Volume 5 Issue 10, October 2023

Bilal Sheikh and Yuxiong Feng share their scientific journey and how it has taken them around the world and given them freedom to pursue their curiosity and own ideas. They share the passion that drives their research and highlight the importance of building a strong, collaborative and complementary team.

Brown adipose tissue has a crucial role in regulating body temperature in mammals. Recent research delves into the notion of thermogenic memory and identifies a subset of adipocytes that enhance the response to repeated stimulation events via de novo lipogenesis.

In this issue of Nature Metabolism, a study shows that glutarate increases memory T cells as well as T cell cytotoxicity and reduces tumour growth. During T cell activation, glutarate levels and glutarylation increase. Glutarate inhibits α-ketoglutarate-dependent dioxygenases, and glutarylation reduces pyruvate dehydrogenase complex activity and enhances glycolysis.

Okreglak et al. explore the molecular mechanisms that link organellar pH dynamics with the cell cycle, and find that vacuolar pH oscillates during cell cycle phases to ensure an adequate supply of amino acids during cell division. This study offers metabolic insight into the fundamental mechanisms that couple amino acid availability to the cell cycle through pH fluctuations.

Glucagon-like peptide 1 (GLP-1) controls insulin secretion and body weight through activation of its receptor, GLP1R. Large-scale functional analysis of 60 GLP1R genetic variants revealed that loss-of-function (LoF) phenotypes, in particular of cell surface expression, are associated with impaired glucose control and increased adiposity.

This Review article discusses how the emerging field of metabolomic epidemiology gives insight into the aetiology of various diseases and how these findings could be translated into clinical applications.

Gao et al. perform functional profiling of 60 genetic variants of glucagon-like peptide 1 receptor (GLP1R) in vitro, and link variants with impaired GLP1R cell surface expression or cAMP activation to defective insulin secretion in vitro and to impaired glucose homeostasis and adiposity in the UK Biobank.

The authors develop synthetic biotics, engineered from bacteria, that could treat phenylketonuria, an inherited defect of phenylalanine (Phe) metabolism.

Lundgren et al. show that in response to transient cold exposure, a distinct subpopulation of brown adipocytes carries out a lipogenic response involving production of acylcarnitines, which enables an improved thermogenic response to secondary cold exposure.

Yao and Gong et al. identify WD40 repeat-containing protein 6 (WDR6) to be upregulated in the liver of insulin-resistant mice. WDR6 contributes to promoting hepatic de novo lipogenesis during insulin resistance by upregulation of fatty acid synthase, and the authors identify a small molecule to inhibit this effect of WDR6 and reduce hepatic steatosis.

This study presents a comprehensive pipeline to profile transmembrane receptors involved in macrophage-driven inflammation in pancreatic islets during the onset of diabetes. The authors identify GPR132 as a mediator of macrophage-driven inflammation and find compounds that reduce inflammation and improve glycaemic control.

Minogue et al. show that glutarate, a metabolite derived from tryptophan catabolism, has the ability to shape anti-tumour T cell responses by modulating pyruvate handling and alpha-ketoglutarate-dependent dioxygenases.

In this study, Wang et al. show that the glycolytic metabolite phosphoenolpyruvate, produced by enolase 2, contributes to colorectal cancer malignancy and resistance to antiangiogenic therapy by inhibiting endogenous histone deacetylase 1 and favouring β-catenin signalling.

TMEM164 is an early-response intrinsic factor that inhibits the induction of neurotoxic reactive astrocytes, and whose astrocyte-specific overexpression alleviates the symptoms of neurodegenerative diseases in mice.

In this study, Okreglak et al. identify dynamic regulation of pH in the lysosome-like vacuole of growing S. cerevisiae cells and link pH dynamics in this subcellular compartment to amino acid release into the cytoplasm to meet metabolic demands during cell cycle progression.

Miller et al. use fast thermal preservation and mass spectrometry imaging to reveal rapid neuron-layer metabolic responses to stimulation within a brain slice. Stimulation increases glucose use and converts spent ATP into metabolic fuel, via inosine.