Reviews & Analysis

Diabetes mellitus invariably involves impaired regulation of insulin secretion from pancreatic β cells, as a result of unfavourable environmental influences in combination with aberrant expression of risk genes at either the transcriptional or the translational level. A recent report in Nature Metabolism explores a novel role of mRNA methylation in β-cell function and suggests that its downregulation causes type 2 diabetes.

Mitochondrial H⁺ leak, which is responsible for basal respiration, appears to be a transport process mediated by the ADP/ATP carrier and regulated by fatty acids and adenine nucleotides.

Lymphedema, a condition of fluid retention and tissue swelling, is currently incurable and is treated primarily with physical therapy. Studies in mice reveal that intake of a ketogenic diet or exogenous ketone bodies may alleviate lymphedema by increasing the formation of lymphatic vessels, which can drain excess lymph fluid.

The loss of T cell immune function as a result of human immunodeficiency virus (HIV) infection leads to opportunistic infections and certain HIV-associated cancers. Two recent studies shed light on the complex immunometabolic changes during HIV infection and open the door to metabolic treatment options that could ultimately cure HIV.

A multi-faceted translational study provides the first evidence that gut microbial conversion of lactate to propionate may enhance athletic performance during high-intensity endurance exercise.

The gut hormone FGF19 and its mouse orthologue Fgf15 are important mediators of the metabolic transition between the fasted and fed state. Here, Gadaleta and Moschetta provide a concise overview of the history of FGF15/FGF19, their physiological role and their molecular mechanism of action.

The entry of remnants of cholesterol-rich lipoproteins, such as low-density lipoprotein (LDL), from the blood stream into the intima of large arteries initiates and then perpetuates atherosclerosis. A study published in Nature sheds new light on this important process by identifying scavenger receptor BI (SR-BI) as a major receptor that mediates LDL delivery across the endothelium into arteries.

Living organisms face the dual challenge of acquiring enough iron to perform biological functions while preventing toxic iron accretion. A study now shows that sensing of iron-catalysed free radicals by a druggable gene-regulatory pathway helps the body avoid iron poisoning.

Interorgan communication is emerging as a critical contributor to nutrient and energy homeostasis. A new study has identified a secreted liver factor that stimulates lipid synthesis in white adipose tissue and exacerbates obesity and insulin resistance.

A common missense variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) was strongly linked to human fatty liver disease in 2008, but the underlying mechanisms have since remained unclear. Compelling data from Yang et al., published in Nature Metabolism, suggest that PNPLA3 binds ABHD5, sequestering it and preventing it from activating ATGL, the major intracellular triglyceride lipase.

Increasing pancreatic β-cell proliferation in autoimmune type 1 diabetes (T1D) might restore β-cell mass but would be predicted to exacerbate islet inflammation. A study in Nature Metabolism, however, reports that boosting β-cell proliferation in mouse models of T1D is beneficial, preserving the immunological self-tolerance of islets through the induction of regulatory T cells.

Obesity is a manifestation of a positive energy balance in which energy intake exceeds energy expenditure, thus often leading to insulin resistance and type 2 diabetes. A new study provides evidence that pharmacological inhibition of hyaluronan, an extracellular-matrix glycosaminoglycan, increases energy expenditure and insulin sensitivity by activating thermogenesis in brown adipose tissue.

Understanding the mechanisms by which tumour cells adapt or succumb to targeted therapies is crucial to improving cancer treatment. A study in this issue of Nature Metabolism demonstrates how microRNAs, metabolic pathways and pseudohypoxia play a major role in the drug tolerance to epidermal growth factor receptor (EGFR) inhibitors in lung adenocarcinoma.

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.

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.

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.

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.