Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis.

BACKGROUND/OBJECTIVES: Glucose from the diet may signal metabolic status to hypothalamic sites controlling energy homeostasis. Disruption of this mechanism may contribute to obesity but its relevance has not been established. The present experiments aimed at evaluating whether obesity induced by chronic high-fat intake affects the ability of hypothalamic glucose to control feeding. We hypothesized that glucose transport to the hypothalamus as well as glucose sensing and signaling could be impaired by high-fat feeding. SUBJECTS/METHODS: Female Wistar rats were studied after 8 weeks on either control or high-lard diet. Daily food intake was measured after intracerebroventricular (i.c.v.) glucose. Glycemia and glucose content of medial hypothalamus microdialysates were measured in response to interperitoneal (i.p.) glucose or meal intake after an overnight fast. The effect of refeeding on whole hypothalamus levels of glucose transporter proteins (GLUT) 1, 2 and 4, AMPK and phosphorylated AMPK levels was determined by immunoblotting. RESULTS: High-fat rats had higher body weight and fat content and serum leptin than control rats, but normal insulin levels and glucose tolerance. I.c.v. glucose inhibited food intake in control but failed to do so in high-fat rats. Either i.p. glucose or refeeding significantly increased glucose hypothalamic microdialysate levels in the control rats. These levels showed exacerbated increases in the high-fat rats. GLUT1 and 4 levels were not affected by refeeding. GLUT2 levels decreased and phosphor-AMPK levels increased in the high-fat rats but not in the controls. CONCLUSIONS: The findings suggest that, in the high-fat rats, a defective glucose sensing by decreased GLUT2 levels contributed to an inappropriate activation of AMPK after refeeding, despite increased extracellular glucose levels. These derangements were probably involved in the abolition of hypophagia in response to i.c.v. glucose. It is proposed that 'glucose resistance' in central sites of feeding control may be relevant in the disturbances of energy homeostasis induced by high-fat feeding.

Neonatal monosodium glutamate treatment alters rat intestinal muscle reactivity to some agonists.

The following study is an investigation of the changes in the contractile reactivity of visceral muscles in response to agonists and alterations in metabolic parameters after neonatal rat treatment with monosodium-L-glutamate. This treatment markedly sensitizes ileum and colon preparations to adenosine-5'-triphosphate (ATP) stimulation and also increases the colon activity to acetylcholine (p<0.05). Response to bradykinin remained unchanged, while ileum activity to angiotensin II was characterized by a reduction in the maximal tension (E(max)) and an increase in the EC(50) (p<0.05) value. The responses of nonintestinal muscle preparations from monosodium-glutamate-treated rats to both ATP and bradykinin did not show a significant difference when compared to the controls. This treatment diminished food intake, feces excretion and increased plasma insulin, nonesterified fatty acids and triglyceride concentrations (p<0.001). These results suggest that the changes in intestinal muscle activity, in response to agonists, can be due to metabolic alterations as well as the monosodium glutamate action on enteric neurons and/or smooth muscle receptors.

Neonatal treatment with monosodium glutamate increases plasma corticosterone in the rat.

Monosodium glutamate (MSG) has been shown to alter several neuroendocrine functions in neonatally treated rats. To evaluate for possible alterations in the hypothalamic-pituitary-adrenal axis, we injected rats during the neonatal period with MSG or saline (controls). An increase in basal plasma corticosterone levels associated with a blunted circadian variation was observed. Ether exposure produced a significant elevation in plasma corticosterone concentration in both groups of animals. However, while the increase in controls was 181.3% for male and 193.9% for female rats, in the MSG-treated rats it was only 60.7 and 31.6%, respectively. The intraperitoneal administration of high dexamethasone doses blocked corticosterone secretion in both groups. However, whereas the lowest dose (0.10 microgram/kg) suppressed corticosterone secretion in control animals, it was ineffective in MSG-treated rats. The morphological study of adrenals revealed signs of a hyperfunctional state in MSG-treated rats. These data suggest that the central lesions produced by MSG treatment disrupt the regulation of the hypothalamic-pituitary-adrenal axis.