Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), improve obesity and type 2 diabetes (T2D). Both surgeries affect the gut microbiota, but their contribution to T2D remission remains unclear. In this subanalysis (RYGB, n = 39; SG, n = 38) of the randomized controlled Oseberg trial ( NCT01778738 ), in which participants underwent either RYGB or SG surgery, we profiled the faecal microbiome of individuals with obesity and T2D before and 12 months after surgery. We show that both surgeries altered the microbiome in the same direction, but with larger changes after RYGB. The SG-associated altered microbiome composition correlated positively with circulating glucagon-like peptide 1 levels, beta-cell function and 5 year T2D remission. Remission was also linked to increased gene richness and metabolic potential for fermentation, methanogenesis and butyrate production. Notably, these associations persisted after accounting for the extent of weight loss. Our findings indicate that surgery-specific microbial adaptations influence metabolic improvements and may help to explain heterogeneity in T2D remission after bariatric surgery.

Bile acids (BAs) flow through ducts lined by biliary epithelial cells (BECs), which preserve ductal integrity and liver homeostasis. Failure of this barrier causes BA accumulation in the liver parenchyma, and ultimately fibrosis. Here we show that BECs safeguard biliary barrier integrity and restrain BA-induced fibrogenesis through a cell-intrinsic mechanism involving farnesoid-X-receptor (FXR)-YAP signalling. Using a combination of mouse genetics, computational analysis and human samples, we show that BECs express FXR, which transcriptionally activates YAP to maintain their adhesion, thereby preventing BA efflux and subsequent FXR-dependent hepatic stellate cell activation and fibrosis in BA-dysregulated liver disease models. Genetic ablation of FXR or YAP in mouse BECs triggers β-catenin activation, mesenchymal-like conversion and BEC proliferation, promoting fibrosis-to-cirrhosis progression. Diminished FXR-YAP signalling in human BECs also parallels fibrosis severity. Consistently, obeticholic acid worsens fibrogenesis in mice with FXR-depleted BECs. Thus, BAs reprogram BECs into active guardians of tissue integrity via FXR-YAP-β-catenin signalling, preserving biliary identity and maintaining liver homeostasis.

Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.

Irisin is an exercise-induced myokine that confers multiple physiological benefits, including browning of subcutaneous adipose tissue (SAT) in mice. However, the underlying cellular and molecular mechanisms of irisin’s effects on obesity are unclear. Here, we show that irisin modulates adipose-tissue inflammation by increasing IL-33 production and preserving ST2+ regulatory T cells in white adipose tissues. Administered chronically to high-fat-diet-fed male mice, irisin preserves in visceral adipose tissue (VAT) levels of ST2+ regulatory T cells, an important immunomodulatory population that usually contracts after long-term high-fat-diet feeding. This protection results from increases in IL-33-producing mesenchymal stromal cells (mSCs) and IL-33 levels in VAT. These effects are primary, as irisin directly induces IL-33 expression in cultured VAT mSCs. Irisin-mediated changes in VAT IL-33 dynamics are accompanied by IL-33-dependent upregulation of thermogenic gene expression in SAT. These irisin-driven cell-cell and inter-tissue interactions improve obesity and glucose intolerance, and increase energy expenditure, with no reduced food intake and muscle loss in obese mice.

The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP-TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.

The hypothalamus regulates feeding and metabolic balance in response to metabolic cues. Here we report that extracellular vesicles (EVs) are secreted from the mediobasal hypothalamus in a diurnal manner that is influenced by daily feeding. Sox2-positive tanycytes have a critical role in maintaining the diurnal pattern of hypothalamic EV release. Inhibition of tanycyte EV release leads to a loss of feeding diurnality, weight control and blood glucose homoeostasis, whereas supplementation with tanycytic EVs confers metabolic benefits. We show that a subset of tanycytic EVs carries surface prepro-insulin (ppIns), which mediates recognition and uptake by insulin-receptor-positive hypothalamic neurons. These EVs are loaded with mTORC components, including Rictor in a low-phosphorylation state, and support hypothalamic neuronal signalling. Both ppIns and Rictor are important for the EV-mediated preservation of feeding rhythmicity and resistance to diet-induced metabolic dysfunction. Collectively, these findings identify tanycyte-derived EVs as regulators of feeding diurnality through insulin precursor-directed targeting and delivery of mTORC components to hypothalamic neurons.

Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer.