الفهرس 
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Abstract
By 2030, it is predicted that 38% of adults worldwide would be overweight and another 20% will be obese if secular trends continue. Along with diabetes, dyslipidemia, and hypertension, obesity is one of the main risk factors for cardiovascular disease and contributes to the metabolic syndrome. When paired with lifestyle adjustments, pharmacotherapy may be crucial in aiding in the condition’s recovery. The non-invasive management of obesity can be carried out by two main approaches: physiological and/or pharmacological approach. The physiological approach is getting failed due to patient noncompliance. Pharmacological approaches weight loss drugs to decrease or regulate weight by modifying calorie absorption or appetite; for example, orlistat. The global progress towards tackling obesity has been “unacceptably” slow and failed until now to reverse the global obesity epidemic. So, researchers are looking to new treatment for obesity and its associated health risks. One of the widely used treatments of obesity is the ketogenic diet (KD) which is a low carbohydrate-high fat diet (HFD) known as the KD has been used for many years to address specific medical conditions. The KD has been researched and used under very controlled circumstances for the treatment of epilepsy, diabetes, cancer, polycystic ovarian syndrome, and Alzheimer’s disease. The present study aimed to explore the central effects of ketogenic diet on cerebral cortex and hippocampus during the treatment of obesity in rats and to compare its effect with the orlistat as the conventional drug used for obesity. Also, the effect of β-hydroxybuterate (βHB) as one of the ketone bodies was explored.
The present study included 48 male albino rats (2-3 months) and fed with an obesogenic diet for three months for obesity induction. Animals classified into six groups: group I (Control): consists of 8 normal male rats which were fed with a normal diet represent in the control group. group II (Untreated): consists of 8 untreated obese male rats. group III (Orlistat): consists of 8 obese rats receiving an oral orlistat at dose of 30 mg / kg body weight daily. group IV (β-hydroxybutyrate): consists of 8 obese rats receiving an oral dose βHB 200 mg/kg body weight daily. group V (Combined): consisted of 8 obese rats received a combination of oral β-HB and orlistat daily for two months with the same doses daily. group VI (GVI): consists of 8 obese rats receiving KD. At the end of treatment period, rats in all studied groups were overnight fasting, blood samples were collected for assessment of serum levels of fasting blood glucose (FBG), insulin, and lipid profile then all rats was scarified using isofurane as anesthesia, the brain was dissected. The cortex and hippocampus were excised for ELISA determination of levels of amyloid beta (Aβ1-42), acetylcholine (ACh), serotonin, dopamine, and acetyl cholinesterase (AChE) activity, and the Relative Expression of β-site APP cleaving enzyme 1 (BACE1), Brain Drive Neurotrop Factor (BDNF) and Tumor necrosis factor-α (TNF- α) by using quantitative Real-time polymerase chain reaction (qPCR).
In the present study, we used rat model of obesity induced by high fat diet (HFD) which developed the classical picture of obesity, about 60% heavier than the control rats and weight gains about 3.8-fold the control rats during the experimental period, hyperglycemia, increased insulin levels, and insulin resistance as indicated by elevated HOMA-IR. Also, the obese rats showed dyslipidemia as indicated by significantly elevated serum levels of triglycerides (TG), total cholesterol (TC), and LDL-C, and significant decline in the level of HDL-C compared with the control rats.
Additionally, the levels of the three neurotransmitters ACh, dopamine, and serotonin in the cortex and hippocampus of the obese rats are much lower than those of the control rats. These decreases were accompanied by a sharp down regulation of the expression of BDNF, high AChE activity, higher content of Aβ1-42 and up-regulation of the expression of BACE1, also induced expression of (TNF-α) in the cortex and hippocampus tissues of obese rats.
The present study demonstrated a negative correlation between BDNF and TNF-α expression in both cortex and hippocampus. There were a link between the BACE1 expression and Aβ1-42 which was confirmed in the present study by the strong positive correlation between them in both the cortex and hippocampus.
The orlistat mediated its effect through its lipotropic effect as it significantly ameliorates the lipid profile by significantly decreasing the TG compared and significantly declining the TC, LDL-C, and HDL-C compared with the untreated obese rats and control rats. The obese rats treated with βHB alone or combined with orlistat showed no significant changes in the TG level and showed significant decline in the levels of TC, LDL-C and HDL-C. The obese rats feed KD showed no significant changes in the TG and HDL-C levels showed compared with the untreated rats while the TC and LDL-C levels showed near normal values. On the other hand, the KD and βHB can be suggested as a hypolipidemic agent depending on their effects on TC and LDL-C which will be of great advantage for obesity. However, they have no significant effects on TG and significantly exaggerated the decline in the HDL-C that considered a risk for cardiovascular diseases.
The results indicated the anti-cholinesterase effects of KD which inhibited and completely normalized the activities of AChE in both cortex and hippocampus of the obese rats these effects resulted significant correction of the cortical ACh content and completely normalized the hippocampal ACh content. Whereas at the dopaminergic level, the administration of KD and βHB completely restore the dopamine level in cortical and hippocampal tissues of the obese rats. Regarding the serotonergic pathway, the KD or βHB in the present study significantly increase the cortical serotonin level in the obese rats but does not affect the hippocampal level significantly.
One of the main effects of KD in the obese rats is normalization of the cortical and hippocampal expression of BDNF. This effect is lacked with the other treatments except for βHB which partially correct the BDNF expression. At the amyloidogenic pathway, the KD and βHB induce a protective effect against the activation of the amyloidogenic pathway through suppressing the expression of BACE1 and declining the level of Aβ1-42 in both cerebral cortex and hippocampus of the obese rats. These effects together with the significant suppression of neuroinflammation through down regulating the cortical and hippocampal expression of TNF-α may decline the risk of developing AD in the treated rats.
Collectively the results of the present study and the above discussion clearly confirmed the potential anti-obesity potential of KD and βHB in HFD-rat model of obesity and their beneficial neurological effects. These effects may be mediated through activation of cholinergic, dopaminergic and serotonergic pathway, suppression of neuroinflammation, and suppression of the amyloidogenic pathway.
According to the current study, KD is a more effective anti-obesity agent than βHB and the commonly prescribed medication orlistat. In obese mice, KD therapy drastically reduced and fully normalized weight growth, hyperglycemia, insulin resistance, and dyslipidemia. Surprisingly, KD therapies significantly improved the dys-regulated gene expression in the brain at the molecular level.