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Lactogenic and Somatogenic Hormones Regulate the Expression of Neuropeptide Y and Cocaine- and Amphetamine-Regulated Transcript in Rat Insulinoma (INS-1) Cells: Interactions with Glucose and Glucocorticoids

Departments of Pediatrics and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Drs. Ramamani Arumugam and Michael Freemark, Box 3080, Duke University Medical Center, Durham, North Carolina 27710. E-mail: freem001{at}mc.duke.edu.

Lactogenic hormones stimulate food intake in rodents, ungulates, and birds. To test the hypothesis that lactogens regulate expression of neuropeptides that control appetite, we used the prolactin (PRL)-responsive rat insulinoma (INS-1) cell line as an experimental paradigm. INS-1 cells express mRNA for neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) but little or no agouti-related peptide or proopiomelanocortin. As in the hypothalamus in vivo, the levels of NPY mRNA in INS-1 cells were increased by glucose deprivation. Conversely, high media glucose concentrations (11 mM) reduced the levels of NPY mRNA and increased levels of CART mRNA. Rat PRL stimulated a 4- to 7-fold increase in NPY mRNA in INS-1 cells (P < 0.001) and reduced by 50–80% the levels of CART mRNA (P < 0.001). The effects of PRL on NPY mRNA were time and dose dependent and potentiated by glucose deprivation or exogenous dexamethasone (Dex). Hormonal induction of NPY mRNA was accompanied by increased secretion of NPY peptide into cellular conditioned media. PRL stimulated a 1.8- to 3.5-fold increase in expression of AMP-activated protein kinase (AMPK), which mediates in part the effects of hypoglycemia on NPY expression in the hypothalamus in vivo. Pharmacological inhibition of AMPK activity blunted slightly the effects of PRL on NPY and CART but reversed entirely the effects of Dex or of PRL plus Dex on CART mRNA. The effects of PRL on NPY, CART, and AMPK mRNA were mirrored by those of other lactogens and somatogens including placental lactogen and GH. Rat PRL and rat GH in combination had no additive or synergistic effects, suggesting that lactogenic and somatogenic hormones regulate neuropeptide gene expression through similar mechanisms. We conclude that lactogens act in concert with glucose deprivation and glucocorticoids to induce NPY expression and inhibit CART. We speculate that the lactogens facilitate food intake in response to fasting or nutrient deprivation, when glucose levels decline and cortisol levels rise.

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