Research articles

The conventional view holds that hypoxia confers drug resistance. In contrast, here the authors use a multilayer ‘omics data approach to characterize the molecular features associated with tumour hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to approved drugs.

Amino acids are required for cell survival and growth. However, the different requirements of amino acid metabolic pathways in normal haematopoiesis and leukaemogenesis have not been explored. Here the authors focus on the transporter of neutral amino acids and show that malignant blood cells rely more on ASCT2-mediated amino acid metabolism than normal cells.

The oxidative pentose-phosphate pathway (oxPPP) is a major NADPH producer. Here the authors show that malic enzyme or isocitrate dehydrogenase can support the growth of cells lacking the oxPPP, but the oxPPP is necessary to maintain a normal NADPH/NADP ratio, DHFR activity and folate metabolism.

Obesity is associated with an increased risk of colitis-associated cancer (CAC). Here Ostermann et al. show that a high-fat diet induces insulin resistance in intestinal epithelial cells (IECs) and that genetic inactivation of insulin and IGF1 signalling in IECs impairs intestinal regeneration and enhances tumour formation in a CAC mouse model.

AMPK is a master regulator of cellular metabolism. Here the authors show that a constitutively active AMPK mutation protects mice fed a high-fat diet from obesity by increasing energy expenditure in subcutaneous white adipocytes, possibly as a result of the emergence of a hitherto-unknown type of adipocyte.

Creatine can be used for thermogenesis in adipocytes. Here Kazak et al. show that creatine uptake is required to sustain this thermogenic pathway. Knockdown of the creatine transporter, CrT, in adipocytes decreases thermogenesis and energy expenditure, whereas creatine supplementation increases energy expenditure in mice fed a high-fat diet.

Olfactory food perception is known to extend lifespan in C. elegans. Here the authors demonstrate food-odour-dependent brain-to-gut communication that extends lifespan in worms. Food odour downregulates tir-1 mRNA in AWC neurons, in a manner dependent on the miRNA miR-71, which triggers downstream effects in the gut, due to neuropeptide secretion, that promote proteostasis and longevity.

Many beneficial effects of exercise are mediated by factors secreted from the exercising muscle, so-called myokines. Here, the authors identify what might be the first exercised-induced adipokine, TGF-β2, which is secreted from subcutaneous fat in response to exercise-induced increases in serum lactate levels and has beneficial metabolic effects in mice.

Neurons and astrocytes cooperate metabolically but differ in key aspects of their metabolism, including the production of mitochondrial reactive oxygen species (ROS). Here, the authors show that mitochondrial ROS produced in astrocytes affect neuronal metabolism and mouse memory and behaviour.

Hypothalamic melanocortin neurons control energy homoeostasis by modulating appetite. Here, the authors reveal a role for the transcription factor Tbx3 as a regulator of the peptidergic identity and function of immature and mature mouse melanocortin neurons.

Bone marrow-derived cells can rapidly enter the systemic circulation, but how this is achieved is unclear. Grüneboom et al. identify tiny capillaries, termed trans-cortical vessels (TCVs), that connect the bone marrow cavity to the systemic vasculature, and show that the majority of blood in long bones passes through TCVs.

Perineuronal nets (PNNs) are extracellular matrix structures that have been linked to neuronal plasticity in the cortex and hippocampus. Here, the authors report the existence of PNN-like structures in a key region regulating energy homoeostasis, the hypothalamic arcuate nucleus, and show that PNN formation in this area early in life is influenced by the hormone leptin.

ACC1 is a rate-limiting enzyme during fatty acid biosynthesis. Here the authors describe how loss of ACC1 enhances CD4⁺ memory T cell formation and improves outcome in a murine model of parasite infection, indicating that lipid biosynthesis directs cell-fate determination during the generation of memory T cells.

As opposed to circulating factors that promote energy expenditure, hormones that suppress energy expenditure have remained largely elusive. Here, Wang et al. show that the hepatokine Tsukushi is upregulated in obesity and inhibits sympathetic activity and thermogenesis in fat by promoting whitening.

Ageing is associated with deteriorating immune function and metabolic diseases. Here, the authors show that plasma levels of the stress-response protein MANF decline with age in various organisms and that MANF has beneficial effects on immune and metabolic function, particularly in the liver, in old mice.

Extracellular matrix (ECM) homeostasis is essential for normal tissue function, and its perturbation by injury, trauma or disease results in fibrosis. Here, the authors show that glycolysis and the fatty acid oxidation pathway regulate fibroblast behaviour and have reciprocal effects in ECM upregulation and downregulation, respectively.

Despite the similarity of metabolic flux patterns in different organisms, the underlying governing principles remain unclear. Using a constraint-based thermodynamic–stoichiometric model as well as quantitative metabolome and physiological data, Niebel et al. identify an upper limit on the cellular Gibbs energy dissipation rate, which could shape metabolism across organisms.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD⁺, but how NMN is taken up into cells has not been entirely clear. Here the authors discover a specific NMN transporter, encoded by the Slc12a8 gene, which regulates NMN uptake and cellular NAD⁺ levels in vitro and in the mouse intestine in vivo.

Transferrin receptor 2 (Trf2) is known to regulate iron homeostasis through its action in the liver. Here the authors report a previously unrecognised role of Trf2 in regulating bone homeostasis mediated by modulation of BMP signalling specifically on osteoblasts.

Endothelial cells (ECs) require glycolysis during angiogenesis; however, the function of the mitochondrial respiratory chain during this process is unclear. Here the authors show that mitochondrial respiration in ECs is required for angiogenesis as the biosynthetic role of mitochondria is needed for EC proliferation.