Reviews & Analysis

Ceramides are bioactive lipids that regulate cellular signalling processes and metabolic pathways, and are implicated in various metabolic diseases. Here, Summers, Chaurasia and Holland provide a concise overview of the history of ceramides and their physiological roles, mechanisms of action and therapeutic potential.

Lifespan is increased and ageing is delayed by lifelong dietary restriction. A study in Nature Metabolism shows that these benefits are reduced when dietary restriction is started in old age, owing to the development of an inflexible nutritional memory within white adipose tissue.

Generally, most metabolic diseases are not caused by a mutation or defect in a single gene but instead are multi-factorial, resulting from a combination of genetic and environmental factors; thus, studying them requires a holistic approach. Here, Seldin and colleagues review systems genetics approaches, including their resources and advantages, for studying metabolic diseases.

Nuclear DNA damage has detrimental effects on cellular homoeostasis and accelerates the ageing process. A new study causally links error-prone mitochondrial replication to increased nuclear DNA damage, thus suggesting that the hallmarks of ageing are associated with nuclear genome instability, a potential unifying denominator in the ageing process.

GDF15 is an anorectic hormone that signals organismal stress to the brain. New data suggest that GDF15 enhances tolerance to acute inflammation by modulating liver lipid metabolism and triglyceride availability in mice.

The authors of this Review present a framework for understanding fundamental principles of metabolic regulation, drawing analogies between metabolic control and economic theory to discuss supply- and demand-driven metabolism.

Falkenberg et al. summarise major metabolic pathways operating in endothelial cells, discuss their roles in the growth and function of blood and lymph vessels, and highlight therapeutic opportunities that arise from targeting endothelial cell metabolism.

Findeisen et al. have engineered IC7Fc, a cytokine for the treatment of type 2 diabetes, that selectively activates beneficial metabolic pathways systemically and in metabolic tissues without promoting an inflammatory response.

In this issue, Diehl et al. report that exogenous serine is essential for the cellular redox state and cancer nucleotide production, despite the ability of cancer cells to synthesize serine de novo in vitro.

Obesity is the result of an imbalance between caloric intake from the diet and energy expenditure. A new study provides evidence that alterations in calcium transport efficiency in muscle lead to an increased metabolic rate and protect mice against diet-induced obesity.

Systemic accumulation of branched-chain amino acids (BCAAs) is a major metabolic hallmark and contributor to insulin resistance associated with obesity. A recent report identifies SLC25A44 as the BCAA transporter in mitochondrial membranes and shows that BCAA catabolism in brown adipose tissue significantly affects thermogenic activity, systemic BCAA clearance, energy expenditure and overall metabolic health.

Dopamine is an important neurotransmitter with essential roles in movement control and salience, and implications in addiction as well as weight loss, decreased food intake and a reduced motivational drive to eat. Folgueira et al. now demonstrate that dopamine causes weight loss and increases brown adipose tissue temperature via activation of the dopamine receptor D2R in hypothalamic GABA-expressing neurons in mice, and treatment with the dopamine agonist cabergoline causes weight loss in humans.

Cells contributing to atherosclerotic disease are highly plastic and can shift their phenotype in a changing microenvironment. A study in Nature Metabolism now reveals that transforming growth factor-β (TGF-β) can transform endothelial cells into pro-inflammatory cells and that inhibition of TGF-β-receptor signalling in the endothelium can reverse atherosclerosis in mice.

The gene encoding the RagC GTPase (RRAGC), an activator of a nutrient-sensing pathway that drives cellular anabolism, is mutated in 15% of follicular lymphoma cases. A new study provides evidence that RRAGC mutations promote lymphomagenesis by distorting the nutrient-dependent control of paracrine signals from the microenvironment, thus enhancing B-cell activation.

A recent study by Esteghamat et al., published in Nature Genetics, has reported that CELA2A, encoding a pancreatic enzyme, is a novel genetic cause of metabolic syndrome and atherosclerosis.

Jeffrey Friedman reviews the biology and evolutionary role of leptin as a regulator of behaviour and metabolism. He goes on to propose the existence of two states of obesity, distinguished by hyposecretion or hypersecretion of leptin, referred to as ‘Type 1 obesity’ and ‘Type 2 obesity’, respectively.

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.