Reviews & Analysis

The molecular underpinnings of the extensive cellular, morphological and functional plasticity of skeletal muscle in exercise training are poorly understood. We have now begun to unravel the complex epigenetic, transcriptional and proteomic networks that determine the muscle response to exercise in a manner depending on the training state.

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.

Mishra and Townsend present an overview of the regulation, function and plasticity of adipose tissue sensory nerves that are relevant for metabolic processes in health and disease.

A mouse pancreatic islet atlas comprising over 300,000 single-cell transcriptomes was integrated from nine biologically diverse datasets to unify existing knowledge in the islet biology community. This interactively accessible resource reveals new insights into the molecular identity and plasticity of islet and β-cells across sex, life span and diabetes progression.

Sa et al. identified a distinct neuronal subpopulation that controls brown adipose tissue thermogenesis. In mice fed a high-fat diet, hypothalamic GABRA5 neurons are deactivated by GABA released by surrounding astrocytes and inhibition of GABA synthesis ameliorates diet-induced obesity.

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.

In this Review, TeSlaa, Ralser, Fan and Rabinowitz comprehensively review the fundamental biochemical aspects of the pentose phosphate pathway and discuss its biological relevance in the context of physiology and pathology.

Rosenbaum and Foster discuss the metabolic underpinnings of weight loss and weight loss maintenance, as well as the implications of considering them as distinct metabolic states for the treatment of obesity.

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.

Sensory association learning is impaired in people with insulin resistance but can be restored following a one-time intervention with liraglutide. These findings provide ample evidence for metabolic signals as modulators of adaptive behaviour and suggest a potential role for GLP-1 receptor agonists in obesity management.

The relationship between stress and gastrointestinal function is poorly understood and of major clinical importance as a potential contributor to irritable bowel syndrome, functional dyspepsia and numerous other disorders of gut–brain interaction. A recent study investigates a descending neural circuit that regulates gastric motility and is inversely modulated by chronic versus acute stress.

By combining multimodal metabolomics technologies to investigate colorectal tissues and tumours in situ, Vande Voorde et al. found tumour genotype-specific metabolic profiles and revealed the methionine-cycle enzyme AHCY to be a potential therapeutic target in colorectal cancer.

By using a combination of transcriptomics, primary adipocyte culture and experimental medicine approaches, we identified the sodium-dependent serotonin transporter SERT as a novel regulator of human brown adipose tissue function.

Methionine restriction modulates tumour growth and ageing processes through its influence on diverse metabolic processes. Ji et al. demonstrate that methionine restriction compromises production of hydrogen sulfide (H₂S), which impairs H₂S-mediated immune signalling and results in increased cancer progression in immunocompetent mice.

Lynch and colleagues give an overview of the classical roles of the cytokine IL-17 in host immunity, and look deeper into the emerging roles of IL-17 in cross-talk between the nervous system and gut and how IL-17 regulates and is regulated by systemic metabolic processes.

Astrocytes are usually viewed as archetypical glycolytic cells. A study now shows that fatty acid oxidation in astrocytes rearranges the respiratory chain to a configuration that safeguards neuronal functionality and proper cognitive performance in mice.

Cook and colleagues discuss the nature of hepatic insulin resistance and argue that liver hyperinsulinization (excessive hepatic insulin action) is a driver of hepatic steatosis.

Mao et al. discover that heart failure-associated metabolic derangement results in cardiomyocyte cholesterol overload and accumulation of bile acid intermediates, which in turn trigger mitochondrial damage and inflammatory activation and thus promote heart failure.

Impaired tricarboxylic acid cycle and oxidative phosphorylation cause reduced energy content in neurons upon neuroinflammation and contribute to axonal degeneration in multiple sclerosis.

This study shows that a 10% weight loss induced by calorie restriction and multimodal exercise training results in a much greater increase in whole-body insulin sensitivity than matched weight loss induced by calorie restriction alone. This result underscores the importance of adding regular exercise to a weight loss programme, as it improves metabolic health.