Browse Articles

The transcription factor Klf15 controls various metabolic processes, including bile acid synthesis. Here the authors show that Klf15 acts as an upstream regulator of xenobiotic and endobiotic metabolism by controlling expression of a variety of phase I–III metabolic genes via direct and indirect mechanisms.

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.

A recent large genetic study by Sanna et al., published in Nature Genetics, has shown that short-chain fatty acids, which are produced by gut microbes, have a significant causal effect on insulin secretion, postprandial glycaemic responses and risk of type 2 diabetes.

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.

This month, we introduce a new series of articles, called Metabolic Messengers, dedicated to molecules involved in cellular communication and inter-tissue cross-talk.

Secreted from adipocytes, adiponectin exerts primarily anti-apoptotic, antiinflammatory, anti-fibrotic and insulin-sensitizing activities on multiple tissues. Here, Straub and Scherer provide a concise overview of the history of adiponectin, its physiological role and molecular mechanism of action.

As one of the most highly consumed amino acids in cultured cancer cells, glutamine is an attractive target for anti-cancer therapy, and glutaminase inhibitors are currently in clinical trials. In this issue, Ni et al. show that blocking this pathway by targeting the glutamine importer ASCT2 (SLC1A5) decreases tumorigenesis in mouse leukaemia models while largely sparing normal haematopoiesis.

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.

The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a key cellular nutrient and energy sensor that integrates several inputs to regulate cell growth. Here, the authors discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism.

Activation of tissue-resident myeloid cells in the brain, known as microglia, is thought to drive obesity-associated hypothalamic dysfunction. The authors of this Perspective present a more nuanced view of microglia, echoing lessons learned from the field of adipose macrophage biology: instead of simply responding to diet-induced damage, microglia are proposed to act as nutrient and environmental sensors that regulate hypothalamic physiology, a role that, if hijacked by chronic overnutrition, can produce disease.

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.

Patients with severe diabetes rely on insulin injections to control their blood glucose. A study now provides evidence that human cells that normally do not release insulin can be converted into insulin-producing cells that are able to normalize glycaemia in diabetic mice.

The senescence-associated secretory phenotype (SASP) is responsible for the deleterious effects of senescent cells in ageing and cancer. A new study shows that NAD⁺ metabolism can regulate the pro-inflammatory SASP, thereby promoting tumorigenesis.

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.