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Adiponectin receptors in the brain of rats on HFHS diet

INTRODUCTION. Body’s energy balance is precisely controlled by hypothalamic satiety centers which are responsive to signals coming from adiponectins (leptin, kisspeptin etc.) and other hormones involved in maintenance of energy balance (e.g. insulin, glucagon). Chronic overnutrition may disrupt this balance and lead to disease state, such as metabolic disorder or neurodegeneration. The mechanism of disruption of involved pathways is still not clearly explained. METHODS. Study included sixty four male and female 44-weeks-old Sprague-Dawley rats divided in 4 groups: 1. Standard diet (SD), 2. Diet rich in carbohydrates and fat (HFHSD), 3. HFHSD + metformin treatment (50 mg/kg/day), 4. HFHSD + liraglutide treatment (0.3 mg/kg/day). The experiment lasted for 20 weeks. The obesity was induced during first 5 weeks. The treatment started in week 6 and lasted till the end of experiment, when the rats were 64 weeks old. Then the brains were collected and free- floating immunohistochemical staining was performed using antibodies for following receptors ; insulin (IR-α), leptin (ObR), insulin-like growth factor 1 (IGF-1Rβ) and kisspeptin (GPR54). The immunopositive cells in hippocampus (HIPP) and hypothalamus (HTH) were counted. RESULTS. Here we present analysis of IR-α and ObR positive cells in HTH satiety regions (arcuate - ARC, lateral hypothalamic - LH, paraventricular - PA, and periventricular nuclei - PE) omitting data about other brain regions. Preliminary data indicate that HFHSD induced downregulation of IR-α and ObR in ARC and PA of female rats what is expected physiological response to HFHSD and a good sign of maintained balance. At the same time, levels of both receptors are equal in males on regular and HFHSD. We supposed that, after so long period of HFHSD, males lost ability to downregulate sensitivity to hyperleptinaemia and hyperinsulinaemia by downregulatin of receptor levels in ARC. Metformin and liraglutide treatment of obese females could not bring levels of IR-α to control level (in experimental time), except in LH region. Metformin managed to bring IR-ɑ and ObR levels in ARC of females back to ‘regular chow’ levels and it reflects much lower food consumption while maintaining body weight close to HFHSD controls. Contrary, liraglutide treated females consumed highest amount of food, weighted the least at the end of the study, lost signs of liver statosis, but had the worst glucose tolerance. If compared to HFHSD females, liraglutides females increased ObR in ARC what is sign of developed leptin resistance without development of insulin resistance. Metformin treated males showed similar changes in food consumption and body weight as females. Contrary to females, their IR-α levels in ARC stayed at the level of obese animals while ObR went even higher as a sign of leptin resistance. Like liraglutid treated females, males also lowered food consumption and lost some weight, even corrected liver steatosis to some point. Liraglutid significantly downregulated IR-α in ARC and that way lowered insulin sensitivity. At the same time liroglutid treated males increased ObR in ARC what is a sign of leptin resistance. DISCUSSION AND CONCLUSION. HFHSD is much better endured in females which sustain physiological response even after prolonged period of diet. Males are more prone to development of insulin and leptin resistance in satiety centers. Metformin corrected insulin and leptin resistance in ARC of females on HFHSD, while same treatment was successful in lowering food consumption and body weight, but not leptin resistance in males. Liraglutid corrected insulin resistance in ARC of HFHSD females and even lowered sensitivity to insulin in males, but did not corrected leptin resistance.

leptin receptor, insulin receptor, kisspeptin receptor, obesity, diabetes, brain, rat

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