The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in Nature, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.

Two homologous catalytic subunits, AMPKα1 and AMPKα2, exist in AMPK complexes. Mao et al. find that AMPKα2 specifically responds to amino acid insufficiency to inhibit protein translation. Loss of AMPKα2 causes increased protein synthesis and induces Alzheimer’s disease (AD)-like symptoms in mice, whereas amino acid restriction or AMPK activation α2-dependently prevents these symptoms.

Yin et al. show that paternal exercise improves offspring endurance capacity and metabolic health via sperm microRNAs that reprogram gene expression in early embryos, revealing how exercise benefits can be inherited across generations.

Picard and Murugan introduce the energy resistance principle (ERP), a testable framework outlining how resistance to energy flow sustains life and shapes health. Excess resistance (éR) promotes hallmarks of disease, whereas restorative states minimize éR, thus linking the biophysics of energy to human health, aging, and healing.

Zhang et al. reveal that the gut bacterium Catenibacterium mitsuokai promotes hepatocellular carcinoma by disrupting the gut barrier, colonizing HCC cells via its surface protein Gtr1/RagA and receptor γ-catenin, and secreting quinolinic acid, which binds to TIE2 and activates the oncogenic PI3K/AKT pathway in HCC cells.

Li et al. demonstrate that fatty livers foster a favorable metabolic landscape for breast cancer via adipocyte-oriented exosomes. These exosomes display tropism to mammary adipocytes through the ErbB4-Nrg4 axis. Exosomal TRMT10C triggers adipocyte ROS production, boosts IL-6 secretion, and subsequently enhances free fatty acid release, thereby facilitating tumor initiation and growth.

Cao et al. show that hepatic hydrolysis of acetyl-CoA by acyl-CoA thioesterase 12 serves as a crucial source of circulating acetate mediating liver-brain communication, which signals the brain to buffer stress via bolstering immunomodulatory checkpoint molecule expression in astrocytes to limit neuroinflammation.

Xiao et al. conducted a systematic investigation into the crucial immuno-metabolic crosstalk within triple-negative breast cancer. They found that HEBP2 promoted FOXA1 nuclear translocation to upregulate GSTP1 expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing antitumor immunity. Targeting GSTP1 could sensitize immunotherapy.

Unal et al. engineered a cholesterol-responsive genetic circuit, which was designed to sense and counteract the elevated levels of cholesterol in circulation. The circuit managed to attenuate a healthy cholesterol profile in a murine model of experimental dyslipidemia within days upon intraperitoneal implantation.

Metabolomic profiling of chemoresistant AML shows branched-chain amino acid accumulation that fuels protein translation. Mayerhofer et al. identify the ribosomal hydroxylase OGFOD1 as a regulator of this BCAA-dependent protein synthesis program, linking its activity to post-chemotherapy relapse.

Muñoz et al. show that circulating metabolites are differentially enriched in portal versus peripheral blood. Enrichment patterns are influenced by diet, host genetics, and the gut microbiome. These metabolites, especially mesaconate/itaconate/citraconate isomers, can directly influence hepatic insulin signaling and gene expression, highlighting an important role in obesity-linked insulin resistance.

Metabolic and reproductive abnormalities are closely interconnected in polycystic ovary syndrome (PCOS). In this perspective, Zhang et al. propose a conceptual framework positioning metabolic dysfunction as a critical contributor to PCOS pathogenesis and inheritance, highlighting emerging metabolic interventions that offer new therapeutic opportunities for this complex disorder.

Xian et al. report an elevation of H2S in the anterior cingulate cortex of two mouse models of autism spectrum disorders (ASDs) and their corresponding human neurons. Over-sulfhydration of synaptic proteins, e.g., mGluR5, contributes to the synaptic and social deficits of these two ASD models.

This randomized controlled nutrition intervention conducted in males of reproductive age shows that, compared with an unprocessed diet, consumption of ultra-processed foods impairs metabolic and reproductive health. Effects of ultra-processed foods were independent of caloric load, providing evidence that the ultra-processed nature of food is detrimental to health.

(Cell Metabolism 23, 206–219; January 12, 2016)

Lin et al. discover homocysitaconate, an anti-inflammatory metabolite formed during inflammation via AHCY-catalyzed adduction of homocysteine and itaconate. Homocysitaconate is recognized by MARS, inducing an N-homocysteinylation metabolic shift that leads to NLRP3 inhibition. Exogenous homocysitaconate supplementation and endogenous homocysitaconate boosting (via NAD+-dependent AHCY activation) offer novel therapeutic strategies for inflammatory disorders.

Noncanonical clock regulators bridge genetics and nutrition to mediate 3D enhancer-promoter interactions, contributing to diurnal rhythm variation and metabolic disease risk.

Hansford et al. show that GIPR, a target of new weight-loss drugs, is found in brain cells called oligodendrocytes. GIPR helps these drugs access the brain and boosts weight loss. Without GIPR in these cells, the drugs are less effective, revealing a new mechanism behind their action.

Liu et al. show that diabetes induces immunosuppressive Schwann cells via lactate-METTL16-CTCF signaling in PDAC, promoting PD-1 resistance. Targeting this pathway restores anti-tumor immunity and enhances therapy, providing key insights into metabolic-immune interactions and offering a promising strategy to improve immunotherapy outcomes in patients with high risk.

Bernardo et al. uncover a transcription-splicing regulatory axis driven by HNF1A and A1CF in pancreatic β cells. Targeted perturbations, single-cell studies, and human genetic evidence demonstrate that failure of this network leads to defective β cell function and glucose homeostasis.

Glucose is required for T cell proliferation and function, but its key metabolic fates in vivo are not well defined. Longo et al. demonstrate that in CD8+ effector T cells, glucose metabolism extends beyond energy production by fueling glycosphingolipid biosynthesis, a pathway critical for T cell expansion and cytotoxic function.

D-lactate from the gut microbiota influences blood glucose and fatty liver disease. Trapping D-lactate in the gut improves blood glucose and lowers liver inflammation and fibrosis during obesity.

Shi et al. demonstrate that CD8+ T cell-mediated elimination of high-XYLB tumor cells releases relatively high Xu5P, establishing a feedforward loop to sustain Xu5P-responsive SLC35E2+ CD8+ progenitor-like exhausted T cell effector expansion and suppress metastasis. Xu5P supplementation enhances antitumor immunity and synergizes with PD-1 blockade therapy.