Leptin receptor missense mutation in the fatty Zucker rat

The Koletsky (“corpulent”) obese rat is homozygous for an autosomal recessive mutation of the leptin receptor (Lepr) that results in hyperphagia, obesity, and hyperlipidemia. Unlike the Lepr mutation that characterizes the fatty Zucker rat ( Lepr fa ), the Koletsky mutation ( Lepr fak ) is null. Because the Leprfak mutation is null, exogenous leptin should have no effect on body weight or food intake in fak/fa k rats. We confirmed that prediction: murine leptin, administered into the third ventricle for 5 consecutive days, did not affect daily food intake or body weight in fak/fa k rats but produced dose-related inhibitions of food intake and body weight in +/+ and +/fa k rats. Although fak/fa k rats did not respond to leptin, their response to CCK-8 (4 μg/kg ip) injected before 30-min test meals of 10% sucrose was not different from that of +/+ or +/fak rats. These results demonstrate that the fak/fa k rat is a good model in which to analyze the controls of food intake, energy expenditure, and energy storage in the absence of leptin effects.

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Molecular Cloning of Rat Leptin Receptor Isoform Complementary DNAs—Identification of a Missense Mutation in Zucker Fatty (fa/fa) Rats

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1996.1133 ◽

1996 ◽

Vol 225 (1) ◽

pp. 75-83 ◽

Cited By ~ 182

Author(s):

Kazuhiko Takaya ◽

Yoshihiro Ogawa ◽

Naohi Isse ◽

Taku Okazaki ◽

Noriko Satoh ◽

...

Keyword(s):

Molecular Cloning ◽

Missense Mutation ◽

Leptin Receptor

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Localization of leptin receptor immunoreactivity in the lean and obese Zucker rat brain

Brain Research ◽

10.1016/s0006-8993(97)01388-7 ◽

1998 ◽

Vol 785 (1) ◽

pp. 80-90 ◽

Cited By ~ 41

Author(s):

Deborah O Yarnell ◽

David S Knight ◽

Kathryn Hamilton ◽

Orien Tulp ◽

Patrick Tso

Keyword(s):

Rat Brain ◽

Leptin Receptor ◽

Zucker Rat ◽

Obese Zucker Rat

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Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats

Clinical Science ◽

10.1042/cs0960307 ◽

1999 ◽

Vol 96 (3) ◽

pp. 307-312 ◽

Cited By ~ 12

Author(s):

Simon DRYDEN ◽

Peter KING ◽

Lucy PICKAVANCE ◽

Patrick DOYLE ◽

Gareth WILLIAMS

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Food Intake ◽

Neuropeptide Y ◽

Leptin Receptor ◽

Zucker Rats ◽

Mrna Levels ◽

Zucker Rat ◽

Direct Effects ◽

The Central Nervous System

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P< 0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 μg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P< 0.01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P< 0.01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P< 0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.

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