Reviews & Analysis

Under a high-fat diet, the amyloid precursor protein, which is involved in the development of Alzheimer’s disease, accumulates at the protein-entry gate of mitochondria in white adipose tissue, thus leading to mitochondrial dysfunction, adipocyte hypertrophy and obesity.

Pancreatic islets are heterogeneous clusters of endocrine cells responsible for glucose homeostasis. Here Noguchi and Huising review the main stimuli for each islet-cell type and their response, guided by insights from islet-cell transcriptomes.

GDF15 is an anorectic hormone that relays systemic stress to the brain. In the current issue of Nature Metabolism, Day et al. elegantly demonstrate that the frontline anti-diabetes drug, metformin, lowers body weight by increasing circulating levels of GDF15.

Systemic homeostasis is finely orchestrated by the action of several organs and molecules. Here Priest et al. provide a comprehensive review that highlights the inter-organ communication complexity in metabolic regulation.

Di Gioia and colleagues report on how the oxidized phospholipid oxPAPC alters metabolism in macrophages via glutamine and oxaloacetate, thus boosting production of the cytokine IL-1β and promoting atherosclerosis.

A study in Nature Metabolism reveals a hitherto-unknown enzymatic and physiological role of ABHD5, which acts as a protease that couples extracellular cues to the epigenome of cardiomyocytes by cleaving histone deacetylase 4 (HDAC4).

A new study by Menegaz et al. in this issue of Nature Metabolism addresses fundamental questions on the acute regulation and role of GABA secretion in pancreatic islets.

The mechanism of alcohol-induced changes in the brain is multi-faceted. Acetate, the product of hepatic alcohol metabolism, might contribute to addictive behaviour by regulating gene expression.

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.