Evanna Mills and Edward Chouchani share the experience of their successful mentor–mentee relationship and talk about the challenges of starting a new lab — both from a recent perspective and five years on.

A better understanding of how the brain controls whole-body energy use and storage, as well as eating behaviour, will pave the way for improving therapeutics to fight metabolic diseases. This Focus presents a collection of Reviews, Perspectives and research Articles that integrate the most recent evidence on how the brain controls key aspects of whole-body metabolism.

While fibroblast growth factor (FGF) 1 is expressed in multiple tissues, only adipose-derived and brain FGF1 have been implicated in the regulation of metabolism. Adipose FGF1 production is upregulated in response to dietary stress and is essential for adipose tissue plasticity in these conditions. Similarly, in the brain, FGF1 secretion into the ventricular space and the adjacent parenchyma is increased

Itaconate is an immunomodulatory Krebs cycle-derived metabolite. Description of two isomers of itaconate, mesaconate and citraconate, which have overlapping and distinct properties when compared with itaconate in macrophages, expands the knowledge of this intriguing family of immunomodulatory metabolites.

Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1,2,3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated

Strong evidence suggests that early-life exposures to suboptimal environmental factors, including those in utero, influence our long-term metabolic health. This has been termed developmental programming. Mounting evidence suggests that the growth and metabolism of male and female fetuses differ. Therefore, sexual dimorphism in response to pre-conception or early-life exposures could contribute to known

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson’s disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation

Activation of resting regulatory T cells (Tregs) upon antigen encounter is essential for proper Treg function. However, the metabolic pathways that mediate this transition are unknown. Liu et al. have identified the non-oxidative pentose phosphate pathway as a central regulator of Treg activation and function.

Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite

Nature Metabolism and the Nature journals are raising the standards for reporting on sex and gender in research. Starting this June, authors will be prompted to provide details on how sex and gender were considered in study design.

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that β-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic β-cells independent of the actions

The severity and mortality of COVID-19 are associated with pre-existing medical comorbidities such as diabetes mellitus. However, the underlying causes for increased susceptibility to viral infection in patients with diabetes is not fully understood. Here we identify several small-molecule metabolites from human blood with effective antiviral activity against SARS-CoV-2, one of which, 1,5-anhydro-d-glucitol

A glucose-like metabolite, which is reduced in the serum of diabetic patients, inhibits the entry of SARS-CoV-2 into key cellular targets. The work led by Cheng and colleagues provides a molecular explanation for the increased risk of severe COVID-19 in patients with diabetes.

Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism

Until now, the BDNF–TrkB signalling pathway was thought to be exclusively regulated by neurons. Ameroso et al. show that astrocytic TrkB.T1 is a critical substrate of BDNF in the regulation of energy balance and that its defective signalling in hypothalamic circuits leads to obesity.

Brain-derived neurotrophic factor (BDNF) is essential for maintaining energy and glucose balance within the central nervous system. Because the study of its metabolic actions has been limited to effects in neuronal cells, its role in other cell types within the brain remains poorly understood. Here we show that astrocytic BDNF signaling within the ventromedial hypothalamus (VMH) modulates neuronal

Glucose clamps are challenging to conduct in mice and experimental approaches vary between laboratories, which complicates data interpretation and comparison of results. Here, we highlight key methodological differences and propose reporting standards for glucose clamps.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium

Global scientific collaboration should endure despite the humanitarian crisis in Europe.

Maria Ermolaeva and Liron Boyman share their scientific journeys in this instalment of Career pathways and highlight the value of mentors and collaborators, and the importance of following your research interests.

Although food-craving episodes during pregnancy are common in humans, the neural, cellular and molecular mechanisms that underlie these eating bouts remain unknown. New work points to dopamine receptor D2-expressing neurons of the reward system as critical mediators of compulsive feeding during pregnancy.

Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development1. Cravings for highly palatable foods are highly prevalent during pregnancy2 and contribute to the maintenance and development of gestational overweight or obesity3. However, the neurobiology underlying the distinct ingestive

Oncometabolites are pro-tumourigenic metabolites that can determine tumour aggressiveness. This study found that methylmalonic acid is upregulated in breast lung metastasis and metastatic cancer cells. Methylmalonic acid alters the gene expression profile to induce a pro-metastatic phenotype in breast and lung cancer cells.

The clearance of dying cells by macrophages releases mediators that switch off inflammation. Ampomah et al. reveal how an amino acid derived from apoptotic cargo changes the methylation epigenome of macrophages to take the brakes off an ERK-dependent pathway that terminates inflammatory responses.

Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphatase Dusp4. We focus on two