Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor ␥ agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.Endocannabinoids, acting via the presynaptic cannabinoid type 1 receptor (CB 1 ), 1 stimulate appetite in the hypothalamus(1), but direct peripheral effects have also been observed in animal studies implicating endocannabinoids in peripheral signaling of nutritional status and lipogenesis (2). The CB 1 antagonist rimonabant (SR141716) inhibits food intake, and phase III clinical trials have shown sustained effects on weight loss in humans through effects on glucose and fat metabolism (3-5).Ghrelin is a circulating brain-gut peptide with growth hormone-releasing and appetite-inducing effects, with predominant expression in the gastric mucosa but low level widespread expression throughout the body (6 -8). Intracerebroventricular (i.c.v.) ghrelin treatment increases appetite and body weight, with a direct stimulatory effect on adipose tissue deposition demonstrated in both in vivo and in vitro studies (9, 10). It has been suggested that ghrelin favors preservation of lipid stores and the catabolism of carbohydrate-derived fuel, thereby increasing the respiratory quotient (11, 12). Ghrelin levels are high during fasting and in subjects with low body mass index, while low ghrelin levels are observed after food intake and in patients with insulin-resistant states such as type 2 diabetes, obesity, or polycystic ovarian syndrome (8). Both cannabinoids and ghrelin have been shown to have beneficial effects on the ischemic heart (13, 14). We have previously shown that ghrelin and the endocannabinoid system interact, as subanorectic doses of rimonabant can inhibit the orexigenic effect of ghrelin (15). Here we demonstrate a previously unrecognized interaction betw...

Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3 H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

The prevalence of thyroid microcarcinomas found at autopsies is 100-1000 times higher than in clinical cancer. The epidemiological and histological characteristics of thyroid microcarcinomas in consecutive series of autopsies performed in two areas of different iodine intake were investigated. Iodine deficient (ID) area: n = 222 (M = 109, F = 113), median age: 74-76 years, median iodine excretion (MIE) of nursing home residents from this area: 70 microg/g creatinine. Iodine sufficient (IS) area: n = 221 (M = 132, F = 89), median age: 68 years, MIE: 500 microg/g creatinine. When compared to the IS area, the results obtained in the ID area showed a higher thyroid weight (mean 27.75 g +/- 18.43 g vs. 16.5 g +/- 9.6 g, p < 0.0001) and a larger number of goitrous glands (50/222 vs. 5/221, p < 0.0001). Altogether 21 microcarcinomas were found (4.74%) with no iodine intake- or gender-related difference: ID n = 11 (4.95%), M/F = 8/3; IS n = 10 (4.52%), M/F = 6/4. Microcarcinomas seemed to be more prevalent in the 40-59-year age group. All microcarcinomas were of the papillary type. In conclusion, compared to clinical cancer, thyroid microcarcinomas are characterized by a two-scale higher prevalence, are not related to iodine intake, gender or nodularity, are most exclusively of the papillary type.

Formation of new blood vessels occurs in many physiological states (during development of the embryo, cycling changes of the female reproductive tract), as well as in pathological processes (such as diabetic retinopathy and wound healing). Angiogenesis has been shown to be related to tumor formation, prognosis, and response to treatment in many tumor types. Intratumoral microvessels can be related to tumor behavior or hormone secretion in different endocrine tumors. For example, invasive prolactinomas are more vascular than noninvasive adenomas; a surgical approach is more successful in macroprolactinomas with lower microvessel density. A higher number of microvessels have been found in papillary thyroid carcinomas during recurrences. A correlation between microvessel count and prognosis in papillary and medullary thyroid carcinomas has been suggested. Several stimulating and inhibiting factors involved in the regulation of angiogenesis have been identified. Among them, vascular endothelial growth factor (VEGF) has been shown to be critically involved in angiogenesis and also in the neovascularization of solid tumors. Dopamine agonists (already in clinical use for prolactinomas) have potent inhibitory actions on VEGF signaling, and thus may be a new tool in antiangiogenic therapy. Secretion of VEGF in the great majority of human pituitary adenomas is inhibited by dexamethasone. This suggests that glucocorticoids can be considered in the treatment of certain pituitary tumors. The cyclic nature of angiogenesis in the female reproductive tract indicates that stimulation or inhibition of paracrine angiogenic factors may lead to new approaches for being able to influence reproductive endocrine disorders. Experimental and clinical aspects of interactions between angiogenic factors and tumor growth of the endocrine system are also discussed.