Volume 3 Issue 10, October 2021

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.

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.

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.

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.

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.

Merlin et al. find that non-canonical glutamine transamination is required for macrophage efferocytosis in atherosclerotic plaques by sustaining redox buffering and fueling energy production for cytoskeletal rearrangements.

Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

While on a high-fat, high-calorie diet, a monthly cycle of 5 days of a fasting-mimicking diet can prevent obesity and related detrimental effects on cardiometabolic health and lifespan in mice.

Ma et al. find that PHGDH, which catalyses serine metabolism in the cytoplasm, transits to the nucleus during nutrient stress, where it promotes cell growth and tumorigenesis.

By using an integrated omics approach, a landscape of metabolic remodelling of early-stage mouse embryogenesis is reconstructed, identifying key metabolites for epigenetic reprogramming.

Chou, Lee and Zhu et al. describe a synthetic metabolic pathway for C1 compound utilization using formate, formaldehyde and methanol as substrates.

Syt7-dependent pancreatic insulin release is shown to be mediated by 5-IP₇ in response to parasympathetic stimulation of the GPCR M3R.

Milbank et al. show that specific targeting of AMPKα1 in SF1 neurons of the VMH through systemic injection of small extracellular vesicles causes weight loss via increased brown adipose tissue thermogenesis.