Improved Leptin Sensitivity as a Potential Candidate Responsible for the Spontaneous Food Restriction of the Lou/C Rat

PLOS ONE, Dec 2019

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).

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Improved Leptin Sensitivity as a Potential Candidate Responsible for the Spontaneous Food Restriction of the Lou/C Rat

et al. (2013) Improved Leptin Sensitivity as a Potential Candidate Responsible for the Spontaneous Food Restriction of the Lou/C Rat. PLoS ONE 8(9): e73452. doi:10.1371/journal.pone.0073452 Improved Leptin Sensitivity as a Potential Candidate Responsible for the Spontaneous Food Restriction of the Lou/C Rat Christelle Veyrat-Durebex 0 Anne-Laure Poher 0 Aurlie Caillon 0 Emmanuel Somm 0 Philippe Vallet 0 Yves Charnay 0 Franoise Rohner-Jeanrenaud 0 Ren Zhang, Wayne State University, United States of America 0 1 Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva , Geneva , Switzerland , 2 Division of Development and Growth, Department of Pediatrics, Geneva University Hospital , Geneva , Switzerland , 3 Department of Psychiatry, Geneva University Hospital , Geneva , Switzerland 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). - Funding: This work was supported by the Swiss National Science Foundation (31003A-134919). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. 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]. Among them, the Lou/C rat, an inbred strain of Wistar origin, was described as being resistant to obesity development with age [24] or in response to a high fat diet [5,6]. Interestingly, this rodent model also 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, similarly to what was observed during long-term moderate (40%) caloric restriction [9]. Of note, low plasma leptin levels are also observed in dietary-resistant (DR) Sprague Dawley rats compared to diet-induced obese (DIO) animals exhibiting high leptin levels [10]. 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]. Following a first experiment bearing on the analysis of the meal pattern in Wistar and Lou/C rats, the aim of the present study was to compare leptin sensitivity between the two groups. For this purpose, different protocols of acute leptin treatment (centrally, peripherally, in addition to Glucagon-like peptide 1, GLP-1) were used to measure the leptin effects on food intake, as well as different parameters involved in leptin action. Considering the literature, two hypotheses have received considerable attention concerning the occurrence of leptin resistance during the development of obesity: 1) failure of circulating leptin to reach its central targets [12] and 2) impaired intracellular leptin signaling [13]. Leptin transport through the blood-brain-barrier (BBB) was shown to be blunted by high levels of circulating triglycerides [14, (...truncated)


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Christelle Veyrat-Durebex, Anne-Laure Poher, Aurélie Caillon, Emmanuel Somm, Philippe Vallet, Yves Charnay, Françoise Rohner-Jeanrenaud. Improved Leptin Sensitivity as a Potential Candidate Responsible for the Spontaneous Food Restriction of the Lou/C Rat, PLOS ONE, 2013, Volume 8, Issue 9, DOI: 10.1371/journal.pone.0073452