Hypothalamic obesity induced by monosodium glutamate (MSG) in rats: changes in the endocrine pancreas in the course of and after induction obesity

Abstract

It has been reported that the neonatal administration of monosodium glutamate (MSG) in rodents produces lesions of the arcuate nucleus and the ventromedial nucleus of the hypothalamus and results in obesity in adulthood. Though there are a large number of reports using MSG-treated animals, most of them deal with neuronal and neuroendocrinological pathophysiology within the central nervous system. The present study, therefore, was designed to investigate the time-course of metabolic and hormonal changes in relation to the development of hypothalamic obesity induced by MSG in female Wister rats. In addition, responses of insulin and somatostatin to glucose loading were examined in rats with hypothalamic obesity. MSG, 2mg per g of body weight, was subcutaneously injected for 5 consecutive days after birth. Body weight, plasma glucose and immunoreactive insulin (IRI) were measured at one- to four-week intervals in rats aged from 6 days to 11 months. The Lee index, plasma triglyceride and immunoreactive glucagon (IRG) were measured at one-month intervals from one to 11 months. Immunoreactive somatostatin (IRS) and gastrin (IRGa) were determined at the 7th month or later. All parameters in plasma described above were assayed on samples drawn from the jugular vein. In addition, IRI and IRS in the pancreas were measured until 6 months. Further, responses of glucose, IRI and IRS to intragastric glucose loading (3g/kg body weight) were examined in portal plasma at the 11th month. All parameters in the MSG rats were compared with those in age-matched female controls which received the vehicle alone. Plasma IRI was elevated by 54% in the MSG rats even at the 6th day. Thereafter, the MSG rats showed a progressive increase in plasma IRI which was 96% and 237% higher at the 1st and 3rd month, respectively. Parallel with the change in plasma IRI, there was a constant 1.5-fold elevation of pancreatic IRI in the MSG rats aged between the 21st day and the 6th month, though pancreatic IRI decreased by 20% at 6 days. Pancreatic IRS also increased at the 21st day, but thereafter decreased by 48% at the 6th month. A progressive increase in plasma TG which was 37,139,203 and 279% higher at 2, 3, 4 and 5 months, respectively, was followed by a 2- to 3-fold elevation during following 6 months. The MSG rats showed a constant 20% reduction in body weight for the first 2 months, but thereafter showed a progressive increase throughout the observation which was 17, 39 and 55% higher at 4, 7 and 11 months, respectively. The Lee index of obesity also progressively increased from 337 ± 4 at the 3rd month to 390 ± 6 at the 8th month, but thereafter maintained a constant 1.2-fold elevation. In contrast with the marked changes in plasma IRI, no significant differences in plasma glucose were found between the two groups for the entire period of observation. Plasma IRG also showed a constant 1.2- to 2.0-fold elevation irrespective of the duration of obesity. Rats with obesity induced by MSG had markedly elevated levels of IRI and IRS not only in jugular plasma but also in portal plasma. In addition, responses of the two hormones to intragastric glucose loading were exaggerated in portal plasma, whereas response of plasma glucose was unchanged. Plasma IRGa was also observed to be increased by 38 - 81%. These findings indicate that hyperinsulinemia is the primary factor in the development of hypothalamic obesity induced by MSG. Hypothalamic obesity induced by neonatal administration of MSG in the rat is characterized by hypersecretion of glucagon and somatostatin as well as insulin, and may provide a readily available and valuable animal model for studying the hypothalamico-pancreatic axis.