Bariatric surgery induces morphological changes in the extensor digitorum longus muscle in the offspring of obese rats.

INTRODUCTION: The effects of the maternal nutritional environment on the growth and metabolism of the offspring, and its impacts on health in adult life are defined as metabolic programming. Thus, the objective of this study was to evaluate the effects of Roux-en-Y gastric bypass (RYGB) on the morphology of muscle fiber and neuromuscular junction (NMJ) of the offspring of rats submitted to RYGB. METHODS: Three-week-old Wistar rats were separated into two groups: 1) CAF SHAM which received a cafeteria diet and was submitted to a sham operation and 2) CAF RYGB, which received a cafeteria diet and was submitted to RYGB. The first generation (F1) offspring (male) was named according to the treatment of mothers as CAF SHAM-F1 and CAF RYGB-F1 and received a standard diet after weaning. At 17 weeks, the animals were euthanized, and the extensor digitorum longus muscle (EDL) was collected and processed in light microscopy and transmission electron microscopy for morphological and morphometric analysis. RESULTS: The CAF RYGB-F1 group showed a reduction in the weight of the EDL muscle and also a reduction in the area of type I, IIa and IIb fibers and a nucleus/fiber ratio. This same group also showed an increase in the capillary density and myofibrillar disorganization and in the Z-line, as well as a reduction in the area of the NMJs. CONCLUSION: The RYGB surgery in mothers produced morphological changes in the skeletal striated muscles of the offspring.

Perinatal exposure to low doses of glyphosate-based herbicide combined with a high-fat diet in adulthood causes changes in the jejunums of mice.

AIM: Exposure to pesticides and consumption of high-fat diets are widespread in society. Reports have shown that exposure to glyphosate and a high-fat diet can cause gastrointestinal disorders and increase susceptibility to obesity. Thus, this study evaluated the impacts of perinatal exposure to glyphosate followed by consumption of a high-fat diet in adulthood on the histology and morphometry of jejunums and enteric nervous system of C57BL/6 mice. MATERIAL AND METHODS: After mating, 20 C57BL/6 female mice were separated into a control group (CG) and a glyphosate group (GLY) that received water with 0.5% glyphosate. After the lactation period, some male offspring were randomly separated into CG-SD and GLY-SD (standard diet) groups or CG-HD and GLY-HD (high-fat diet) groups. After 12 weeks, jejunum samples were collected and submitted to histological analysis. KEY FINDINGS: Indirect exposure to glyphosate changed the morphometry of the intestinal wall, increased the proportion of intraepithelial lymphocytes (IELs) and goblet cells, and altered the area occupied by collagen fibers. The hyperlipidemic diet hypertrophied the jejunal total wall, total muscular and submucosal layers, decreased IELs, and increased the proportion of goblet cells. GLY-HD mice had shallower crypts, shorter villi, and less goblet cells and IELs than mice from GLY-SD group. GLY-HD also showed an increased number of neurons in myenteric and submucosal plexuses. Groups exposed to glyphosate and/or fed a high-fat diet had atrophied submucosal neurons. SIGNIFICANCE: This study suggests that perinatal glyphosate exposure combined with a high-fat diet in adulthood increases the risk of jejunum inflammation and dysfunction.

Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats.

