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1 Neurology Service, Veterans Affairs Medical Center, E. Orange, NJ, USA; Neurosciences, New Jersey Medical School, Newark, NJ, USA
2 GRECC, Veterans Affairs Medical Center, St. Louis, MO, USA; Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: levin{at}umdnj.edu.
Rats selectively bred to develop diet-induced obesity (DIO) were compared to those bred to be diet resistant (DR) on a 31% fat high energy (HE) diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15mg/kg, i.p.) into lean 4-5wk old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21%, 63% and 64% less leptin-induced immunoreactive phosphorylated STAT3 (pSTAT3) expression in the hypothalamic arcuate (ARC), ventromedial (VMN) and dorsomedial (DMN) nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4-5wk old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23wk of age on low fat chow or after 6wk on HE diet. In addition, leptin receptor (OB-Rb) mRNA expression was 23% lower in the ARC of 4-5wk old DIO compared to DR rats. Thus, a pre-existing reduction in hypothalamic but not brainstem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age.
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