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In this issue of Nature Metabolism, it is shown that the abundance of Caenorhabditis elegans branched-chain aminotransferase-1 (BCAT-1) — which catalyses the first step of branched-chain amino acid (BCAA) catabolism — declines sharply in aged wild-type nematodes but not in slowly ageing mutants, and that stimulating BCAA catabolism extends reproductive longevity.
In male mice with diet-induced obesity, deletion of insulin inhibitory receptor (inceptor) in the whole body, in the brain and in pancreatic β cells improves glucose homeostasis, underlining a role of inceptor in regulating glucose homeostasis in the brain and pancreas.
The microbiome is implicated in a study that involves the metabolism of dietary fibre into short-chain fatty acids, which provides a biochemical link to the poorly understood histone butyrylation.
The authors report a genetic screening method that preserves mitochondrial physiology under cell permeabilization, which allows in-depth genetic dissection of mitochondrial bioenergetics.
Gates et al. show that histone butyrylation and propionylation in the intestinal epithelium are regulated by the gut microbiota and histone butyrylation is associated with gene regulatory programmes.
Resistant starch is a prebiotic fibre that is fermented by the gut microbiota and leads to benefits for host physiology. A clinical trial in Nature Metabolism demonstrates weight loss when resistant starch was given to individuals with excess weight.
Individuals with osteoporosis have increased risk of Alzheimer’s disease or cognitive impairment during ageing. We elucidated a partial explanation for bone dysmetabolism’s association with such cognitive decline, by demonstrating how elevated sclerostin secretion from osteocytes in bone impaired cognitive function in aged mice and in an Alzheimer’s disease mouse model.
The authors show that abnormal elevation of osteocyte-derived sclerostin deregulates Wnt–β-catenin signalling in the brain and aggravates cognitive impairment under pathological conditions.
In a randomized placebo-controlled trial in 37 individuals with excess body weight, dietary supplementation with resistant starch lowers body weight and induces changes in gut microbiota composition. Mechanistic analysis in male mice shows that resistant starch at least partially facilitates weight loss through the action of Bifidobacteriumadolescentis.
The immunosuppressive metabolic tumour microenvironment in solid tumours limits the antitumour activity of cell-based immunotherapy. In this Perspective, McPhedran et al. propose a framework to overcome this issue by engineering metabolic networks in T cells to enhance chimeric antigen receptor T cell efficiency
Non-alcoholic liver disease (NAFLD) is now metabolic dysfunction-associated steatotic liver disease (MASLD), emphasizing the key metabolic factors of obesity, insulin resistance, vascular dysfunction and dyslipidaemia. Here, we discuss impacts on the existing body of clinical and preclinical liver disease research and on research moving forward.
Succinate can be released from contracting skeletal muscle and accumulate in brown adipose tissue (BAT) to drive thermogenesis and protect against obesity. A study in this issue of Nature Metabolism uncovers the mechanistic underpinnings of BAT succinate sequestration through MCT1-dependent uptake and cytosolic pH changes, thus strengthening the role for cellular shuttling of succinate in the control of systemic energy homeostasis.
Hypothalamic neural pathways control appetite and food intake, and thereby influence body weight and metabolism. De Solis et al. apply chemogenetics to simultaneously manipulate two subpopulations of hypothalamic neurons. Using this approach, the authors identify a pathway that regulates feeding behaviour.
In the context of succinate uptake to promote adipose tissue browning, Reddy, Winther et al. show how the directionality of succinate transport across membranes is coupled with metabolic flux-derived changes in pH gradients.
De Solis and Del Río-Martín et al. investigate the reciprocal interplay between AgRP and POMC neurocircuits that governs the precise regulation of food intake and systemic metabolic homeostasis.
Glycerol-3-Phosphate (G3P) and phosphoethanolamine (pEtN) biosynthetic pathways are modulated during senescence establishment to sustain lipid droplet accumulation and senescence-associated secretome. These findings reveal new targets for an immunomodulatory approach against senescent cells.
Although obesity is associated with higher risk of cardiometabolic disease, high-protein diets can reduce fatness but still promote cardiometabolic disease. Zhang et al. address this contradiction and show that high-protein diets, and subsequently higher blood leucine levels, promote mTORC1 activation in macrophages in humans and mice, and that an increase in dietary leucine raises the risk of atherosclerosis in a mouse model.
Zhang et al. use human studies and mechanistic work in mouse models to describe how leucine serves as the key amino acid derived from dietary protein to drive deleterious macrophage mTORC1 signalling and promote cardiovascular disease.