Differences in feed intake and production efficiency in lactating Holstein-Friesian (HF), Jersey (JE), and JE × HF (F(1)) dairy cows have been reported. The liver-gut axis is important in the regulation of energy homeostasis, appetite behaviour, and production efficiency. The objectives of this study were to determine: 1) the effect of dairy cow genotype on the expression profiles of genes involved in energy homeostasis in duodenal and hepatic tissue, and 2) the association between the expression of these genes across both tissues and with economically important production efficiency traits. The expression of 27 candidate genes involved in energy homeostasis, feed intake, and energy storage was measured by qPCR. Duodenal expression of the pro-opiomelanocortin (POMC), glucagon-like peptide 1 receptor (GLP1R), and insulin-like growth factor 1 (IGF1) genes was highest in HF. In contrast, hepatic expression of the leptin receptor (LEPR), insulin-like growth factor 1 receptor (IGF1R), protein kinase, AMP-activated, beta 1 (AMPKB1), and POMC genes was highest in the F(1) cross. In the duodenum, positive correlations were observed between mRNA expression of anorectic peptides (POMC and GLP1R), whereas a negative correlation was detected between orexigenic (ghrelin) and anorectic (peptide YY) gene expression. A negative correlation was observed between duodenal POMC gene expression and both residual feed intake and milk production efficiency traits, while GLP1R gene expression was negatively correlated with milk production efficiency traits. A heterotic effect was observed in hepatic expression of AMKPB1, IGF1R, LEPR, POMC in the F(1) genotype, possibly mediating improved feed efficiency in cross-bred cows. In conclusion, key genes involved in energy homeostasis and appetite behaviour are differentially expressed due to cow genotype in a tissue-dependent fashion. POMC and GLP1R are potential candidate genes for the identification of single nucleotide polymorphisms regulating energetic efficiency in the dairy cow, which may be incorporated into future breeding programmes.