FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice 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.