Modifications in life-style and/or pharmacotherapies contribute to weight loss and ameliorate the metabolic profile of diet-induced obese humans and rodents. Since these strategies fail to treat hypothalamic obesity, we have assessed the possible mechanisms by which duodenal-jejunal bypass (DJB) surgery regulates hepatic lipid metabolism and the morphophysiology of pancreatic islets, in hypothalamic obese (HyO) rats. During the first 5 days of life, male Wistar rats received subcutaneous injections of monosodium glutamate (4 g/kg body weight, HyO group), or saline (CTL). At 90 days of age, HyO rats were randomly subjected to DJB (HyO DJB group) or sham surgery (HyO Sham group). HyO Sham rats were morbidly obese, insulin resistant, hypertriglyceridemic and displayed higher serum concentrations of non-esterified fatty acids (NEFA) and hepatic triglyceride (TG). These effects were associated with higher expressions of the lipogenic genes and fatty acid synthase (FASN) protein content in the liver. Furthermore, hepatic genes involved in ß-oxidation and TG export were down-regulated in HyO rats. In addition, these rats exhibited hyperinsulinemia, ß-cell hypersecretion, a higher percentage of islets and ß-cell area/pancreas section, and enhanced nuclear content of Ki67 protein in islet-cells. At 2 months after DJB surgery, serum concentrations of TG and NEFA, but not hepatic TG accumulation and gene and protein expressions, were normalized in HyO rats. Insulin release and Ki67 positive cells were also normalized in HyO DJB islets. In conclusion, DJB decreased islet-cell proliferation, normalized insulinemia, and ameliorated insulin sensitivity and plasma lipid profile, independently of changes in hepatic metabolism.

Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats

The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca2+ mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca2+ mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats.

Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats.

The parasympathetic nervous system is important for ß-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic ß-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca(2+) mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and ß-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and ß-cell area/pancreas section, respectively. Also, the ß-cell number per ß-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca(2+) mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater ß-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats.

Physical exercise introduced after weaning enhances pancreatic islet responsiveness to glucose and potentiating agents in adult MSG-obese rats.

Physical exercise represents an alternative way to prevent and/or ameliorate chronic metabolic diseases. Disruption of sympathetic nervous system (SNS) activity contributes to adiposity in obese subjects. Here, we verified the preventive effect of swimming training upon adiposity, adrenal catecholamine storage, and pancreatic islet function in obese monosodium glutamate (MSG)-treated rats. Male neonatal Wistar rats received MSG (4 mg/g body weight) during the first 5 days of life and, at weaning, half of the rats were submitted to swimming training, 30 min/day, 3 days a week, until 90 days of age (exercised rats: MSGex). Half of the rats were used as controls (sedentary group, MSGsd). Exercise training (ET) decreased insulinemia and fat deposition in MSGex, and increased adrenal catecholamine content, compared with MSGsd rats. Insulinemia during the ivGTT was lower in MSGex rats, despite a lack of difference in glycemia. Swimming training enhanced insulin release in islets challenged by 2.8-8.3 mmol/l glucose, whereas, at supraphysiological glucose concentrations (11.1-16.7 mmol/l), MSGex islets secreted less insulin than MSGsd. No differences in insulin secretion were observed following l-arginine (Arg) or K(+) stimuli. In contrast, islets from MSGex rats secreted more insulin when exposed to carbachol (100 µmol/l), forskolin (10 µmol/l), or IBMX (1 mmol/l) at 8.3 mmol/l glucose. Additionally, MSGex islets presented a better epinephrine inhibition upon insulin release. These results demonstrate that ET prevented the onset of obesity in MSG rats, probably by enhancing adrenal catecholamine levels. ET ameliorates islet responsiveness to several compounds, as well as insulin peripheral action.

Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium L-glutamate-obesity in mice.

Swimming exercises by weaning pups inhibited hypothalamic obesity onset and recovered sympathoadrenal axis activity, but this was not observed when exercise training was applied to young adult mice. However, the mechanisms producing this improved metabolism are still not fully understood. Low-intensity swimming training started at an early age and was undertaken to observe glycemic control in hypothalamic-obese mice produced by neonatal treatment with monosodium l-glutamate (MSG). Whereas MSG and control mice swam for 15 min/day, 3 days a week, from the weaning stage up to 90 days old, sedentary MSG and normal mice did not exercise at all. After 14 h of fasting, animals were killed at 90 days of age. Perigonadal fat accumulation was measured to estimate obesity. Fasting blood glucose and insulin concentrations were also measured. Fresh isolated pancreatic islets were used to test glucose-induced insulin release and total catecholamine from the adrenal glands was measured. Mice were also submitted to intraperitoneal glucose tolerance test. MSG-obese mice showed fasting hyperglycemia, hyperinsulinemia, and glucose intolerance. Severe reduction of adrenal catecholamines content has also been reported. Besides, the inhibition of fat tissue accretion, exercise caused normalization of insulin blood levels and glycemic control. The pancreatic islets of obese mice, with impaired glucose-induced insulin secretion, were recovered after swimming exercises. Adrenal catecholamine content was increased by swimming. Results show that attenuation of MSG-hypothalamic obesity onset is caused, at least in part, by modulation of sympathoadrenal axis activity imposed by early exercise, which may be associated with subsequent glucose metabolism improvement.

