BackgroundThis study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD).MethodsIn Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs.ResultsWistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver.ConclusionThe increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.

Similar to gestation/lactation, puberty is also a critical phase in which neuronal connections are still being produced and during which metabolic changes may occur if nutrition is disturbed. In the present study we aimed to determine whether peripubertal protein restriction induces metabolic programming. Thirty-day-old male rats were fed either a low protein (LP group) diet (4% w/w protein) or a normal protein (NP group) diet (23%) until 60 days of age, when they received the NP diet until they were 120 days old. Body weight (BW), food intake, fat tissue accumulation, glucose tolerance, and insulin secretion were evaluated. The nerve electrical activity was recorded to evaluate autonomous nervous system (ANS) function. Adolescent LP rats presented hypophagia and lower BW gain during the LP diet treatment (P!0.001). However, the food intake and BW gain by the LP rats were increased (P!0.001) after the NP diet was resumed. The LP rats presented mild hyperglycemia, hyperinsulinemia, severe hyperleptinemia upon fasting, peripheral insulin resistance and increased fat tissue accumulation and vagus nerve activity (P!0.05). Glucoseinduced insulin secretion was greater in the LP islets than in the NP islets; however, the cholinergic response was decreased (P!0.05). Compared with the islets from the NP rats, the LP islets showed changes in the activity of muscarinic receptors (P!0.05); in addition, the inhibition of glucose-induced insulin secretion by epinephrine was attenuated (P!0.001). Protein restriction during adolescence caused high-fat tissue accumulation in adult rats. Islet dysfunction could be related to an ANS imbalance.

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Nutritional insults during developmental plasticity have been linked with metabolic diseases such as diabetes in adulthood. We aimed to investigate whether a low-protein (LP) diet at the beginning of adulthood is able to program metabolic disruptions in rats. While control rats ate a normal-protein (23%; NP group) diet, treated rats were fed a LP (4%; LP group) diet from 60 to 90 days of age, after which an NP diet was supplied until they were 150 days old. Plasma levels of glucose and insulin, autonomous nervous system (ANS), and pancreatic islet function were then evaluated. Compared with the NP group, LP rats exhibited unchanged body weight and reduced food intake throughout the period of protein restriction; however, after the switch to the NP diet, hyperphagia of 10% (P!0.05), and catch-up growth of 113% (P!0.0001) were found. The LP rats showed hyperglycemia, insulin resistance, and higher fat accretion than the NP rats. While the sympathetic tonus from LP rats reduced by 28%, the vagus tonus increased by 21% (P!0.05). Compared with the islets from NP rats, the glucose insulinotropic effect as well as cholinergic and adrenergic actions was unaltered in the islets from LP rats. Protein restriction at the beginning of adulthood induced unbalanced ANS activity and fat tissue accretion later in life, even without functional disturbances in the pancreatic islets.

The aim of this study was determine whether the introduction of a high-fat diet during the peripubertal phase induces significant changes in body weight control, glucose homeostasis and the parasympathetic tonus compared with the administration of this diet to adult rats. High-fat diet was offered to male Wistar rats at weaning or during adulthood. A group of rats received high-fat diet for 60 days, from weaning to 81-day-old (HF81) or from 60 to 120-day-old (HF120), whereas 2 other groups received a normal-fat diet (i. e., NF81 and NF120). We analyzed adiposity, glucose homeostasis, insulin sensitivity, and vagal nerve activity. High-fat diet increased the accumulation of adipose tissue in all of the rats, but the difference was greater in the rats that were fed the high-fat diet since weaning (p<0.001). The HF rats showed glucose intolerance with high levels of insulin secretion during the glucose tolerance test (p<0.01). Rats that were fed the high-fat diet presented severe insulin resistance, indicated by a low K itt (p<0.01). Interestingly, the HF81 rats exhibited greater insulin resistance compared with the HF120 rats (p<0.05). The recordings of vagus nerve activity showed that the HF rats had higher parasympathetic activity than the NF rats irrespective of age (p<0.01). Our results show that a high-fat diet offered to rats just after weaning or in adulthood both cause impairment of glycemic homeostasis and imbalance in parasympathetic activity. Importantly, the consumption of high-fat diet immediately after weaning has more drastic consequences compared with the consumption of the same diet during adulthood.

