FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival

Abstract

Actin-bundling protein Fascin1 (FSCN1) is encoded by the Fscn1 gene and is crucial for cytoskeletal remodeling and cellular migration. Although a previous study linked Fscn1 deficiency to neonatal lethality in mice, the underlying metabolic mechanism remains unclear. In this study, we report that systemic knockout (KO) of Fscn1 leads to 52.2% mortality within 24 h post-birth, accompanied by severe hypoglycemia in KO pups compared with their littermates. Remarkably, this lethality is fully rescued by oral glucose administration, indicating a glucose supply-dependent survival mechanism. Surviving Fscn1-KO neonates display persistent developmental deficits, including growth retardation and depleted lipid stores, despite intact canonical insulin-regulated hepatic gluconeogenic pathways. Transcriptomic profiling of P0 livers reveals that Fscn1 loss predominantly disrupts metabolic pathways, with the glycerol phosphate shuttle being the most significantly downregulated module. Mechanistically, Fscn1-KO livers exhibit markedly reduced protein levels of glycerol-3-phosphate dehydrogenase isoforms (GPD1/GPD2), key enzymes bridging glycolysis and gluconeogenesis. Consistently, glycerol tolerance tests demonstrate impaired glycerol-to-glucose conversion in Fscn1-KO mice, confirming defective glycerol-driven gluconeogenesis. Our findings establish FSCN1 as a novel cytoskeletal-metabolic integrator essential for neonatal survival by sustaining hepatic glucose production from glycerol, thus revealing an unexpected role of actin dynamics in coordinating metabolic adaptation during early postnatal development.

1. Introduction

Fscn1 is a pro-metastasis gene that encodes the actin-bundling protein Fascin1 (also named as Fascin). Fascin1 crosslinks filamentous actin (F-actin) to promote the formation of invasive protrusions that facilitate cell migration and invasion [1–4]. In addition to its classical roles, FSCN1 modulates actin-binding proteins [5–7], interacts with microtubules [8], and integrates with the linker of the nucleoskeleton and cytoskeleton complex [9]. While the oncogenic roles of FSCN1 in cancer progression and metabolic homeostasis are well documented [10–19], its physiological functions remain poorly understood.

In adult tissues, FSCN1 is expressed at low levels in dendritic cells, neurons and vascular endothelial cells, whereas its expression peaks during embryonic development, particularly in the neural and mesenchymal lineages [1]. Although murine studies initially suggested that FSCN1 is dispensable during development [20,21], Fscn1 deficiency causes neonatal lethality post-birth without affecting embryo viability [22]. It was hypothesized that this perinatal lethality was due to postnatal feeding or respiratory challenges in Fscn1-KO pups [22]. More recently, Fscn1-KO females were reported to have lactation defects and feeding abnormalities [23].

Hepatic gluconeogenesis involves the synthesis of glucose from non-carbohydrate precursors such as glycerol, lactate, and amino acids [24,25]. While adults rely on oxaloacetate-mediated gluconeogenesis through phosphoenolpyruvate carboxykinase 1 (PCK1) [26,27], neonates prioritize a glycerol-centric gluconeogenesis pathway to take advantage of lipid-rich maternal milk. This pathway begins with glycerol phosphorylation by glycerol kinase (GK), followed by conversion to dihydroxyacetone phosphate (DHAP) via glycerol-3-phosphate dehydrogenase (GPD1/GPD2), ultimately fueling gluconeogenesis [28]. Neonates undergo rapid metabolic shifts post-birth, marked by elevated glucagon and decreased insulin levels, which rapidly activate hepatic gluconeogenesis to meet the high glucose demand of the brain [29]. Importantly, neonatal gluconeogenesis contributes 8%–9% of total glucose production—a threshold indispensable for survival [30].