Sulfated cholecystokinin-8 activates phospho-mTOR immunoreactive neurons of the paraventricular nucleus in rats

Abstract

The serin/threonin-kinase, mammalian target of rapamycin (mTOR) was detected in the arcuate nucleus (ARC) and paraventricular nucleus of the hypothalamus (PVN) and suggested to play a role in the integration of satiety signals. Since cholecystokinin (CCK) plays a role in the short-term inhibition of food intake and induces c-Fos in PVN neurons, the aim was to determine whether intraperitoneally injected CCK-8S affects the neuronal activity in cells immunoreactive for phospho-mTOR in the PVN. Ad libitum fed male Sprague-Dawley rats received 6 or 10 μg/kg CCK-8S or 0.15 M NaCl ip (n=4/group). The number of c-Fosimmunoreactive (ir) neurons was assessed in the PVN, ARC and in the nucleus of the solitary tract (NTS). CCK-8S increased the number of c-Fos-ir neurons in the PVN (6 μg: 103 ± 13 vs. 10 μg: 165 ± 14 neurons/section; p<0.05) compared to vehicle treated rats (4 ± 1, p<0.05), but not in the ARC. CCK-8S also dose-dependently increased the number of c-Fos neurons in the NTS. Staining for phospho-mTOR and c-Fos in the PVN showed a dose-dependent increase of activated phospho-mTOR neurons (17 ± 3 vs. 38 ± 2 neurons/section; p<0.05), while no activated phospho-mTOR neurons were observed in the vehicle group. Triple staining in the PVN showed activation of phospho-mTOR neurons co-localized with oxytocin, corresponding to 9.8 ± 3.6% and 19.5 ± 3.3% of oxytocin neurons respectively. Our observations indicate that peripheral CCK-8S activates phospho-mTOR neurons in the PVN and suggest that phospho-mTOR plays a role in the mediation of CCK-8S's anorexigenic effects.

Hypothalamic mTOR pathway mediates thyroid hormone‐induced hyperphagia in hyperthyroidism

“…To provide additional insights, we examined the localization of mTOR and thyroid hormone receptor in the rat hypothalamus. In keeping with previous observations, our data show that mTOR is highly expressed in key hypothalamic nuclei modulating feeding, such as the ARC, PVH and VMH [25,30,31]. Notably, our localization studies also show that mTOR is highly co-expressed with TRα in the ARC, raising the possibility of direct regulation of mTOR activity by thyroid hormones at this level.…”

“…Recent evidence has shown that hypothalamic mTOR signalling plays a major role in modulating energy balance [22,[25][26][27][28][29]. In rats, mTOR pathway is highly expressed in specific hypothalamic regions, such as the arcuate (ARC), paraventricular (PVH) and suprachiasmatic (SCN) nuclei [25,30,31]. Within the ARC, mTOR co-localizes with neuropeptide Y (NPY; and thus with agouti-related protein, AgRP [32]) and proopiomelanocortin (POMC) neurons [25,33].…”

Cholecystokinin

“…The PVN neurons activated by CCK express cocaine and amphetamine regulated transcript (CART) and phosphor-mammalian target of rapamycin [17,18]. The PVN neurons activated by CCK express cocaine and amphetamine regulated transcript (CART) and phosphor-mammalian target of rapamycin [17,18].…”

Ingestive Peptides – An Emerging Tool for Diagnostics and Therapeutics: A Review

“…Cholecystokinin control intestinal motility (Schultzberg et al 1980). Gibbs et al (1973) detected that exogenous CCK prohibits dietary intake and also in rodents (Lembke et al 2011;Bewick 2012;Engster et al 2014). CCK can regulate the contraction of the gallbladder, the secretion and the growth of the pancreas, the gastric emptying, the duodenal secretion, satiety, glucose homoeostasis and insulin secretion (Wattez et al 2013).…”