Changes in the hypothalamo-pituitary-adrenal axis of genetically obese fa/fa rats: a structural, immunocytochemical, and morphometrical study.

Most metabolic disorders of genetically obese Zucker rats are reversed by adrenalectomy and are restored by corticosterone treatment, thus suggesting that a functional hypercorticosteronemic state is involved in the pathogenesis of the obesity syndrome in fa/fa rats. However, the hormone content and morphology of the hypothalamo-pituitary-adrenal axis of this animal model have to our knowledge not yet been described. We, thus, investigated morphologically and morphometrically the hypothalamic regions involved in CRF synthesis and secretion in male fa/fa rats. To ascertain if the brain is selectively or uniformly affected, we studied the main nuclei of the lateral and mediobasal hypothalamus, i.e. arcuate, lateral hypothalamic, and ventromedial nucleus and the parvicellular portion of the paraventricular nucleus. Moreover, after immunocytochemical labeling, we analyzed densitometrically the CRF-bearing axons of the median eminence and the ACTH-containing cells of the anterior and intermediate lobe of the pituitary gland. Finally, we investigated the adrenal glands by qualitative light microscopy. In fa/fa rats most hypothalamic nuclei were structurally changed. Furthermore, hypothalamic CRF and anterior pituitary ACTH contents as well as adrenal weight were increased, the zona fasciculata of the adrenal cortex was hypertrophic, and the ACTH content of the intermediate lobe was reduced. In conclusion, our results demonstrate that the obesity syndrome in genetically obese fa/fa rats is associated with lesions of the hypothalamo-pituitary-adrenal axis consistent with hyperadrenocorticism due to hyperactivity of the whole adrenal axis. Alterations also occur in the hypothalamic nuclei controlling glycemia, insulinemia, and circadian corticosterone secretion.