News & Views

In this issue of Nature Metabolism, the research team of Mitchell Lazar reveals unexpected consequences of double loss of the coregulators NCOR1 and NCOR2 (NCOR1/2) in hepatocytes of adult mice, which affects chromatin functioning and glucocorticoid receptor (GR)-mediated gene transcription.

Thiazolidinediones (TZDs) are potent insulin-sensitizing drugs, but their use is accompanied by adverse side-effects. Rohm et al. now report that TZD-stimulated macrophages release miR-690-containing vesicles that improve insulin sensitization and bypass unwanted side-effects.

Maternal circadian rhythms influence the health of infants. Cui, Xu and colleagues find that disruption of maternal rhythms impairs neonatal immune cell function and aggravates neonatal inflammatory disorders, which can be rescued by the administration of docosahexaenoic acid (a metabolite found in breast milk).

The mechanisms that drive cancer cachexia are unclear. Adipocyte activation of GPR81 by high levels of lactate is now shown to drive adipose tissue browning, thermogenesis and a loss of body weight in mouse models of cancer.

The mechanism by which metformin affects food intake remains controversial. Now, two studies link metformin treatment with the induction of the appetite-suppressing metabolite N-lactoyl-phenylalanine, which is produced by the intestine.

Eating requires the sensing in the stomach of not only nutrients, but also volume. A study in Nature Metabolism shows that stretch activation of PIEZO1 on X/A-like cells of the stomach reduces ghrelin production and secretion, which consequently reduces food intake.

A recent study in Nature Metabolism uncovers a mechanism for pain sensitization that involves a regulatory protein of glycogen metabolism in spinal astrocytes. Targeting this protein, or the lactate fluxes linked to glycogen breakdown, may provide novel opportunities for pain management.

In this study in humans, the authors describe distinct phases of adaptions in the plasma proteome to seven days without food, and identify limited associations of protein changes with weight loss.

In this issue of Nature Metabolism, it is shown that the abundance of Caenorhabditis elegans branched-chain aminotransferase-1 (BCAT-1) — which catalyses the first step of branched-chain amino acid (BCAA) catabolism — declines sharply in aged wild-type nematodes but not in slowly ageing mutants, and that stimulating BCAA catabolism extends reproductive longevity.

The microbiome is implicated in a study that involves the metabolism of dietary fibre into short-chain fatty acids, which provides a biochemical link to the poorly understood histone butyrylation.

Resistant starch is a prebiotic fibre that is fermented by the gut microbiota and leads to benefits for host physiology. A clinical trial in Nature Metabolism demonstrates weight loss when resistant starch was given to individuals with excess weight.

Succinate can be released from contracting skeletal muscle and accumulate in brown adipose tissue (BAT) to drive thermogenesis and protect against obesity. A study in this issue of Nature Metabolism uncovers the mechanistic underpinnings of BAT succinate sequestration through MCT1-dependent uptake and cytosolic pH changes, thus strengthening the role for cellular shuttling of succinate in the control of systemic energy homeostasis.

Hypothalamic neural pathways control appetite and food intake, and thereby influence body weight and metabolism. De Solis et al. apply chemogenetics to simultaneously manipulate two subpopulations of hypothalamic neurons. Using this approach, the authors identify a pathway that regulates feeding behaviour.

Although obesity is associated with higher risk of cardiometabolic disease, high-protein diets can reduce fatness but still promote cardiometabolic disease. Zhang et al. address this contradiction and show that high-protein diets, and subsequently higher blood leucine levels, promote mTORC1 activation in macrophages in humans and mice, and that an increase in dietary leucine raises the risk of atherosclerosis in a mouse model.

Selenium is usually incorporated into selenoproteins, with important functions in redox regulation. A new study in Nature Metabolism reveals a previously unappreciated role for selenium-based chemical species as direct electron donors to reduce ubiquinone, thus contributing to redox homeostasis by preventing lipid peroxidation.

High-fat diet (HFD) causes mitochondrial dysfunction in white adipocytes. A study in Nature Metabolism identifies the small GTPase RalA as a culprit in mice. Upon HFD, RalA activates the fission protein Drp1 to cause mitochondrial fragmentation and dysfunction, linking mitochondrial fuel utilization in white adipocytes to systemic lipid metabolism.

Dwibedi et al. carry out a randomized controlled trial to evaluate whether subgroups of patients with diabetes could receive the greatest metabolic benefit from novel anti-diabetic drugs.

Genotype at the LCT locus determines lactase expression and very notably varies across populations. Milk intake variably influences the aetiology of the risk of type 2 diabetes depending on ancestry. In this issue of Nature Metabolism, Luo et al. describe how increased milk intake modifies both gut bacterial abundances and circulating metabolites in favour of decreasing the risk of type 2 diabetes in individuals who are lactase-deficient.

Electron transfer flavoprotein dehydrogenase (ETFDH), respiratory chain complex III and the coenzyme Q10 synthesis regulator COQ2 interact as a protein complex that is disrupted in ETFDH deficiency, with potential implications for disease therapy.

Bone resorption by osteoclasts requires tight control, as overactivation reduces bone mass and strength. Stegen et al. demonstrate that α-ketoglutarate produced during serine synthesis promotes osteoclast development via metabolic–epigenetic coupling and could be a therapeutic target.