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Systematic evaluation of glucose control, body mass index, blood pressure, insulin secretion and insulin resistance is leveraged to identify patients who are likely to receive the greatest metabolic benefit from common antidiabetic drugs.

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.

Todorova et al. characterize the strategies through which embryos secure amino acid supply during the early phases of development. Their findings show that, in the preimplantation phase, embryos uptake whole proteins through macropinocytosis and, over time, they shift towards soluble amino acid uptake. This strategy may contribute to protecting embryos from nutrient fluctuations.

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.

Wei et al. show that proteolytic cleavage of fatty acid synthase (FASN) upon stress contributes to stress resolution. This role in stress resolution of the resulting C-terminal fragment of FASN is independent of its canonical function in fatty acid synthesis.

Li, Barros et al. decipher how distinct mechanisms of protein sensing in the upper small intestine and ileum regulate food intake, glucose homeostasis and gut hormone release in male rats.

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.

Mosteiro et al. show that inhibition of Notch, a signaling pathway frequently associated with cell-fate decisions during development, impairs thyrocyte homeostasis in an active subset of thyrocytes in adult mice through mitochondrial dysfunction and decreased ROS, thereby causing hypothyroidism.

Macrophages that clear apoptotic cells (efferocytosis) proliferate to enhance tissue repair and resolution. Here, we find that a previously elucidated nucleotide ‘cargo’ proliferation pathway that increases Myc mRNA is complemented by efferocytosis-induced lactate, which stabilizes Myc protein through SIRT1-mediated Myc protein deacetylation.

Iron is shown to have a central role in senescence, both by triggering senescence and through its accumulation in senescent cells, which is driving the senescence-associated secretory phenotype and, in turn, promotes fibrogenesis.

The authors present an overview of the metabolism and pleiotropic actions of ketone bodies, summarizing their endogenous sources, signalling mechanisms and systemic metabolic effects.

In this study, Papalazarou et al. screen the solute carrier family and identify candidates involved of serine transport in colorectal cancer cells. They further characterize cytosolic SLC6A14 and mitochondrial SLC25A15 as mediators of adequate serine supply to sustain cancer cell proliferation.

In a two-part randomized phase 2a trial in men and women with overweight or obesity and type 2 diabetes mellitus, cotadutide promoted greater reductions in liver glycogen and fat than placebo and liraglutide.

We demonstrated increased phospholipid peroxidation due to the formation of monolysocardiolipin–cytochrome c complexes in tafazzin-deficient models of Barth syndrome. We found that a specific anti-peroxidase agent inhibited this complex and improved mitochondrial respiration. Thus, targeting the deleterious peroxidase activity offers a potential therapeutic approach to treat Barth syndrome.

The gene-editing tool mitoARCUS has been precisely fine-tuned to reduce m.3243A>G mitochondrial DNA (mtDNA) without harming wild-type mtDNA or nuclear DNA in vitro and in vivo, which paves the road to the first human trials.

Shoop et al. develop mitoARCUS, a mitochondria-targeted nuclease with high specificity, to correct a relatively common pathogenic mtDNA mutation, allowing for beneficial shifts in heteroplasmy while reducing nuclear off-target gene editing.

This Review discusses the role of mitophagy in cellular and organismal health and disease, with a specific focus on human ageing and evidence obtained in clinical studies.

Efferocytosis-induced macrophage proliferation is supported by increased non-canonical upregulation of glycolysis. Ngai, Schilperoort and Tabas provide mechanistic insight to understand how glycolysis-derived lactate contributes to this process by stabilizing MYC via extracellular signalling.

Hildreth et al. show that during diet-induced obesity, conventional type 1 dendritic cells (cDC1s) in white adipose tissue (WAT) take up DNA-containing apoptotic bodies from adipocytes, which triggers STING-dependent interleukin-12 production from cDC1s, contributing to WAT inflammation in mice.