Volume 5 Issue 5, May 2023

In this instalment of Career pathways, we hear from Gerta Hoxhaj and Ed Reznik about how they followed their passion for science, the value of collaborations and mentors, asking big questions and how to think differently about metabolism.

Most of human microbiome research has focused on analysing faecal samples, which represent the final stop of the digestive journey. Two recent articles use a novel sampling approach to capture luminal content at different points during digestion and reveal that the analysis of faecal samples tells only a fraction of the story.

How mammals enter hypometabolic states, known as torpor and hibernation, has fascinated researchers for decades, but the central control mechanisms that regulate entry into torpor have surfaced only recently. Yang and colleagues demonstrate that torpor-like hypometabolic states can be induced non-invasively by ultrasound, providing new routes for exploiting the underlying mechanisms and biomedical applications of this process in the future.

Glycolysis provides building blocks for the proinflammatory activation of macrophages and simultaneously generates pyruvate. In this issue of Nature Metabolism, Ran et al. provide evidence that the transport of pyruvate to fuel the Krebs cycle in the mitochondria is not required in the inflammatory response.

M⁶A RNA modifications mediate RNA processing and stability. Ceramides are lipid metabolites containing an amino acid-based backbone, which promote metabolic dysfunction. Wang et al. describe a novel m⁶A-dependent regulatory node that tunes ceramide-generating enzymes.

Functional genomic analyses reveal a complex relationship between the COBLL1 gene and metabolic health, as well as how the same variant can both reduce body fat and increase the risk of type 2 diabetes.

In this issue of Nature Metabolism, a gut bacterial glucosidase that degrades the antidiabetic drug acarbose is linked to poor treatment response. Its widespread distribution in the human microbiome could compromise the efficacy of acarbose treatment in many patients.

Kim and colleagues discuss the regulatory mechanisms of lipogenesis, the physiological and pathological role of lipogenesis in tissues such as adipose tissue, liver, neurons and cancer, and how lipogenesis may be targeted therapeutically to ameliorate disease.

In this study, Skinner, Blanco-Fernández et al. show that uridine can be salvaged through the non-oxidative branch of the pentose phosphate pathway to feed glycolysis in conditions of glucose scarcity.

The authors use a non-invasive sampling device to collect intestinal samples in 15 healthy male and female participants and analyse them through mass spectrometry and 16S rRNA sequencing. They identify thousands of biomolecules throughout the intestinal tract, many of which remain unknown and highlight differences between intestinal and stool metabolomes.

Using ultrasound to activate noninvasively specific neurons in the hypothalamus, a temporary hypothermic and hypometabolic state is induced in rodents.

Previous work using chemical inhibitors has reported the need for the mitochondrial pyruvate carrier for the classical activation of macrophages. In this study, Ran, Zhang et al. use a genetic approach to show that LPS-stimulated macrophage activation does not require the import of pyruvate into mitochondria.

Lin et al. show that small extracellular vesicles derived from SIRT2-deficient hepatocytes inhibit osteoclast differentiation from mouse and human bone-marrow-derived monocytes and alleviate bone loss in mouse models of osteoporosis.

Wang et al. show that the RNA methyltransferase Mettl3 contributes to hepatic sphingolipid homeostasis by promoting RNA decay of the sphingomyelinase Smpd3 during postnatal liver development, with Mettl3 deficiency leading to ceramide accumulation and liver developmental defects.

Glunk et al. explore target genes and cellular mechanisms related to a metabolic obesity with normal-weight phenotype, and identify a non-coding variant that affects actin remodelling in subcutaneous adipocytes, which in turn affects the capacity of these cells to accumulate lipids.

Results from a randomized clinical trial show that adding exercise to diet-induced weight loss can improve beta-cell function, measured as late-phase disposition index, in people with newly diagnosed type 2 diabetes.

The antidiabetic drug acarbose is shown to be degraded by a Klebsiella species present in the human gut, which is enriched with acarbose treatment and might mediate acarbose resistance and variations in clinical efficacy observed in patients.