Nutritional regulation of hypothalamic leptin receptor gene expression is defective in diet-induced obesity.
Leptin action in the hypothalamus plays a critical role in maintaining normal food intake and body weight. Hyperleptinaemia is associated with obesity in humans and animal models, suggesting a state of leptin resistance. Although the mechanism of leptin resistance is not clearly understood, alterations in leptin receptor (Ob-R) gene expression have been proposed as a potential mechanism mediating modifications in leptin action in obesity and during changes in nutritional status (fed/fasted). The current study examined the effects of diet-induced obesity (DIO) made by feeding rats a high fat diet for 9 weeks, and nutritional status on levels of long form (Ob-Rb) and total (Ob-Rtot) Ob-R mRNA expression in the hypothalamus. In the fed state, hypothalamic Ob-Rb mRNA and Ob-Rtot mRNA levels were similar in DIO and control standard chow fed rats (SC) despite hyperleptinaemia in DIO rats. However, although an overnight fast moderately increased hypothalamic Ob-Rb mRNA levels in SC rats, fasting did not increase Ob-Rb mRNA levels in DIO rats. To address the possibility that elevated leptin concentration in DIO rats may mediate an alteration in OB-R mRNA levels, we examined the effects of adenovirus-mediated hyperleptinaemia on Ob-R gene expression in SC rats. Despite substantially elevated plasma and cerebrospinal fluid concentrations of leptin, hypothalamic Ob-R mRNA levels were similar in both groups. In conclusion, the current study demonstrates that DIO is associated with a loss of nutritional regulation of hypothalamic Ob-R mRNA levels, and that hyperleptinaemia is not sufficient to alter Ob-R mRNA expression.
Sahu
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Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, PA 15261, USA. asahu@pitt.edu
Nguyen
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O'Doherty
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RM
D000256:Adenoviridae / Q000235:genetics; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D004032:Diet / Q000009:adverse effects*; D015870:Gene Expression / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007031:Hypothalamus / Q000503:physiopathology*; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D012016:Reference Values
D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin