Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset.
Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15 mg/kg ip) into lean 4- to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem 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.
Levin
Barry E
BE
Neurology Service, Veterans Affairs Memorial Center, E. Orange, NJ 07018-1095, USA. levin@umdnj.edu
Dunn-Meynell
Ambrose A
AA
Banks
William A
WA
D000375:Aging / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004435:Eating / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D020738:Leptin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000209:etiology / Q000235:genetics*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D012727:Sex Characteristics; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D020738:Leptin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators