Gestational Exposure to Maternal Obesity Influences β3‐Adrenergic Agonist Induced Beiging of White Adipose Tissue in Offspring

Abstract

Maternal obesity is now recognized as an important contributing factor to the currently unfolding epidemic of obesity. In animal models, maternal obesity and exposure to high‐fat diets in utero, unequivocally predisposes the offspring to greater weight gain, metabolic dysfunction and a host of other related comorbidities, such as fatty liver disease. Our previous work in both rat and mouse models of obesity showed that offspring of obese dams are hyper‐responsive to an obesogenic challenge post‐weaning, and gain greater weight and fat mass. In part this is associated with decreased energy expenditure, impaired expression of mitochondrial OXPHOS and lipid oxidative genes and lower expression uncoupling proteins in liver, skeletal muscle and white adipose tissue. Nonetheless, the consequences of maternal obesity on programming of adipose tissue development, especially brown/beige adipose tissue development are unknown. In this report, we investigated role of maternal obesity on beige fat development in offspring following β3‐adrenergic agonist. Female C57BL6/J mice were fed diets with either low (10%) or HFD (45% of calories) for 12 wk starting at 5 wk of age. Dams were mated with males on control diets and provided access to respective diets during pregnancy and lactation. At weaning, offspring were weaned onto control and HFD, creating four groups (CC, CH, HC, HH, denoting maternal and offspring diets respectively). Male offspring from the four groups were followed till 20 wk of age. HFD‐fed offspring from HF dams (HH) gained significantly (p<0.05) greater body weights than offspring from lean dams (CH). At 20 wk of age, offspring were treated with either vehicle or β3‐adrenergic receptor agonist CL‐316,243 (1 mg/kg, ip) for one week (N=4–5 each). CL‐316,243 is a well established activator of beige adipocyte formation. Twenty weeks of diet intervention lead to significantly consistent increased weight gain in HH compared to other groups. One week of CL injection towards to end of study did not affect the weight gain. There were no significant differences in overall body weight between vehicle and CL treated animals. Gene expression analysis of inguinal adipose tissue depot (iWAT) revealed significant differences in vehicle and CL treated groups. Expression of brown‐fat specific genes such as Ucp1, Cidea and Pgc1a was affected by maternal HF diet feeding in both vehicle and CL treated group. Moreover, maternal obesity hampered the response to CL‐316,243 consistent with programming defect in adipose tissue. Further analysis of developmental aspects of beiging of adipose tissue is under investigation. Our findings indicate that maternal obesity influences beige cell formation in response to classical beiging inducers which might influence modulation of energy expenditure, metabolism and overall risk of obesity.Support or Funding InformationSupport USDA CRIS 6206‐51000‐010‐05S