Ghrelin secretion stimulated by β ₁ -adrenergic receptors in cultured ghrelinoma cells and in fasted mice

Abstract

Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding β 1 -adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective β 1 -adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on β 1 receptors on the ghrelinsecreting cells of the stomach.

Surviving Starvation: Essential Role of the Ghrelin-Growth Hormone Axis

“…Of the 10 peptide hormones tested, none stimulated ghrelin secretion in either PG-1 or SG-1 cells. In contrast, norepinephrine stimulated ghrelin secretion two-to threefold at a half-maximal concentration of 0.1 mM in both cell lines (Zhao et al 2010b). Forskolin mimicked the norepinephrine effect, indicating that the neurotransmitter acted by activating adenylyl cyclase (Fig.…”

“…Earlier indirect evidence suggested that the sympathetic nervous system might stimulate ghrelin secretion (Mundinger et al 2006;Hosoda and Kangawa 2008), but the hypothesis could not be tested directly, owing to the paucity of ghrelin-secreting cells in the stomach. To circumvent this problem, we and our colleagues created lines of ghrelin-secreting tumor cells that could be maintained in tissue culture (Zhao et al 2010b). For this purpose, we created a BAC transgene encoding oncogenic SV40 T-antigen driven by the promoter of the ghrelin gene.…”

“…On day 3, cells were centrifuged, resuspended in serum-free medium with 50 mM octanoate, aliquoted into 24-well plates (5 Â 10 4 cells/well), and treated with 100 nM of the indicated peptide hormone or 10 mM norepinephrine. After incubation at 37˚C for 6 h, the medium from each well was harvested for measurement of ghrelin as described (Zhao et al 2010b). (B) Dose-dependent stimulation of ghrelin secretion by adrenergic, but not by a cholinergic or a GABA agonist, in PG-1 cells.…”

“…Tumors were removed, and the cells were dissociated and placed in tissue culture, where they proliferated and secreted ghrelin. Two stable and clonally derived ghrelinoma cell lines were isolated, PG-1 cells from pancreatic ghrelinomas and SG-1 cells from stomach ghrelinomas (Zhao et al 2010b).…”

Obesity and Weight Regulation

“…Psychosocial stress leads to elevations in circulating levels of acyl-ghrelin. As sympathoadrenal tone is increased in stress, speculatively, this stress-induced elevation may involve stimulation of ␤ 1 -adrenergic receptors on ghrelin cells, a pathway that has been implicated in ghrelin release in response to fasting [44,51]. Ghrelin, in turn, interacts with its receptor, GHSR, which is distributed throughout the brain and periphery [52].…”