Research articles

In this study, the authors use ATAC-seq and promoter capture Hi-C data from human adipocytes treated with fatty acids to identify gene–environment (G×E) interactions that influence body-mass index in humans. They report 154 genes that respond to saturated fat and discover 38 new G×E variants for body-mass index in data from the UK Biobank.

Bioproduct synthesis via reductive metabolism occurs with different efficiencies according to the availability of carbons, ATP and reducing agents. To maximize overall product synthesis efficiency, the authors develop a substrate cofeeding strategy, which circumvents catabolite repression and drives synergy in lipid synthesis from CO₂ using two microbes.

Pancreatic β-cells are highly connected, and this network is crucial for the pulsatile release of insulin. Here Salem and colleagues demonstrated the existence of leader β-cells that respond first to glucose and are more closely linked to the other β-cells. They also showed that glucose increases β-cell calcium dynamics and connectivity between the leader and non-leader β-cells.

Iron homoeostasis is tightly orchestrated to avoid toxic iron overload. Here Lim and colleagues show that iron excess activates Nrf2 via mitochondrial reactive oxygen species, enhancing the expression of Bmp6 in liver sinusoidal endothelial cells, which in turn promotes hepcidin expression by hepatocytes, decreasing systemic iron levels.

Metabolism is tightly regulated through communication among cells and organs. Here Gong and colleagues show that a liver-secreted factor, Gpnmb, promotes lipogenesis in adipose tissue and worsens metabolic dysfunctions during diet-induced obesity, whereas its inhibition reduces weight gain and insulin resistance.

Here the authors demonstrate a mechanism by which PNPLA3 and its risk variant I148M contribute to intracellular lipid metabolism. PNPLA3 interacts with ABHD5 to prevent the PNPLA2–ABHD5 interaction, thereby inhibiting lipolysis in brown adipocytes and promoting lipid storage. The PNPLA3 I148M variant enhances this interaction.

Dietary protein influences metabolic health and ageing. Here Solon-Biet et al. show that, rather than having a direct toxic effect, dietary branched-chain amino acids (BCAAs) appear to induce hyperphagia, owing to an imbalance between BCAAs and other amino acids, which reduces lifespan as a consequence of obesity.

Activation of brown adipose tissue can ameliorate obesity and diabetes. Here the authors show that chemical inhibition of hyaluronan synthesis by 4‐methylumbelliferone or genetic deletion of hyaluronan synthases 2 and 3 decreases body-weight gain and improves glucose homeostasis by inducing the thermogenic capacity of brown adipose tissue in mice.

Relapsed disease after conventional cancer treatments is an obstacle in epidermal growth factor receptor (EGFR)-based targeted therapy. Here the authors show that tolerance to the EGFR inhibitor osimertinib in non-small-cell lung cancer is mediated by the effects of miR-147b on the tricarboxylic acid cycle and pseudohypoxia pathways, which can be manipulated with a miR-147b inhibitor.

Inoue et al. use genetic and epigenetic tools to map active gene regulatory elements in leptin-responsive neurons in the mouse hypothalamus. These regulatory elements overlap with several obesity-associated GWAS SNPs.

Here the authors identify the long noncoding RNA lnc-ob1 as a regulator of osteoblast activity. Increased lnc-ob1 expression in osteoblasts, owing to either genetic knock-in or pharmacological delivery of a plasmid, increases bone formation and counteracts bone loss in an osteoporosis mouse model, thus suggesting that modulating lnc-ob1 expression may be therapeutically useful.

Proinflammatory activation of liver macrophages and their secretion of proinflammatory cytokines have been linked to obesity. Here Morgantini et al. report a mechanism through which liver macrophages can impair liver metabolism and promote insulin resistance in obesity in the absence of an overt proinflammatory phenotype, through secretion of non-inflammatory factors such as IGFBP7.

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.

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.

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.

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.