Grb10a knockdown in Danio rerio during early life alters growth and cardiometabolic function associated with a remodelled transcriptome

Abstract

Embryonic growth trajectory is a risk factor for chronic metabolic and cardiovascular disorders and influences birth weight along with early post-natal weight gain in humans. Grb10 is a negative regulator of the main pathways driving embryonic growth and knock-out in mammals increases insulin sensitivity and growth trajectory. This study investigates in Danio rerio the long-term cardiometabolic consequences and associated transcriptomic profiles of morpholino induced early life disruption of grb10a expression. The associated transient knockdown of grb10a increased embryonic growth (+7 %) and metabolic rate (+25 %), while decreasing heart rate (−50 %) in early life. Juvenile growth and respiratory rate were also elevated (+30 % and 7-fold increase respectively). This was associated with permanent remodelling of the transcriptional landscape and the dysregulation of multiple growth-related pathways. This study indicates that zebrafish are a suitable model for life-long investigation of the link between early growth and later life disease risk.