Influence of Exogenous Beta-hydroxybutyrate on Metabolic Efficiency, Luteinizing Hormone, and Hypothalamic and Pituitary Gene Expression in Sheep

Four studies were conducted to determine the effect of central administration of exogenous beta-hydroxybutyrate (BHB) on circulating metabolites, luteinizing hormone (LH), and hypothalamus and pituitary differential gene expression in sheep. In three of the studies, wethers were assigned to be centrally injected into the lateral ventricle of the brain through intracerebroventricular cannulas (ICV) with a single injection of BHB solution (BHB; 12,800 μmol/L) or saline solution (CON; 0.9% NaCl). In Exp. 1, between CON and BHB treated sheep, 11 and 44 genes were differentially expressed (adj. P < 0.05) within the pituitary and hypothalamus, respectively. Functional enrichment analyses revealed BHB altered expression of genes in pathways related to stimulus perception, inflammation, and cell cycle control. In Exp. 2, wethers were injected through the ICV with one of 4 treatments: 0, 400, 800, or 1,600 μmol/L of BHB solution. Serum glucose concentrations tended (P = 0.08) to decrease linearly with increasing concentrations of BHB. Amplitude of LH peaks decreased linearly (P = 0.03) with increasing concentrations of BHB. In Exp. 3, wethers were centrally injected with either 12,800 μmol/L BHB or saline. Serum glucose and insulin concentrations increased (P < 0.01) with BHB injection. Injection of BHB decreased (P < 0.01) circulating serum NEFA concentrations. Injection of BHB did decrease (P < 0.01) mean LH concentration. Wethers injected with BHB had decreased (P < 0.01) amplitudes of LH peaks. In Exp. 3, ovariectomized ewes were assigned to be fed either at BW maintenance (MAINT) or fed at a 30% feed reduction (RES). Ewes were randomly assigned to be centrally injected for 10 d with 300 μl into the lateral ventricle twice daily with one of two treatments of either BHB or saline. Serum glucose concentrations decreased (P = 0.02) with infusion of BHB. Serum NEFA concentration increased (P < 0.01) with RES ewes. Luteinizing hormone exhibited a tendency (P = 0.06) for a diet × treatment interaction. Overall, elevated BHB in the brain may mimic a negative energy signal leading to alterations in serum concentrations of metabolites and LH.