Volume 1 Issue 1, January 2019

Over the past decade, the field of metabolism has witnessed remarkable scientific discoveries that reshaped the understanding of metabolic physiology and disease. As we launch Nature Metabolism, we look at what the future holds for metabolic research.

Many commonly used inbred mouse strains carry random mutations that can affect the results of metabolic studies. Yet, awareness of such mutations as a source for experimental variation and seemingly contradictory results is lacking. It is time that scientists pay more attention to the identification, tracking and accurate reporting of mouse strains used in experiments.

Strategies to restore levels of the enzyme cofactor nicotinamide adenine dinclueotide (NAD) late in life to maintain health by treatment with NAD precursors, such as nicotinamide mononucleotide (NMN), represent an exciting area of research in aging and age-related diseases. A study in Nature Metabolism provides an answer to the hotly debated yet fundamental question: how NMN actually gets into cells.

Cholesterol accumulation in cells and blood vessels promotes the development of vascular diseases. The long non-coding RNA CHROME can help clear excess cholesterol and provide protection from atherosclerosis.

Fibrosis is characterized by excessive extracellular matrix (ECM) production relative to catabolism. A new study shows that the fuel choice of fibroblasts impacts this balance, with glycolysis promoting ECM synthesis and fatty acid oxidation stimulating ECM degradation.

The growth of new blood vessels (angiogenesis) is a bio-energetically demanding process. Surprisingly, the specific role of mitochondria in angiogenesis remains unclear. A study in this issue of Nature Metabolism now demonstrates that mitochondrial respiration is essential for angiogenic growth by controlling endothelial proliferation.

Intermediate metabolites of the Krebs cycle serve bioenergetic and biosynthetic needs but have recently also been linked to signalling. The authors of this Review summarize such non-metabolic signalling functions of succinate, fumarate, itaconate, 2-hydroxyglutarate isomers and acetyl-CoA in both immune cells and cancer cells.

The gut microbiome has emerged as an important regulator of host physiology and disease, including metabolic diseases. Here Cani et al. provide a broad overview of mechanisms through which the gut microbiota affects metabolic regulation in the host.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD⁺, but how NMN is taken up into cells has not been entirely clear. Here the authors discover a specific NMN transporter, encoded by the Slc12a8 gene, which regulates NMN uptake and cellular NAD⁺ levels in vitro and in the mouse intestine in vivo.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut incretin hormone released in response to nutrients. Here, the authors report an anti-inflammatory and antiobesogenic mechanism of GIP by showing that loss of GIP receptor signalling in myeloid cells promotes pro-inflammatory S100A8/A9 release in adipose tissue.

The metabolic dependencies of androgen receptor (AR)-driven growth in prostate adenocarcinoma are largely unknown but could represent a therapeutic target when hormonal manipulations fail. Here the authors demonstrate that the mitochondrial pyruvate carrier (MPC) is transcriptionally regulated by AR and that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions.

Obese and dysfunctional adipose tissue is known to be hypoxic. Here the authors show that adipocyte oxygen consumption increases early after onset of high-fat diet feeding owing to activation of the mitochondrial protein ANT2 and that specific inhibition of ANT2 reduces adipose tissue hypoxia, inflammation and insulin resistance.

Maintenance of cholesterol homeostasis is essential to human health. Here, the authors identify and characterize a primate-specific long noncoding RNA, called CHROME, that controls cholesterol homeostasis through fine-tuning of miRNAs and whose levels are elevated in human atherosclerosis.

Transferrin receptor 2 (Trf2) is known to regulate iron homeostasis through its action in the liver. Here the authors report a previously unrecognised role of Trf2 in regulating bone homeostasis mediated by modulation of BMP signalling specifically on osteoblasts.

Despite the similarity of metabolic flux patterns in different organisms, the underlying governing principles remain unclear. Using a constraint-based thermodynamic–stoichiometric model as well as quantitative metabolome and physiological data, Niebel et al. identify an upper limit on the cellular Gibbs energy dissipation rate, which could shape metabolism across organisms.

Impaired adipocyte insulin signalling characterizes insulin resistance. Here the authors show that the hormone-sensitive lipase can sequester the glucose-responsive transcription factor ChREBP in the cytoplasm, which prevents transcription of its target ELOVL6, resulting in reduced insulin signalling.

Extracellular matrix (ECM) homeostasis is essential for normal tissue function, and its perturbation by injury, trauma or disease results in fibrosis. Here, the authors show that glycolysis and the fatty acid oxidation pathway regulate fibroblast behaviour and have reciprocal effects in ECM upregulation and downregulation, respectively.

Endothelial cells (ECs) require glycolysis during angiogenesis; however, the function of the mitochondrial respiratory chain during this process is unclear. Here the authors show that mitochondrial respiration in ECs is required for angiogenesis as the biosynthetic role of mitochondria is needed for EC proliferation.