Injection of β-hydroxybutyrate in the Lateral Ventricle Suppresses Luteinizing Hormone Release in Castrated Male Lambs
Nutrient imbalances resulting from inadequate supply of metabolic intermediates or poor metabolic adaptation to negative energy balance are often accompanied by decrease reproductive performance and high concentrations of circulating β-hydroxybutyrate (BHB). Elevated BHB concentrations have been reported to cause a delayed resumption of estrus after calving in young beef cows, causing a delay in conception date. The objective of these experiments was to determine the effect of a central injection of exogenous BHB in the lateral ventricle on regulating pulsatile LH secretion, circulating metabolic responses, and central energy sensing in lambs. Ten castrated male lambs were individually housed and fed 1.1 kg/d of a 13.5% CP and 72.5% TDN complete feed diet. Six months prior to the experiments, lambs were fitted with an intracerebroventricular cannula into the lateral ventricle of the brain. At the initiation of both experiments, lambs were centrally injected with 1 mL into the lateral ventricle of one of two treatments: (1) β-hydroxybutyric acid sodium salt solution (BHB; 12,800 µmol/L) or (2) saline solution (CON). In Exp. 1, blood samples were collected every 10 min for 60 min prior to injection of treatments and every 10 min for 120 min after treatments were administered. In Exp. 2, 2 h post treatment infusion, plasma samples, hypothalamus and pituitary tissues were collected for analyses of circulating metabolites and gene expression. In Exp. 1, serum NEFA were decreased (P < 0.01) in lambs injected with BHB. In contrast, serum glucose concentrations were increased (P < 0.01) by BHB injection, suggesting gluconeogenesis was increased with BHB injection. Injection of BHB in the lateral ventricle tended (P = 0.08) to inhibit overall LH secretion (mean LH). Number of LH peaks during the 2 h sampling period after injection of treatments were not different (P = 0.18) between lambs injected with BHB or CON. However, lambs injected with BHB had decreased (P < 0.01) LH amplitudes. In Exp. 2, mass spectrometry-based metabolomic analysis of plasma revealed that BHB infusion significantly increased abundance of dopamine (hydroxyphenylacetic acid, P = 0.017) and serotonin (5-hydroxyindoleacetic acid, P = 0.002) metabolites. This study indicates that elevated β-hydroxybutyrate in the brain acts as a negative energy signal and suppresses pulsatile LH secretion and increases gluconeogenesis by its effects on dopaminergic and serotonergic signaling.
Keywords: β-hydroxybutyrate, luteinizing hormone, energy sensing