Reviews & Analysis

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.

Individuals with osteoporosis have increased risk of Alzheimer’s disease or cognitive impairment during ageing. We elucidated a partial explanation for bone dysmetabolism’s association with such cognitive decline, by demonstrating how elevated sclerostin secretion from osteocytes in bone impaired cognitive function in aged mice and in an Alzheimer’s disease mouse model.

The immunosuppressive metabolic tumour microenvironment in solid tumours limits the antitumour activity of cell-based immunotherapy. In this Perspective, McPhedran et al. propose a framework to overcome this issue by engineering metabolic networks in T cells to enhance chimeric antigen receptor T cell efficiency

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.

Glycerol-3-Phosphate (G3P) and phosphoethanolamine (pEtN) biosynthetic pathways are modulated during senescence establishment to sustain lipid droplet accumulation and senescence-associated secretome. These findings reveal new targets for an immunomodulatory approach against senescent cells.

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.

Here, we reveal functional heterogeneity among β cells and discover that readily releasable β cells (RRβs) are a subpopulation that disproportionally contributes to biphasic glucose-stimulated insulin secretion. We further show that the dysfunction of RRβs has a crucial role in the progression of diabetes.

Demicco, Liu et al. discuss how metabolic adaptations in cancer contribute to tumour progression. These adaptations entail high spatial and temporal metabolic heterogeneity, based on local adaptations in different regions of the tumour microenvironment, as well as metabolic evolution over time as the tumour progresses and metastasizes.

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.

Following one’s passion and curiosity are major drivers for a successful career in science, and finding the right mentors and collaborators is essential in this journey. In the thirteenth part of our Career pathways series, Alexis Jourdain and Feilong Wang share their experience.

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.

Murine blastocysts and embryonic stem cells mimicking the pre-implantation epiblast import extracellular protein through macropinocytosis and engage a robust lysosomal digestive programme to meet their nutrient demands. We found that as development proceeds, post-implantation epiblast-like cells downregulate protein digestion, increase expression of amino acid transporters and become dependent on soluble amino acids.

In nature, organisms constantly face a variety of stresses in the environment. An organism’s ability to resolve a stressful state is crucial in maintaining homeostasis. In this issue of Nature Metabolism, Wei et al. report that redox-dependent caspase cleavage of fatty acid synthase triggers a global cue for stress resolution in Caenorhabditis elegans.

Calcium sensing receptor (CaSR) and peptide transporter 1 (PepT1) have been implicated in protein sensing in the gut, although the mechanisms are poorly understood. We find that, in the small intestine, CasR and PepT1 are necessary for protein sensing to regulate gut peptide release, feeding and glucose tolerance in rats in vivo.

A study in Nature Metabolism shows that the thyroid gland contains two subtypes of thyrocytes (the cells that produce thyroid hormones) and reveals a role for Notch signalling in regulating thyrocyte homeostasis and activity, as reduced Notch activity results in hypothyroidism.