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Updated: May 10, 2026
Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival
Xiangxiang Liu1, Yuanzhao Hu1, Liangwei Wu1
1Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650500, China.
Insights
Systemic knockout of the actin-bundling protein Fascin1 (FSCN1) causes neonatal mortality due to severe hypoglycemia. FSCN1 is essential for glycerol-driven glucose production, crucial for early postnatal survival.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Developmental Biology
Background:
- Fascin1 (FSCN1) is an actin-bundling protein vital for cell structure and movement.
- Previous studies suggested a link between Fscn1 deficiency and neonatal death, but the metabolic basis was unknown.
Purpose of the Study:
- To elucidate the metabolic mechanism underlying neonatal lethality in Fscn1-deficient mice.
- To investigate the role of FSCN1 in neonatal glucose homeostasis and survival.
Main Methods:
- Systemic knockout (KO) of the Fscn1 gene in mice.
- Assessment of neonatal mortality, blood glucose levels, and response to glucose administration.
- Transcriptomic profiling of P0 livers.
- Measurement of glycerol-3-phosphate dehydrogenase (GPD1/GPD2) protein levels.
- Glycerol tolerance tests.
Main Results:
- Fscn1 KO led to 52.2% neonatal mortality within 24 hours, associated with severe hypoglycemia.
- Lethality was rescued by oral glucose, indicating glucose supply dependency.
- Fscn1-KO neonates showed growth deficits and depleted lipids, with intact insulin-regulated gluconeogenesis.
- Transcriptomics revealed disruption of metabolic pathways, notably the glycerol phosphate shuttle.
- Fscn1 KO livers had reduced GPD1/GPD2 levels, impairing glycerol-to-glucose conversion.
Conclusions:
- FSCN1 is essential for neonatal survival by maintaining hepatic glucose production from glycerol.
- Actin dynamics, via FSCN1, integrate cytoskeletal function with metabolic adaptation during early development.
- FSCN1 deficiency disrupts glycerol metabolism, leading to hypoglycemia and neonatal death.
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.