Background/ Aims: Impaired pancreatic beta cell function and insulin secretion/action are a link between obesity and type 2 diabetes, which are worldwide public health burdens. We aimed to characterize the muscarinic acetylcholine receptor (mAChR) M₁-M₄ subtypes in isolated pancreatic islets from pre-diabetic obese rats that had been treated neonatally with monosodium L-glutamate (MSG). Methods: At 90 days of age, both the MSG and the control groups underwent biometric and biochemical evaluation. Anti-muscarinic drugs were used to study mAChR function either in vivo or in vitro. Results: The results demonstrated that atropine treatment reduced insulin secretion in the MSG-treated and control groups, whereas treatment with an M₂mAChR-selective antagonist increased secretion. Moreover, the insulinostatic effect of an M₃mAChR-selective antagonist was significantly higher in the MSG-treated group. M₁mAChR and M₃mAChR expression was increased in the MSG-obese group by 55% and 73%, respectively. In contrast, M₂mAChR expression decreased by 25% in the MSG group, whereas M₄mAChR expression was unchanged. Conclusions: Functional changes in and altered content of the mAChR (M₁-M₄) subtypes are pivotal to the demand for high pancreatic beta cell insulin secretion in MSG-obese rats, which is directly associated with vagal hyperactivity and peripheral insulin resistance.

Low intensity exercise during pregnancy and lactation may create a protective effect against the development of obesity in offspring exposed to overnutrition in early life. To test these hypotheses, pregnant rats were randomly assigned into 2 groups: Sedentary and Exercised, low intensity, on a rodent treadmill at 30% VO2Max /30-minute/session/3x/week throughout pregnancy and the lactation. Male offspring were raised in small litters (SL, 3 pups/dam) and normal litters (NL, 9 pups/dam) as models of early overnutrition and normal feed, respectively. Exercised mothers showed low mesenteric fat pad stores and fasting glucose and improved glucose-insulin tolerance, VO2max during lactation and sympathetic activity. Moreover, the breast milk contained elevated levels of insulin. In addition, SL of sedentary mothers presented metabolic dysfunction and glucose and insulin intolerance and were hyperglycemic and hyperinsulinemic in adulthood. SL of exercised mothers showed lower fat tissue accretion and improvements in glucose tolerance, insulin sensitivity, insulinemia and glycemia. The results suggest that maternal exercise during the perinatal period can have a possible reprogramming effect to prevent metabolic dysfunction in adult rat offspring exposed to early overnutrition, which may be associated with the improvement in maternal health caused by exercise.

Metabolic malprogramming has been associated with low birth weight; however, the interplay between insulin secretion disruption and adrenal function upon lipid metabolism is unclear in adult offspring from protein-malnourished mothers during the last third of gestation. Thus, we aimed to study the effects of a maternal low-protein diet during the last third of pregnancy on adult offspring metabolism, including pancreatic islet function and morphophysiological aspects of the liver, adrenal gland, white adipose tissue, and pancreas. Virgin female Wistar rats (age 70 d) were mated and fed a protein-restricted diet (4%, intrauterine protein restricted [IUPR]) from day 14 of pregnancy until delivery, whereas control dams were fed a 20.5% protein diet. At age 91 d, their body composition, glucose-insulin homeostasis, ACTH, corticosterone, leptin, adiponectin, lipid profile, pancreatic islet function and liver, adrenal gland, and pancreas morphology were assessed. The birth weights of the IUPR rats were 20% lower than the control rats (P < .001). Adult IUPR rats were heavier, hyperphagic, hyperglycemic, hyperinsulinemic, hyperleptinemic, and hypercorticosteronemic (P < .05) with higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol, adiponectin, ACTH, and insulin sensitivity index levels (P < .01). The insulinotropic action of glucose and acetylcholine as well as muscarinic and adrenergic receptor function were impaired in the IUPR rats (P < .05). Maternal undernutrition during the last third of gestation disrupts the pancreatic islet insulinotropic response and induces obesity-associated complications. Such alterations lead to a high risk of metabolic syndrome, characterized by insulin resistance, visceral obesity, and lower high-density lipoprotein cholesterol.