Effects of maternal blood beta-hydroxybutyrate on brown adipose tissue functions and thermogenic and metabolic health in neonatal calves

Maternal metabolic health, particularly during late pregnancy, plays a crucial role in fetal development and postnatal metabolic function. Elevated levels of BHB in dry cows, commonly observed in late gestation, may affect offspring development, but the effects on brown adipose tissue (BAT) and metabolic health remain unclear. In this study, 60 pregnant Holstein dairy cows were categorized into 2 groups based on serum BHB concentrations measured at 1, 3, 5, and 7 wk after dry-off: maternal low BHB (n = 30; mean ± SEM, 0.21 ± 0.005 mM) and maternal high BHB (n = 30; mean ± SEM, 0.64 ± 0.02 mM). Blood metabolites, including BHB, nonesterified fatty acids, and glucose, were monitored throughout the dry period. Calves born from these cows were evaluated for body growth, body temperature, glucose sensitivity, fecal, and cough score during the first month of life, with perirenal BAT and skin samples collected for analysis of thermogenic gene expression. Expression of stress genes, including CIRBP, HSP70, and HSBP1, was analyzed in skin tissue. Expression of thermogenic genes, including UCP-1, CREBP4, and CPT1B, and protein contents of UCP-1, PGC-1a were analyzed in BAT. In vitro, stromal vascular fractions were also isolated in calf's BAT, and further induced for brown adipocyte formation with dosed BHB supplementation. Results showed no differences in birth weight, body size, and body temperatures of calves born to maternal high BHB cows compared with calves born to maternal low BHB cows. However, the calves from the maternal high BHB group had higher expressions of stress genes in the skin, and decreased BAT mass and expression of thermogenic genes. Compared with the maternal low BHB group, 1-mo-old calves in the maternal high BHB group also showed significantly lower BAT mass, decreased expression of thermogenic genes, such as UCP-1, CREBP4, and CPT1B, and decreased mitochondrial density, indicating impaired BAT development. In addition, the calves from the maternal high BHB group showed reduced glucose sensitivity, as evidenced by their inability to maintain stable blood glucose levels during a glucose tolerance test. Protein concentrations of UCP-1 and PGC-1a were significantly lower in the BAT of calves born to maternal high BHB cows. In vitro, BHB supplementation inhibited brown adipocyte differentiation and thermogenesis, supporting the elevated maternal BHB impairs brown adipogenesis and mitochondrial biogenesis. Overall, this study demonstrates that calves born from elevated maternal BHB levels (∼0.64 mM) within the normal physiological range in the dry period significantly had impaired perinatal BAT development, thermogenesis, and glucose metabolism, highlighting the roles of maternal metabolic health in programming metabolic and thermoregulatory capacity in offspring.

calf; maternal ketone bodies; mitochondrial biogenesis; thermogenesis.