We previously described a mouse point mutation in the Zfhx3 gene which encodes zinc-finger homeobox 3, named short circuit (Sci), during an N-ethyl-N-nitrosourea mutagenesis screen (1). The mutation is homozygous lethal while Zfhx3Sci/+ mice have a short circadian period, driven in the suprachiasmatic nucleus by decreased activation of an AT motif bound by ZFHX3. We have also demonstrated a role for Zfhx3 in the hypothalamus of adult mice (2). RNA-seq comparison of Zfhx3Sci/+ (Sci) and Zfhx3+/+ (WT) mice indicated differential expression of genes implicated in energy balance in the hypothalamus (1). The role of ZFHX3 in energy balance is supported by a recently identified protein-altering variant of ZFHX3 in a human genome-wide association study, associated with decreased body mass index (3). We aim to investigate the metabolic phenotype of Sci mice. Here we show reduced body mass in two cohorts of male and female Sci mice at 6 and 12 months, with shorter body length at 12 months (all data in table 1). At 6 months, Sci mice had reduced fat mass % and bone mineral density. At 12 months, lean mass and fat mass were both reduced in proportion to body mass and mesenteric fat pad mass was reduced in Sci mice. Overnight fasted hormone measurements in these mice revealed reduced circulating insulin and insulin-like growth factor-1 (IGF1) in Sci mice and leptin concentration was not altered in mutants when corrected for fat mass. In addition, preliminary data from 3 month old female mice indicates that Sci mice have reduced dark phase food intake (24 h single housed, TSE Phenomaster). These data together indicate a role for Zfhx3 in the regulation of growth and energy balance. A further cohort of mice (n=12 / group) will undergo calorimetric measurements at 3 months to confirm preliminary observations. Brains from these mice will be collected in order to measure hypothalamic gene expression and localisation of candidate genes by in situ hybridisation to investigate potential mechanisms of ZFHX3 action to alter appetite, growth and/or energy expenditure pathways.