows that LDHA, independently of its enzymatic activity, directly interacts with and activates Rac1.
A mutation leading to ubiquitous ectopic expression of agouti signaling protein, which is not picked up in conventional genetic screenings, is reported in patients with severe childhood obesity.
Hosios et al. demonstrate that inhibition of mechanistic target of rapamycin complex 1 in cells and in tumors in mice leads to a lysosome-dependent but autophagy-independent shift in membrane lipid metabolism, resulting in increased intracellular triglyceride pools.
Jing et al. show that COVID-19 infection causes white adipose tissue (AT) browning in mice and hamsters, which is mediated by VEGF action in the AT. VEGF blockade can ameliorate browning phenotype and COVID-19-induced weight loss, potentially providing a strategy to treat infection-induced AT atrophy.
Mitochondria of young adipocytes release RNA molecules that serve as signals to stimulate the transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis. Mitochondrial RNA (mtRNA) efflux thus establishes retrograde mitochondria–nucleus signalling and triggers heat production from fat. Stimulating this signalling protects against obesity in mice.
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.
Zhong et al. show that increased lipid intestinal absorption can contribute to fat mass increase after dieting and this is mediated by Lactobacillus-secreted metabolites. Notably, Lactobacillus growth can be counteracted by refeeding a high-protein diet, thus preventing weight regain.
A maternal high-fat diet (mHFD) alters behavior in offspring in a sex-specific manner. We demonstrate that mHFD increases endotoxin levels in fetal tissues and decreases long-term serotonin bioavailability in male offspring owing to removal of serotonin neurons by microglia in the embryonic brain.
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.
Hoang et al. show that mitochondrial RNA in young beige adipocytes triggers mitobiogenesis and thermogenesis, while an interferon response is avoided through vitamin D-mediated suppression of IRF7 expression.
Chronic pain is often accompanied by decreased appetite. The authors uncover the neuronal circuits that lead to reduced feeding in a mouse model of persistent pain, which involves cortical-to-hypothalamic glutamatergic signalling.
Ceasrine et al. show that a maternal high-fat diet leads to impaired serotonin bioavailability in the male fetal brain by disrupting the placenta–brain axis, which can cause long-lasting behavioural changes in the offspring.