Increased maternal non-esterified fatty acid concentrations during late gestation impair adipose tissue development and metabolic function in Holstein offspring calves.

In late gestation, dairy cows often experience a negative energy balance (NEB) due to rapid fetal growth, leading to greater circulating levels of non-esterified fatty acids (NEFA). Circulating NEFA are recognized as critical factors of adipose tissue growth, but the impact of greater maternal NEFA during late gestation on offspring subcutaneous white adipose tissue (sWAT) development and remodeling remains unclear. This study aimed to investigate the effects of greater circulating NEFA during late gestation on sWAT development, structural remodeling and metabolic health in calves. A total of 48 pregnant Holstein cows with similar parity (1.95 ± 0.15), body weight (743 ± 8.99 kg), and days in milk (291.4 ± 2.23 d) were categorized into lesser NEFA (DCL-NEFA; n = 24; 246 ± 5.67 μM) and greater NEFA (DCG-NEFA; n = 24; 384 ± 13.36 μM, P < 0.01) groups based on the median of average serum NEFA measured at 1, 3, 5, and 7 wk after dry-off. Calf sWAT was collected at birth and one month to assess tissue growth and metabolic functions in vivo. In vitro, stromal vascular fractions isolated from sWAT of independent donor cattle were induced for adipogenesis to evaluate dose-dependent NEFA effects. Data were analyzed using linear mixed- and fixed-effects models. Although birth weight was similar between groups (P = 0.94), calves born to DCG-NEFA dams exhibited lesser sWAT mass (P = 0.01). Reduced thermogenic capacities (P < 0.01) and increased interleukin 6-mediated inflammatory signaling at birth (P = 0.01) were observed. At one month of age, DCG-NEFA calves showed greater sWAT mass (P = 0.04), impaired glucose sensitivity (P = 0.04), increased insulin resistance (P = 0.02), persistently suppressed thermogenic capacities (P < 0.01), and activated stimulator of interferon genes inflammatory signaling (P < 0.01). In vitro, NEFA addition also consistently impaired white adipogenesis and thermogenic activity (P < 0.01), and promoted inflammatory mRNA expression (P < 0.01). Greater maternal circulating NEFA concentrations during the dry period impaired sWAT development, thermogenic activity and inflammatory regulations, attributing to the dysfunctions of glucose and insulin sensitivity in offspring calves. These findings demonstrate that increased maternal lipid mobilization during late gestation programs offspring sWAT development and metabolic function, highlighting circulating NEFA as a potential target for improving metabolic health in dairy calves.