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Abstract The present study was designed to investigate sex differences in metabolic responses to immobilization stress and to clarify the underlying mechanism(s). The possible beneficial effects of vitamin D3 and lipoic acid supplementation on the assumed stress- induced metabolic alterations were, also, studied. The study was performed on 80 adult albino rats of both sexes, initially weighing 200-300 gm, half of the rats being males and half being females. Rats were allocated into four main groups, each of which were further subdivided into a male group and a female group (10 rats in each group). - group І: Control group. - group ІІ: Stressed untreated group: Rats in this group were subjected to immobilization stress by being encaged 2 hours daily, 5 days/ week, for 4 weeks. - group ІІІ: Vitamin D3- treated Stressed group: Rats in this group were subjected to immobilization stress as in group ІІ, and were treated at the same time by intraperitoneal injection of vitamin D3 in a dose of 10 μg /Kg BW, every other day.group ІV: Alpha-Lipoic acid- treated Stressed group: Rats in this group were subjected to immobilization stress, and were treated at the same time by α-lipoic acid in a dose of 50mg/Kg BW, given daily by gavage. All rats were subjected to determination of: - Anthropometric parameters, including body weight, body mass index (BMI), waist circumference (WC), visceral fat weight (VFW), absolute and relative pancreatic weights (APW, RPW; respectively) and absolute and relative liver weight (ALW, RLW; respectively). - Glycemic parameters, including fasting plasma glucose, glucose uptake by diaphragm and glucose output by kidneys. - Lipid profile, including plasma levels of triglycerides (Tg), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and atherogenic index (AI). - Oxidative stress markers, including plasma levels of malondialdehyde (MDA), nitrite and total antioxidant capacity (TAC).- Hormones, including plasma levels of insulin, leptin, testosterone and estradiol. - Homeostatic model assessment of beta cell function (HOMA-B) and homeostatic assessment of insulin resistance (HOMA- IR). - Histological examination of pancreas and liver. - Caspase 3 in pancreatic tissue by immunehistochemistry. The results of the current study revealed that upon exposure to stress both male and female rats showed significantly decreased visceral fat weight, accompanied by hyperglycemia and dyslipidemia, manifested by significantly increased plasma level of glucose, TC, LDL-C and AI, as well as significantly reduced plasma levels of TAC indicating low antioxidant defenses together with significantly low plasma insulin and HOMA-B denoting pancreatic B- cell affection. In addition, plasma estrogen level was significantly elevated in both male and female rats. Moreover, in male rats, stress additionally resulted in significantly decreased BMI%, plasma levels of testosterone, HDL-C and glucose uptake by the diaphragm and significantly increased RLW, glucose output by the kidneys, as well as plasma levels of Tg and MDA. Also, in female rats, stress additionally resulted in significantly increased plasma levels of nitrite and testosterone. In comparison to the stressed male group, the stressed female group displayed significantly higher BMI% and plasma estrogen, whereas, the ALW, glucose output by the kidneys, plasma Tg, TC, AI, TAC and plasma testosterone were all significantly lower. Regarding the histopathological examination of the pancreas, both stressed male and female groups showed degenerative and apoptotic changes in the pancreatic islet cells, that were significantly worse in the male groups compared to the female groups. Further, the liver histopathological examination in both stressed male and female groups revealed hepatocyte degeneration, apoptosis, necrosis and fibrosis that were significantly greater in male compared to female rats. Upon vitamin D3 treatment, both stressed male and female rats revealed significant increase in BMI %, accompanied by a significant decrease in plasma levels of TC, fasting blood glucose and glucose output by kidneys. Additionaly, vitamin D treated stressed male rats exhibited significant increase in plasma testosterone, glucose uptake by the diaphragm and HOMA-B, together with a significant decrease in plasma levels of estrogen, Tg, LDL-C and AI. On the other hand, plasma levels of TAC and insulin were normalized to reach control values. It was worth noting that only vitamin D- treated stressed female rat group showed significantly increased waist circunference and plasma levels of MDA and leptin and significantly decreased plasma levels of testosterone and estrogen to the control values, while HOMA-B was elevated to approach the normal values. In comparison to the vitamin D- treated stressed male rat group, vitamin D- treated stressed female group showed significantly lower glucose output by kidneys, plasma levels of testosterone and insulin as well as HOMA-IR and significantly higher plasma estrogen. Further, vitamin D treated stressed female rats showed greater improvement of pancreatic structure as compared to vitamin D-treated stressed male group, although caspase 3 was significantly reduced in both treated groups compared to their respective untreated groups. Vitamin D3 administration resulted in significant improvement of the liver architecture of stressed male rats, whereas it resulted in less improvement in the liver architecture of the stressed female group. Upon alpha lipoic acid treatment, on the other hand, both male and female stressed rats displayed significant increase of BMI% and plasma testosterone, accompanied by significant lowering of plasma glucose and estrogen levels. In stressed male rats, alpha lipoic acid, also, significantly increased plasma levels of TAC, insulin, glucose uptake by the diaphragm and HOMA-B and significantly decreased glucose output by the kidneys as well as the plasma levels of Tg, TC, LDL-C and AI. Compared with alpha lipoic acid- treated stressed male rats, alpha lipoic acid- treated stressed female rats revealed significantly higher plasma levels of estrogen and testosterone and significantly lower plasma levels of insulin and HOMA-IR. Regarding the histological picture of the pancreatic islets of Langerhans, alpha lipoic acid- treated male rats showed evident improvement as compared to the untreated stressed male rats, whereas the alpha lipoic acid-treated female rats showed little improvement as compared to the untreated stressed female rats and the treated male rats. In addition, alpha lipoic acid administration to stressed male and female rats resulted in improvement of the histological structure of the liver, as compared to their corresponding untreated stressed groups, the improvement being significantly greater in the treated female group compared to treated male group. |