Reviews & Analysis

Whether and how host energy metabolism can be controlled by commensal microorganisms remains controversial. New work shows that the microbe-derived metabolite δ-valerobetaine contributes to obesity and hepatic steatosis by modulating mitochondrial fatty acid oxidation and increasing lipid storage in the adipose tissue and liver.

Tilg et al. explore how metabolic dysfunction, altered gut microbiome and dysregulated innate and adaptive immunity contribute to NAFLD and how the interplay between these factors mediates disease progression.

Levine and colleagues demonstrate that the effects of caloric restriction on hepatic gene expression, circulating acylcarnitines and body temperature are largely mediated by an increase in the daytime peak of NADH concentration in the liver.

Lipolysis generates fatty acids that are burned in peroxisomes for energy, and dysregulation in this process creates toxic reactive oxygen species (ROS) and contributes to diseases such as non-alcoholic fatty liver disease. In this issue of Nature Metabolism, Ding et al. reveal how the peroxin PEX2 senses cellular ROS to fine-tune ATGL-mediated lipolysis.

Zechner and colleagues discuss mechanisms facilitating the mobilization of intracellular fatty acids and how they affect lipid-mediated signalling, metabolic regulation and energy homeostasis in health and disease.

Two studies unmask the essentiality of methionine synthase activity in powering the folate cycle to replenish the tetrahydrofolate pool from 5-methyltetrahydrofolate; this generates nucleotides that support tumour growth. Dietary manipulation alters folate availability and holds implications for anti-cancer therapy response.

Immune cells can promote the thermogenic phenotype of white adipocytes during cold exposure, in a process known as ‘browning’ or ‘beiging’. Wang et al. now reveal a potential mechanism whereby alternatively activated macrophages prompt adipose sympathetic nerve fibres to release norepinephrine and promote adipocyte beiging.

Alterations to the extracellular matrix have long been associated with cancer progression and therapeutic resistance. Schwörer et al. describe a mechanism whereby fibroblasts reroute metabolites to fuel the demands of collagen synthesis, leading to cancer progression.

A recent study shows how hyperinsulinaemia in obesity unexpectedly activates the cell cycle of overworked mature adipocytes in a process known as endo-reduplication, which represents a ‘last gasp’ strategy to remain functionally competent. However, this strategy fails and triggers premature senescence and tissue dysfunction.

Incorporating one-carbon molecules into metabolic engineering has involved altering central metabolism, which must overcome metabolic regulation. Developing one-carbon metabolic pathways that are orthogonal to central metabolism offers a promising alternative for bioproduct synthesis. Here, Chou, Lee, Zhu et al. describe an orthogonal pathway that has the potential for bioproduct synthesis from one-carbon molecules and can be independent of central metabolism.

Small extracellular vesicles (SEVs) can be used for the selective delivery of therapeutic agents from the blood to the brain. Milbank et al. make use of SEVs to selectively target neurons in the ventromedial hypothalamus of mice, extending this exciting approach to potential applications for the treatment of obesity.

In this study, the serine biosynthetic enzyme PHGDH is shown to transition from the cytosol to the nucleus following nutrient stress. Nuclear PHGDH reduces local NAD⁺ availability needed for the PARylation of the transcription factor c-Jun. Consequently, c-Jun activity is reduced, contributing to sustained cancer cell proliferation.

Wiley and Campisi discuss metabolic inducers of senescence and alterations in cellular metabolism associated with senescence, while pointing out interventions that target metabolic processes to mitigate senescence.

Dysfunctional efferocytosis impairs clearance of apoptotic cells in disease. A new study shows that glutamine catabolism supports efficient apoptotic cell efferocytosis via non-canonical glutamine transamination but not canonical GLUD1-dependent α-ketoglutarate production, in a process that may operate in human atherosclerosis.

The fasting-mimicking diet is a five-day cycle of near total fasting each month that extends healthspan in male mice. In this issue of Nature Metabolism, Mishra et al. demonstrate life-extending and cardioprotective benefits of the fasting-mimicking diet in middle-aged female mice that are consuming a high-fat diet.

Tumour necrosis factor is a classical pro-inflammatory cytokine. Sethi and Hotamisligil provide a comprehensive overview of its pleiotropic immunometabolic actions, while presenting a framework that is applicable to the complex network of other pro-inflammatory signals and their relevance to metabolic diseases such as obesity and diabetes.

In this instalment of Career pathways, James White and Wenjing Du reflect on the importance of recruiting the right people, staying excited and making work and home life coexist.

Over-nutrition is a major driver of obesity, but the mechanisms that promote and perpetuate it remain poorly understood. A recent study explores a role for umami taste in driving leptin resistance, hyperphagia and hypothalamic inflammation via overproduction of uric acid.

When is a calorie not just a calorie? In the current issue of Nature Metabolism, Roy et al. use recombinant inbred strains of mice to investigate the role of genetic background in the response to dietary fat. Notably, both lifespan and weight gain have been found to be highly dependent on genotype, thus highlighting the need for a personalized approach to dietary interventions.

The maternal diet can impact offspring development, yet the mechanisms responsible for this remain largely unknown. New research shows that oocyte metabolites, specifically NAD⁺ and the methyl donor S-adenosylmethionine, can mediate the impact of maternal nutrient stress on the progeny through metabolic reprogramming in Drosophila.