Induction of ependymal, glial, and neuronal transactivation by intraventricular administration of the SGLT1 Na+-D-glucose cotransporter inhibitor phlorizin

Reports that food intake is stimulated by intracerebroventricular (icv) adm inistration of the SGLT1 Na+-D-glucose cotransport inhibitor, phlorizin, su ggest that decreased central glucose uptake is a stimulus for compensatory motor activity underlying restoration of energy imbalance. In order to iden tify central cell populations that are functionally responsive to decreased SGLT1 function in the brain, the present study utilized immunocytochemical techniques to demonstrate cellular expression of the inducible activator p rotein-1 transcription factor, Fos, following icv delivery of phlorizin. Gr oups of adult male rats were treated with phlorizin at a dose of 10, 50, or 250 mug/animal, then sacrificed 2hr later by transcardial perfusion. Epend ymal expression of immunoreactivity (-ir) was observed throughout most of t he cerebroventricular system, except the medullary fourth ventricle, at eac h dose examined. Higher doses of the transport inhibitor elicited immunosta ining of periventricular glia, characterized by cytoplasmic glial fibrillar y acidic protein-ir, underlying the lateral, third, and rostral fourth vent ricles and cerebral aqueduct. These doses also resulted in the transcriptio nal activation of neurons in discrete brain sites, including the. rostral m edial preoptic area, median preoptic n., preoptic and hypothalamic perivent ricular n., subfornical organ, thalamic medial habenular and paraventricula r n., hypothalamic paraventricular, ventromedial, and arcuate n., and n. of the solitary tract. These results show that nonexcitable cells located thr oughout much of the central neuroaxis and discrete populations of neurons i n the brain are genomically responsive to pharmacological inhibition of cen tral SGLT1 function. Evidence for the functional responsiveness of these ce ll types to manipulation of energy-dependent glucose transport suggests tha t cellular uptake of this metabolic fuel may serve as an indicator of centr al energy substrate availability, and that alterations in glucose uptake vi a this specific mechanism may be the source of regulatory signals involved in the maintenance of energy homeostasis.