Thermogenesis, aging and obesity in the LA Ntul/-cp (corpulent) rat

Abstract

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 trended to decrease modestly by 24 months (p=<0.05) and were greater than resting metabolic rates in the obese phenotype at all ages studied (p=<0.05). Cold exposure at 4°C resulted in a dramatic ~5-fold increase in the oxygen consumption after 5 minutes in 4-month-old rats, which subsided to ~2x resting metabolic rate within 15 minutes and remained constant thereafter in the lean phenotype. In 14-months old lean rats the increase in oxygen consumption at 5 minutes averaged ~4-fold increase over resting levels and returned to ~2x resting levels from 15 to 45 minutes 4°C exposure. 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 results of this study demonstrate that the body weights of the obese phenotype are significantly greater than their lean littermates throughout the age spectrum studied, and that both resting metabolic rates, 4°C cold, and norepinephrine-stimulated thermogenesis are decreased in the obese compared to the lean phenotype and become further decreased with advancing age

A Review of Brown Adipose Tissue Development in T2DM-SHR/N-cp (Corpulent) Rats

“…The characteristics of non-shivering thermogenesis have been reported to be impaired in both obese and obese-T2DM rats bearing the -cp trait, despite having a greater mass of BAT than occurs in their lean littermates. 20,32 While measures of metabolic rate or the thermogenic impact of exogenously adminis-tered norepinephrine were not included in the current study, norepinephrine is the neurohormone that normally innervates BAT, and the greater IBAT mass exhibited hyperplasia and hypertrophy of brown adipocytes and would be expected to demonstrate an increased capacity for NST independent of the stigmata of obesity and T2DM. [1][2][3]5 In the presence of the obese-2DM stigmata and its associated insulin resistance however the endogenous capacity for NST would likely become impaired, thereby enabling a greater efficiency of caloric utilization.…”

“…19 Urine glucose was det1ermined qualitatively, and urinary vanilmandelic acid as a reflection of sympathetic activity measured as outlined previously. 20,21 Tissue depots were dissected in their entirety and weighed on an Ohaus electronic balance to the nearest 0.1gram within one minute, and before significant dehydration could occur. Values beyond 9 months of age were not obtained in this other studies with this strain as the lifespan of the obese-T2DM rats began to decline beyond 10 months of age and seldom exceeded 12 months of age, while the lean phenotype was often observed to survive to 12-15 months of age.…”

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“…All animals used in this study were females due to the less severe magnitude of insulin resistance and disordered magnitude of glucose intolerance that develops in female than in male obese animals of this strain. 21 Animals were housed in plastic showbox cages, lined with one inch of pine shavings, and received Purina Chow (#5012) and house water ad libitum, at 22 ±1°C. and 50% RH on a conventional light cycle.…”

“…Measures of resting oxygen consumption were obtained in animals after an 8 hour fast in a small animal respiratory apparatus as described previously. 21,22 After obtaining a satisfactory RMR in quietly resting animals, lean and obese rats were administered caffeine (20 mg/rat, s.c., EPH 200 µg/KG BW, s.c) or both agents together, and measures of VO2 continued for up to 45 minutes post injection. An additional group was administered a submaximal dose of the β-agonist norepinephrine, 100 µg/kg BW for comparison.…”

“…Over time the rate of weight loss for an individual is likely to occur only gradually as the energy content of the stored fat is considerable greater than is observed during the oxidation of carbohydrate or protein in concert with hyperinsulinemia and the insulin-linked antilipolytic effects in adipose tissue in addition to the protein sparing effects of hyperinsulinemia on protein turnover. 21 As a potential added attribute, the mood stabilizing effects of the caffeine and ephedrine likely compliment and improve the psychological impact that may occur during dieting and attempted processes associated with weight loss.…”