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In male Wistar rats the influences of age and experimental obesity on the activity of malic enzyme (EC 1.1.1.40) in different organs were studied. Obesity was induced in newborn rats by injection of Na(+)-L-glutamate (2 mg/g b.w. daily) subcutaneously in the first 5 days. The enzyme activity was measured at the ages of 2, 6 and 18 months. In control animals the highest enzyme activities were found in the heart muscle, liver, epididymal fat pad and skeletal muscle after 6 months. After 18 months the activities in these organs are considerably reduced. In the kidneys the activity between the 2nd and the 18th months tends to decrease continuously and only the brain shows an opposite trend. In comparison with the control animals, in glutamate treated rats the enzyme activity doubles nearly in the lipogenic organs liver and fat tissue in all age groups. In liver and fat tissue of 6-month-old rats, previously treated with clonidine to stimulate growth hormone secretion, the activities are lower than in glutamate obese rats without clonidine, but still higher than in normal control animals. The qualification of glutamate obese rats as a model for the study of age-associated diseases like obesity or diabetes mellitus type II needs further investigation.

Glutamate-induced obesity of Wistar-rats is known to develop under normophagic and normoinsulinemic conditions, although hyperphagia and hyperinsulinemia are common to obese individuals. Rats of this obesity model show retarded growth, reduced mass of some organs, carcass and whole body as well as an extraordinary high fat content, whereas protein content is reduced. In this study, nitrogen (N) balance, urinary excretion of urea-N, ammonia-N, creatine-N and alpha-amino acid-N and plasma free fatty acid concentration of growing, glutamate-induced obese rats were determined. The main results were independent of frame of reference (mmol N/kg body mass; mmol N/kg0.75 metabolic body mass; N in % of nitrogen intake): Nitrogen intake, urinary excretion of alpha-amino acids and nitrogen excretion in faeces were equal between lean and obese rats. Nitrogen excretion in urine was elevated in obese rats, mainly resulting from increased amounts of urea and ammonia. Nitrogen balance was positive in both groups, but reduced in obese rats. These data point to normal digestion of food proteins, but an unusual high oxidative desamination rate of the absorbed amino acids in obese rats. Taking into account the various hormonal and nerval alterations in glutamate-induced obese rats, resulting e.g. in increased hepatic insulin concentration, the retained amino acid carbon should be channelled into hepatic fatty acid synthesis. Really, unfasted and overnight fasted obese rats showed elevated plasma free fatty acid concentrations. Channeling of amino acids into lipogenesis may explain the low muscle mass and striking fat accumulation--despite normophagia and peripheral normoinsulinemia--of growing, glutamate-induced obese Wistar-rats.

Injection of Na-L-glutamate into neonate Wistar-rats (2 mg/g body mass s.c.; day 1-5 of life) induces hypothalamic lesions, which are followed by hypoplastic-hypertrophic obesity despite normophagia. In contrast to other animal models of obesity, these rats develop obesity under peripheral normoinsulinemic conditions. However, beginning at an age of 2 months (growing rats), peripheral insulin concentration rises gradually and at an age of 6 months (adults rats) hyperinsulinemia becomes manifest. Surprisingly, adult rats show normoglycemia, pointing to alterations in insulin sensitivity. In continuation to previous work, insulin binding of different organs of growing and adult rats was investigated using the in vivo radioreceptor assay described by Whitcomb et al. in 1985. In contrast to in vitro methods, this assay works under real metabolic and hormonal conditions in plasma of lean and obese rats. Insulin binding of liver, pancreas, adrenals, stomach, duodenum, spleen, and heart muscles was found to be not statistically different between lean and obese rats of both age groups. Thus, liver insulin binding was 6323 +/- 458 pg/g wet organ in growing, and 7586 +/- 959 pg/g in adult lean rats. Corresponding values for obese rats were 5755 +/- 445 pg/g and 7830 +/- 526 pg/g, respectively. Organ specific down regulation of insulin binding in obese rats was not detected, suggesting unalterated insulin sensitivity. It is concluded that hyperinsulinemia of adult glutamate-induced obese rats cannot be explained by diminished insulin binding and reduced organ specific insulin clearance.

Na,K- and Ca,Mg-ATPase activities in the membrane of red blood cells (RBC) were determined in glutamate treated obese rats (GOR). Both activities are related oppositely. In the obese rats the Na,K-ATPase is higher but the efficiency in maintenance of Na/K-ion concentration gradients is diminished. Ca,Mg-ATPase is decreased in GOR. Under the hypermetabolic condition of cold adaption the Na,K-ATPase activity decreases and the Ca,Mg-ATPase activity rises in both animal groups. The Na,K-ATPase activity in RBC-membranes is positively related to fat accumulation and age.

Development of hyperinsulinemia was investigated which appeared late in the obese state in rats postnatally treated with L-glutamate. Insulin concentrations were estimated in the blood plasma of the caval and portal vein, and morphometric and immunohistochemical measurements of cells in the islets of Langerhans were performed, and also glucose tolerance tests. Not earlier than at 3 months hyperinsulinemia is shown in glutamate obese rats (GOR) in the peripheral blood plasma. Also in the portal blood plasma the insulin concentration is higher (167%) in GOR relative to controls. The insulin concentrations in the portal vein rise further in both animal groups whereas insulin concentration in the peripheral blood remains at the different levels in both animal groups. Impaired glucose tolerance was observed for GOR only. Islets of Langerhans in the Pancreas show enlargement and increased proliferation of B-cells in GOR. In contrast the number of D-cells is diminished. The hyperplasia of islets differs remarkably to hypoplasia of other organs in GOR. We conclude that the peripheral hyperinsulinemia is caused by a permanent hypersecretion of insulin.

Administration of monosodium glutamate to neonate rats causes hypothalamic lesions in the region of the nucleus arcuatus and the eminentia mediana, followed by massive accumulation of triglycerides, diminished secretion of growth hormone, reduced body length and organ weights and diminished number of adipocytes (hypoplastic-hypertrophic obesity). Locomotor activity of obese animals is reduced by about 50%. Food intake is increased by about 10% during growth and development of obesity but decreased beneath the level of that in control animals in the stationary phase of obesity. Hyperinsulinemia coupled with insulin resistance develops in the stationary phase of obesity, i.e. when adipocyte diameter has reached approximately 100 microns. The effects of reduced secretion of growth hormone are considered to be a main factor of fat accumulation in this type of obesity.

Injections of monosodium glutamate to neonate rats induce chronic growth hormone deficiency by hypothalamic lesions in the regions of the nucleus arcuatus and the eminentia mediana. The glutamate treated rats develop massive obesity. By this type of obesity hyperinsulinemia in the dynamic phase is not evident. The adipose tissue of the GOR (glutamate obese rat) is characterized by hypertrophic adipocytes and diminished number of adipocytes. In the GOR glucose oxidation and glucose lipid conversion are increased, but insulin sensitivity of glucose metabolism is diminished. The enhanced glucose utilization in adipose tissue of the GOR is discussed as being the consequence of the chronic growth hormone deficiency.