Abstract
The Lou/C rat, an inbred strain of Wistar origin, was described as a model of resistance to age- and diet-induced obesity. Although such a resistance involves many metabolic parameters described in our previous studies, Lou/C rats also exhibit a spontaneous food restriction due to decreased food consumption during the nocturnal period. We then attempted to delineate the leptin sensitivity and mechanisms implicated in this strain, using different protocols of acute central and peripheral leptin administration. A first analysis of the meal patterns revealed that Lou/C rats eat smaller meals, without any change in meal number compared to age-matched Wistar animals. Although the expression of the recognized leptin transporters (leptin receptors and megalin) measured in the choroid plexus was normal in Lou/C rats, the decreased triglyceridemia observed in these animals is compatible with an increased leptin transport across the blood brain barrier. Improved hypothalamic leptin signaling in Lou/C rats was also suggested by the higher pSTAT3/STAT3 (signal transducer and activator of transcription 3) ratio observed following acute peripheral leptin administration, as well as by the lower hypothalamic mRNA expression of the suppressor of cytokine signaling 3 (SOCS3), known to downregulate leptin signaling. To conclude, spontaneous hypophagia of Lou/C rats appears to be related to improved leptin sensitivity. The main mechanism underlying such a phenomenon consists in improved leptin signaling through the Ob-Rb leptin receptor isoform, which seems to consequently lead to overexpression of brain-derived neurotrophic factor (BDNF) and thyrotropin-releasing hormone (TRH).
Highlights
Since many years, numerous studies tried to identify neuroendocrine mechanisms involved in the regulation of food intake and body weight gain in normal, as well as in pathological conditions, such as in rodents presenting different susceptibilities to develop obesity [1]
No significant intergroup difference was noted for insulinemia, while plasma triglyceride levels were decreased in Lou/C compared to Wistar animals
As the main alterations in meal pattern in Lou/C rats is similar to the changes elicited by central and peripheral leptin administration, we hypothesized that leptin sensitivity is enhanced in this group of animals compared to Wistar rats
Summary
Numerous studies tried to identify neuroendocrine mechanisms involved in the regulation of food intake and body weight gain in normal, as well as in pathological conditions, such as in rodents presenting different susceptibilities to develop obesity [1]. The Lou/C rat, an inbred strain of Wistar origin, was described as being resistant to obesity development with age [2,3,4] or in response to a high fat diet [5,6] This rodent model exhibits a reduced daily food intake under standard [4], selfselection [7] and a high fat diet [5] compared to age-matched Wistar rats. Such changes are accompanied by a lower body fat mass [4,5] and low circulating leptin levels [4,5,8] in Lou/C rats, to what was observed during long-term moderate (40%) caloric restriction [9]. In DIO rats, reduced central leptin sensitivity seems to partially explain their propensity to develop obesity under a high energy diet, since both NPY mRNA expression and food intake were poorly modulated after 4 weeks of food restriction and intracerebroventricular leptin injection, respectively [11]
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