Unique alterations of neuropeptide content in median eminence, amygdala, and dorsal vagal complex of 3- and 6-week-old diabetes mutant mice

Abstract

The nature of the genetic defects which define the obese ( ob) and diabetes ( db) loci in mice remain unknown, but both produce similar syndromes when maintained in the same strain of mice. There is some evidence suggesting a lesion in the central nervous system (CNS) in db db mice, while ob ob mice appear to have a primary lesion outside the CNS. In a search for further evidence of a unique central lesion in db db mice, we have examined neuropeptide content in selected, microdissected brain areas in both of these mutants and lean controls. In order to rule out possible interactions of the db mutation with the genetic background, diabetes mice of both C57BL KsJ and C57BL 6J strains were studied. When concentrations of nine neuropeptide immunoreactivities were examined in up to seven microdissected areas of the brain, C57BL 6J ob ob mice showed only one reproducible alteration, a lower content of β-endorphin-like immunoreactivity (LI) in the preoptic area at both 3 and 6 weeks of age as compared with lean littermates. In contrast, db db mice of both C57BL 6J and C57BL KsJ strains exhibited alterations in a total of four peptides in three brain areas: lower concentration of somatostatin-LI in median eminence, higher Met-enkephalin-LI in dorsal vagal complex of the medulla oblongata, higher substance P-LI and lower vasoactive intestinal polypeptide (VIP)-LI in amygdala. The concentrations of the peptides studied in medial basal hypothalamus, lateral hypothalamus, substantia nigra, and preoptic area were not reproducibly altered in db db mice. These data provide preliminary evidence for unique brain abnormalities in db db mice in specific areas that are involved in processing of neural signals that can affect the islets of Langerhans, gonadotropin secretory patterns, and many other visceral functions. The observations suggest that selected neurons or fibers in the amygdala, dorsal vagal complex (DVC), and/or median eminence may be directly affected by the genetic defect in db db mice, ultimately resulting in obesity, insulin resistance, and hyperinsulinemia, as well as associated endocrine abnormalities. The very different findings in brain areas of ob ob mice are consistent with the hypothesis that a somewhat different mechanism, or possibly a defect in a different component of the same neuroendocrine pathway, is primarily involved in producing the similar syndrome in ob ob mice of the same strain.