Parasympathetic activity changes insulin response to glucose and neurotransmitters.

Pancreatic islet isolated from hyperinsulinemic obese rodents showed high glucose sensitivity to stimulation of insulin secretion. Current research evaluates the effect of subdiaphragmatic vagotomy on insulin secretion stimulated by glucose and by a cholinergic agonist carbachol (Cch) in islets isolated from monosodium L-glutamate (MSG)-obese rats. During the first 5 days after birth, MSG was intradermically injected into the cervical area of male Wistar rats (n=26). Control animals were injected with hyperosmotic saline solution (n=26). Vagotomy was performed on 30-day-old rats. On the 90th day, after a 12-h fast, the animals were killed. Pancreatic islets were isolated by collagenase. Batches of islets (n=30) were incubated for 60 min in glucose 2.8-20.0 mM or 0.1-2.0 mM Cch in the presence of glucose 8.3 mM. Released insulin was measured by radioimmunoassay. Insulin secretion stimulated by glucose in islets from MSG-obese rats shifted to the left when compared to that of controls, 63.8+/-3.9 and 42.2+/-2.6 ng/ml/islet/60 min (p<0.001), respectively. Vagotomy decreased by 56% (p<0.001) the secretion induced by all glucose concentrations in islets from MSG-obese rats. In the controls the operation caused a 30% (p<0.01) reduction. Cch stimulated insulin secretion in normal and obese rat islets. Response to obese rat islets was 1/3 less than normal ones (p<0.05). Vagotomy produced a greater potentiation of Cch induced insulin secretion on islets from obese rats. Data suggested that parasympathetic modulation is important to insulin secretion control.

Vagotomy reduces obesity in MSG-treated rats.

In order to study the role of vagus nerve activity at the onset of obesity induced by monosodium glutamate (MSG), 30-day-old MSG-rats were vagotomized or sham operated. Body weight and food intake were recorded until animals were 90 days old and then sacrificed. Naso-anal length was recorded for all animals. Periepididymal and retroperitoneal fat pads were isolated and weighed. Reduction of body weight and naso-anal length were registered in 30-day-old MSG-rats. Obesity could also be observed, as increase of Lee index indicated. Results were most evident in 90-day-old MSG-rats. In both groups neither body weight gain nor food intake was changed by vagotomy. However, fat accumulation on tissues was reduced by vagotomy in MSG-rats. The results showed that MSG-obesity is not related to an increment in food intake behavior. Vagotonia might play a role at the onset of MSG-obesity.

Low protein diets administered to lactating rats affect in a time-dependent manner the development of young.

The effects of diets with different protein levels were evaluated when given at different intervals to lactating rats. Food intake by the litter and weight gain by the young are investigated. From the time of birth, groups of five litters were fed with commercial diet (23% protein) or with semi-synthetic diets (4,8,12 and 16% protein) during the 1st, 1st and 2nd, or 1st, 2nd and 3rd weeks of lactation. After weaning, the young of dams, which were fed hypoprotein diets (4 and 8%), showed less food intake capacity, reduced growth capacity and, in adult life, low body weight in comparison to animals raised on commercial ration with higher protein contents. 12 and 16% protein diets did not cause any change in feeding behavior or in weight development as opposed to the 4 and 8% protein diets. Results suggest that the effects of early undernourishment are time-dependent and may cause irreversible changes in the regulation of metabolism and pathogenesis.