Volume 4 Issue 2, February 2022

GDF15 is a hormone with the potential to regulate energy intake. GDF15 signals via the GFRAL/RET receptor complex, and besides the ligand activation of the receptor complex, our knowledge on control of receptor signalling is limited. Chow et al. show that MT1-MMP controls GDF15 actions by regulating levels of GFRAL.

Although glucose classically serves as the main neuronal fuel source in the brain, Silva et al. demonstrate that ketones produced by local glial cells are critical for memory formation in starving flies. Here we discuss the implications of these findings for aging, neurodegeneration and the genetics of ketone metabolism.

Enzyme–enzyme interactions are largely assumed to act co-operatively to render biochemical pathways more efficient. However, under stress the glutamate synthase of B. subtilis does the exact opposite: it inhibits glutamate degradation by sterically hindering the activity of glutamate dehydrogenase.

This Perspective summarizes the ongoing development of CAR-based therapies in indications beyond cancer, including for cardiometabolic diseases, fibrosis, autoimmune diseases and ageing.

Interleukin 6 is a pleiotropic cytokine that can be pro- or anti-inflammatory, depending on the metabolic context. Kistner et al. propose that these context-dependent effects are due to its adaptive role for short-term energy allocation, particularly during physical activity.

Fujimaki et al. show that soluble Dll4 from endothelial cells triggers atrophy in myofibres via Notch2 signalling, suggesting Dll4 as a therapeutic target for muscle atrophy.

Maqdasy, Lecoutre et al. show that increased an phosphocreatine/creatine ratio in white adipocytes drives changes in AMP-activated protein kinase activity and promotes white adipocyte inflammation during obesity.

The GDF15–GFRAL axis is key for regulating energy homeostasis and body weight. Membrane-bound matrix metalloproteinase 14 is shown to negatively regulate GFRAL, whereas its downregulation protects against diet-induced obesity through increased GDF15 signaling.

In the Drosophila starved brain, memory formation undergoes adaptive plasticity. Silva et al. show that neurons in the olfactory memory centre of the starved fly are fuelled by glial-derived ketone bodies in order to sustain memory formation.

Mutant p53 protein is stabilized by direct binding to 2-HG produced by malic enzyme 2, resulting in enhanced tumour growth.

Zhao et al. report a role for glutamine synthetase in regulating cell proliferation that does not require the catalytic activity of the enzyme.

Hirano et al. show that expression of the MYC family member Mycl in adult pancreatic islets can increase proliferation and expand the functional β-cell population, thereby improving glucose control.

Zhong, Wan and Cai et al. show that deficiency of the microsomal prostaglandin E synthase-2 (mPGES-2) in pancreatic β-cells improves glucose metabolism and insulin secretion in mice by inhibiting β-cell senescence and dysfunction during diabetes.

Fasolino et al. provide insights into ductal cell roles and type 1 diabetes pathogenesis using a pancreatic islet single-cell atlas generated by the Human Pancreas Analysis Program.