Summary
To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the “insulinized” than in the control groups. Conversely muscles from “insulinized” rats became insulin resistant. Such divergent consequences of prior “insulinization” on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.
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Abbreviations
- VMH:
-
Ventromedial hypothalamic area
- GLUT 4:
-
insulin responsive glucose transporter
- HPA:
-
hypothalamo-pituitary-adrenal
- NPY:
-
neuropeptide Y
- CRF:
-
corticotropin-releasing factor
- i.c.v.:
-
intracerebro-ventricularly
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Jeanrenaud, B. Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM. Diabetologia 37 (Suppl 2), S169–S178 (1994). https://doi.org/10.1007/BF00400841
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DOI: https://doi.org/10.1007/BF00400841