Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin-induced diabetic rats

To assess the dominance between hypoinsulinemia and hypoleptinemia as facto rs in the development of hyperphagia in streptozotocin (STZ)-induced diabet es mellitus (STZ-DM) rodents with respect to hormone-neuropeptide interacti ons, changes in gene expression of agouti gene-related protein (AGRP) in th e arcuate nucleus of the hypothalamus were investigated using STZ-DM rats, fasting Zucker fa/fa rats and STZ-DM agouti (STZ-DM A(y)/a) mice. AGRP mRNA and neuropeptide Y mRNA were both significantly up-regulated in STZ-DM rat s, which are associated with body weight loss, hyperglycemia, hypoinsulinem ia and hypoleptinemia. We proceeded to analyze whether insulin or leptin pl ayed the greater role in the regulation of AGRP using Zucker fa/fa rats. Th e AGRP mRNA did not differ significantly between fasted fa/fa rats, which h ave both leptin-insensitivity and hypoinsulinemia, and fed Zuckers, which h ave leptin-insensitivity and hyperinsulinemia. We further found that up-reg ulation of AGRP expression was normalized by infusion of leptin into the th ird cerebroventricle (i3vt), but not by i3vt infusion of insulin, although up-regulation of AGRP was partially corrected by systemic insulin infusion. The latter finding supports hypoleptinemia as a key-modulator of STZ-DM-in duced hyperphagia because systemic insulin infusion, at least partially, re stored hypoleptinemia through its acceleration of fat deposition, as demons trated by the partial recovery of lost body weight. After STZ-DM induction, A(y)/a mice whose melanocortin-4 receptor (MC4-R) was blocked by ectopic e xpression of agouti protein additionally accelerated hyperphagia and up-reg ulated AGRP mRNA, implying that the mechanism is triggered by a leptin defi cit rather than by the main action of the message through MC4-R. Hypoleptin emia, but not hypoinsulinemia per se, thus develops hyperphagia in STZ-DM r odents. These results are Very much in line with evidence that hypothalamic neuropeptides are potently regulated by leptin as downstream targets of it s actions.