Effect of Genetic Obesity on Thermoregulatory Activity Responses to Inversion of the Light/Dark Cycle

In this pilot work, the authors compared the circadian rhythm responses of 3-month-old female fatty Zucker rats with those of lean Zucker rats and Sprague-Dawley rats to reversal of the light/dark (LD) cycle. Core temperature and spontaneous cage activity were continuously monitored by implanted microtelemetry devices prior to and for 5 days following complete LD cycle reversal. By the 5th day after LD reversal, temperature rhythm nadir had phase-advanced 10.5 hours in the lean Zucker rats, 10.8 hours in the Sprague-Dawley rats, and only 3.8 hours in the fatty Zucker rats. Similarly, total activity increased in lean Zucker rats and Sprague-Dawley rats after LD reversal but declined in the fatty Zucker rat during the same time. Results of this study show that obese Zucker rats displayed an impaired ability to reentrain circadian rhythms for temperature and activity when compared to lean Zucker rats and Sprague-Dawley rats. These findings suggest that dysfunction in the circadian pacemaker previously shown to manifest itself by 43 weeks of age in fatty Zucker rats may already be present at 3 months of age and suggest that altered thermoregulation may play a role in the development of obesity in this animal model of genetic obesity.

Effects of leptin and cholecystokinin in rats with a null mutation of the leptin receptorLepr fak

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.