The Effects of Aging, Obesity and Mechanisms of Impaired Nonshivering Thermogenesis in the LA/Ntul//-cp rat

The prevalence of obesity and overweight conditions has now reached epidemic proportions in much of the Western world, and is generally assumed to be due to a metabolic imbalance between energy intake and energy expenditure. Animal models represent the preferred experimental tools to investigate mechanisms of energy metabolism in an attempt to discover a pharmacotherapeutic or other clinical approach to treat the disordered metabolism. The role of impaired thermogenesis contributes to an economy of energy metabolism that persists throughout the lifespan in the obese phenotype of the corpulent rat. Obesity and mild to moderate impaired carbohydrate tolerance develops in the obese phenotype of the LA/Ntul//-cp (corpulent) rat strain by 6 weeks of age. Groups (n=12-20 rats/phenotype] of female congenic lean and obese LA/Ntul//-cp (corpulent) rats were fed ad libitum standardized Purina #5012 diet ad house water for 4, 14, or 24 months of age. Measures of Body weight (BW) and of resting oxygen consumption (RMR; VO2) at thermal neutrality and for up to 45 minutes of (4°C) spontaneous cold exposure, and norepinephrine-stimulated thermogenesis (100 ug. s.c.) were determined at each age. Body weights of lean rats increased only gradually during the study (p=n.s.), but weights of obese phenotype were ~2-fold greater at 4 months (p=<0.05), 14 months (p-<0.01), and ~3.5 to 4-fold greater at 24 months of age (p=<0.01). Resting metabolic rates in the lean phenotype decreased modestly after 24 months (p=<0.05), and they were higher than resting metabolic rates in the obese phenotype at all ages studied (p=<0.05). In 4-month-old rats, cold exposure at 4°C caused a dramatic 5-fold increase in oxygen consumption after 5 minutes, which decreased to 2x resting metabolic rate within 15 minutes and stayed unchanged thereafter in the lean phenotype. In lean 14-month-old rats, the increase in oxygen consumption at 5 minutes was on average ~4-fold higher than resting levels, and it decreased to two times resting levels from 15 to 45 minutes of exposure to 4°C. In 24-month-old lean rats however, the cold induced increases in metabolism were markedly diminished to only ~3x resting metabolic rates at 5 minutes cold exposure but remained similar to the other lean age groups thereafter. In the obese phenotype, the peak responses at 5 minutes were lower than those of lean rats at 5 minutes in 4- and 14-month-old rats and were significantly impaired in 24-month-old rats at all times measured. Norepinephrine resulted in a >1.5-fold increase in oxygen consumption in the lean phenotype at all ages studied, while in obese rats norepinephrine resulted in a~1.4-fold increase in oxygen consumption at 4 months of age with non-significant ~1.1 to 1.2-fold increases at the two older ages. In both phenotypes, the resting and the norepinephrine-stimulated oxygen consumption responses tended to decrease with increasing age. The findings from this research indicate that the obese phenotype has significantly higher body weights than their lean littermates across the age spectrum studied, and that both resting metabolic rates, 4°C cold exposure, and norepinephrine-stimulated thermogenesis are lower in the obese phenotype compared to the lean phenotype and become lower with age. Thus, the economy of energy metabolism is deemed a significant contributory factor in the epigenetic expression of adipogenesis and fat accretion in the obese phenotype of this strain.