ACTH 22-39 (Adrenocorticotropic Hormone (22-39))

C-terminal fragments of ACTH stimulate feeding in fasted rats

Peptides derived from pro-opiomelanocortin, including alpha-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [alpha-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide alpha-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.

Beta-cell tropin: synthesis and biological activity

The structure of beta-cell tropin, an insulin secretagogue released by the neuro-intermediate lobe of the obese (ob/ob) mouse, has recently been determined as the 22-39 moiety of ACTH. A method for the preparation of this octadecapeptide using mild solid-phase procedures followed by preparative high pressure liquid chromatography is described. The molecular weight of the synthetic peptide has been confirmed by Fast Atom Bombardment mass spectrometry. Synthetic beta-cell tropin is indistinguishable in its chromatographic, antigenic and biological properties from natural beta-cell tropin.

Proteolysis of adrenocorticotropin in brain. Characterization of cleavage sites by peptidases in synaptic membranes and formation of peptide fragments

The biotransformation of adrenocorticotropin (ACTH-(1-39)) by brain synaptic membranes has been studied. Peptide fragments of ACTH-(1-39) which were formed during in vitro incubation of the peptide with membrane preparations were isolated by high pressure liquid chromatography and characterized by determination of amino acid composition and NH2- terminal residue. At pH 7.4, ACTH-(1-38) was found as the main metabolite, together with ACTH-(7-21) and ACTH-(7-20). In addition, a series of secondary products was identified. At pH 6.2, ACTH-(1-38), ACTH-(1-37), and ACTH-(1-36) were exclusively formed, while at pH 8.5, ACTH-(1-39) was converted into ACTH-(1-16), ACTH-(17-39), ACTH-(22-39), and ACTH-(3-15). Time course experiments demonstrated the action of a carboxypeptidase activity and a trypsin-like endopeptidase on ACTH-(1-39) as predominant proteolytic events. The carboxypeptidase was optimally active at pH values of 5.7 or below. These enzymes play an essential role in the stepwise conversion of ACTH-(1-39) in brain. It is suggested that they are involved in the modulation of the central activities of ACTH fragments in the brain.

Evidence for the presence of the pituitary insulin secretagogue beta-cell trophin in human plasma

It has been demonstrated that the insulin secretagogue beta-cell-trophin, ACTH(22-39), is present in human plasma. The hormone, separated from plasma by affinity chromatography on a corticotrophin-like intermediate-lobe peptide antibody column, behaves similarly to synthetic beta-cell-trophin on a gel filtration column and on reverse-phase high-performance liquid chromatography. Sufficient amounts of the hormone were isolated from the plasma of two patients with Nelson's syndrome to demonstrate its biological activity on the perfused rat pancreas.

Correlation between plasma beta-cell tropin concentrations and body weight in obese rhesus monkeys

The fasting plasma concentration of the pituitary peptide beta-cell tropin [beta-CT, adrenocorticotropic hormone-(22-39)] was measured in 17 rhesus monkeys from a colony known to develop spontaneous obesity. The weight of the animals was 9.4-23.9 kg (12-46% body fat). Plasma beta-CT concentrations were 0.03-0.84 nmol/l and were strongly correlated with body weight (P = 0.014, r = 0.584). Plasma beta-CT was also correlated with plasma insulin concentration as a power function (P = 0.011, r = 0.600) and with percent body fat up to 40% (P = 0.003, r = 0.0804). Plasma insulin is also correlated with body weight (P = 0.015, r = 0.578) but does not decline when body fat is in excess of 40%, supporting the hypothesis that beta-CT may be involved in a feed-back control mechanism, perhaps mediated by insulin. Because beta-CT has been shown in rodent studies to be a potent insulin secretagogue and lipogenic agent, it is possible that beta-CT is causally involved in the development of obesity and that there may be central determinants of obesity mediated through pituitary secretion of beta-CT.