Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.10.01.679861

Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1

Kalafut, K. C.·Cormerais, Y.·Cisse, M. Y.·Lapp, S. C.·Inouye, K. E.·Hotamıslıgil, G. S.·Manning, B. D.
View original source ↗Export metadata ↓

Abstract

The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, while aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established several regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, a liver-specific mouse model that disconnects mTORC1 activation from AKT-mediated TSC2 phosphorylation is employed. This genetic mouse model demonstrates that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, dietary protein is critical and dictates the insulin-responsiveness of hepatic mTORC1 signaling. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity associated with the phenotypes of type-2 diabetes, including hyperinsulinemia, systemic insulin resistance, and hyperglycemia, and blocking hepatic AKT-TSC-mTORC1 signaling did not prevent these metabolic impairments. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kalafut, K. C., Cormerais, Y., Cisse, M. Y., Lapp, S. C., Inouye, K. E., Hotamıslıgil, G. S., Manning, B. D.. 2025-10-03. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1. https://doi.org/10.1101/2025.10.01.679861

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hummingbird torpor recapitulates key molecular signatures of hibernation without large-scale transcriptomic remodelling

Torpor is a physiological strategy used by which some species conserve energy by lowering metabolic rates and body temperatures. While mammalian hibernation is well-studied, the molecular mechanisms governing the rapid entry into avian torpor remain poorly understood. This study represents the first multi-tissue whole-transcriptomic analysis of torpor entry in an avian system. By combining real-time thermal imaging and respirometry with transcriptomic profiling across seven tissues, we identified the key molecular pathways orchestrating this transition in Anna's hummingbirds (Calypte anna). Our results reveal that avian torpor entry is characterised by a subtle transcriptomic change (<5% of the genome differentially expressed across tissues) compared to mammalian hibernation (10%-60%). Most of these genes are differentially expressed before torpor entry is complete, rather than tracking body temperature linearly. This indicates that active transcriptional reprogramming precedes and potentially drives the transition. Thus, hummingbird torpor entry is not a passive shutdown, but a highly regulated, tissue-specific process. Vital organs, such as the heart and lungs, remain transcriptionally stable to maintain essential functions, while the liver and gut exhibit extensive metabolic rewiring. We found evidence of global transcriptional and translational suppression, and cell-cycle arrest: the three major contributors to cellular energy budgets. We hypothesise that avian torpor entry is orchestrated through an arrest of apoptosis, a metabolic switch from carbohydrate to lipid utilisation, coupled with alterations in alternative splicing and circadian rhythm regulation. Finally, the counterintuitive upregulation of genes involved in mitochondrial metabolism suggests a preparation for rapid arousal despite the depressed metabolic state.

physiology↗
bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗
bioRxiv2026

Genetic Variation, Iron Status, and FGF23 Signaling Converge to Regulate Renal Calcium Buffering in Sickle Cell Disease

Sickle cell disease (SCD) causes heterogeneous mineral imbalances including variable degrees of hypocalcemia. The kidney controls systemic calcium by reabsorbing calcium from the glomerular filtrate via paracellular transport and transcellular transport in the nephron tubules, yet it is unknown whether these processes are modulated by genetic or environmental factors or disrupted in SCD. Using SCD mouse models and single-cell multiomics, we identify the distal convoluted tubule (DCT) as the nephron segment most susceptible to calcium reabsorption dysfunction in SCD, mainly via reduction of calcium buffer protein calbindin 1 (CALB1). We show that CALB1 and its encoding mRNA are decreased in DCT cells in SCD, alongside decreased Klotho (KL)-dependent fibroblast growth factor (FGF) 23 signaling and intracellular calcium signaling. Dietary iron restriction reduces CALB1, KL, and calcium exporter SLC8A1 levels in SCD kidneys. Loss of CALB1 shifts DCT cells toward energy-inefficient glycolysis with the metabolite 2,3-diphosphoglycerate impairing KL-dependent FGF23 signaling to create a feed-forward loop suppressing calcium reabsorption. Analysis of gene expression and protein quantitative trait loci data from kidneys of genetically diverse mice revealed that Calb1 expression levels are highly heritable and co-regulated with Slc8a1, identifying a genetic axis that dictates differential capacities for calcium buffering and trafficking toward blood in the kidney. Together, these findings support a model in which genetic variation, dietary iron status, and FGF23 signaling converge on DCT calcium buffering to reduce renal calcium reabsorption in the SCD kidney. This points to personalized, genotype- and iron-dependent strategies for managing mineral metabolism in SCD patients.

physiology↗