Steroidogenic activity of highly potent melanotropic peptides in the adrenal cortex of the rat

Baumann, J. M.; Eberlé, Alex N.; Christen, E.; Ruch, W.; Girard, J.

doi:10.1530/acta.0.1130396

Cited by 17 publications

(11 citation statements)

References 20 publications

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“…To ensure that this effect represented a true initiation of a secretory response, rather than the amplification of a glucose-induced secretory response (see Ashcroft & Ashcroft 1992), in these experiments the basal glucose concentration was maintained at 2 mM, well below the threshold at which glucose will initiate a secretory response (4-5 mM; Ashcroft & Ashcroft 1992). The naturally occurring hormone, ACTH 1-39 , and a synthetic peptide with full corticotropic activity, ACTH 1-24 (Baumann et al 1986), were similarly effective as insulin secretagogues in static incubations over doses ranging from 100 pM to 10 nM. In perifusion experiments using MIN6 cells configured as pseudoislets, the response to 1 and 10 nM ACTH at 2 mM glucose was characterized by a rapid increase in insulin secretion that returned to almost basal levels within 15 min in the continued presence of the peptide.…”

Section: Discussionmentioning

confidence: 99%

ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans

Al-Majed

Jones

Persaud

et al. 2004

Journal of Endocrinology

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It has previously been suggested that ACTH and ACTHrelated peptides may act as paracrine modulators of insulin secretion in the islets of Langerhans. We have, therefore, examined the expression and function of the ACTH receptor (the melanocortin 2 receptor, MC2-R) in human and mouse primary islet tissue and in the MIN6 mouse insulinoma cell line. Mouse MC2-R mRNA was detected in both MIN6 cells and mouse islet tissue by PCR amplification of cDNA. In perifusion experiments with MIN6 pseudo-islets, a small, transient increase in insulin secretion was obtained when ACTH (1 nM) was added to medium containing 2 mM glucose (control) but not when the medium glucose content was increased to 8 mM. Further investigations were performed using static incubations of MIN6 cell monolayers; ACTH (1 pM-10 nM) provoked a concentration-dependent increase in insulin secretion from MIN6 monolayer cells that achieved statistical significance at concentrations of 1 and 10 nM (150 13·6% basal secretion; 187 14·9% basal secretion, P,0·01). Similar responses were obtained with ACTH 1-39 . The phosphodiesterase inhibitor IBMX (100 µM) potentiated the responses to sub-maximal doses of ACTH . Two inhibitors of the protein kinase A (PKA) signaling pathway, Rp-cAMPS (500 µM) and H-89 (10 µM), abolished the insulin secretory response to ACTH 1-24 (0·5-10 nM). Treatment with 1 nM ACTH 1-24 caused a small, statistically significant increase in intracellular cAMP levels. Secretory responses of MIN6 cells to ACTH 1-24 were also influenced by changes in extracellular Ca 2+ levels. Incubation in Ca 2+-free buffer supplemented with 0·1 mM EGTA blocked the MIN6 cells' secretory response to 1 and 10 nM ACTH 1-24 . Similar results were obtained when a Ca 2+ channel blocker (nitrendipine, 10 µM) was added to the Ca 2+ -containing buffer.ACTH 1-24 also evoked an insulin secretory response from primary tissues. The addition of ACTH 1-24 (0·5 nM) to perifusions of mouse islets induced a transient increase in insulin secretion at 8 mM glucose. Perifused human primary islets also showed a secretory response to ACTH 1-24 at basal glucose concentration (2 mM) with a rapid initial spike in insulin secretion followed by a decline to basal levels. Overall the results demonstrate that the MC2-R is expressed in -cells and suggest that activation of the receptor by ACTH initiates insulin secretion through the activation of PKA in association with Ca 2+ influx into -cells.

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Section: Discussionmentioning

confidence: 99%

ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans

Al-Majed

Jones

Persaud

et al. 2004

Journal of Endocrinology

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“…MC2R is acknowledged only to be activated by ACTH (Baumann et al 1986), for which reason binding studies were not performed on this receptor. In order to assess MCR agonist specificity, competition binding curves of ACTH, -MSH, NDP--MSH, MT-II, PG-901, SHU9119 and LY2112688 were obtained using cells over-expressing murine MC1R (mouse melanoma cells), murine MC3R and MC5R (recombinant CHO-K1 cells) and murine MC4R (recombinant BHK570 cells) (table 1).…”

Section: Binding Studiesmentioning

confidence: 99%

“…These peptides are generated from a common precursor proopiomelanocortin (POMC) and function as MCR agonists. It has previously been shown, that MC2R binds ACTH and none of the other POMC derived peptides (Baumann et al 1986;Boston & Cone 1996). When a MCR is stimulated, it couples to G s , which activates intracellular adenylyl cyclase and increases cAMP production.…”

Section: Introductionmentioning

confidence: 99%

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Møller

Raun

Jacobsen

et al. 2011

Molecular and Cellular Endocrinology

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The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R-MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and -melanocyte stimulating hormone (-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH-analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphateactivated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by -MSH, NDP--MSH, MT-II, SHU9119and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes. INTRODUCTIONThe melanocortin system acts through multiple pathways relevant for the prevention of obesity and obesity-related complications (Cone 1999;Marks et al. 2002;Spiegelman & Flier 2001). The system is acknowledged to have an important function in regulation of satiety and energy expenditure (Yaswen et al. 1999;Spiegelman & Flier 2001;Cheung et al. 1997;Azzara et al. 2002). MC4R knockout mice exhibit a well-described phenotype defined by increased lean body mass and fat mass, hyperphagia and disturbances in the metabolic response to overnutrition (Mountjoy et al. 1994;Huszar et al. 1997;Tschop & Heiman 2001). Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al. 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al. 2003). Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al. 2000;Huo et al. 2009). The melanocortin peptides and their receptors are also suspected to have a direct lipolytic effect on adipose tissues in rodents (Cho et al. 2005;Boston 1999;Spirovski et al. 1975). However this effect is controversial in humans (Hoch et al. 2007). The effect of melanocortins on adipocytes have by some researchers been explained by neuronal regulation of lipolysis (Brito et al. 2007), since MC4R mRNA has been identified in sympathetic neurons connected to white adipose tissue (WAT), indicating that central MC4R might stimulate lipid mobilization in the periphery (Song et al. 2005). However, studies in differentiated murine 3T3-L1 adipocytes suggest a direct lipolytic effect stimulated by melanocortin peptides ACTH and -MSH (Bradley et al. 2005;Cho et al. 2005), Page 3 of 24 A c c e p t e d M a n u s c r i p t 3 which supports the earlier identification of MC2R and MC5R mRNA in this cell line (Boston & Cone 1996). MC1R...

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“…However, recent investigations have shown an increase in anterior lobe content of IR-a-MSH in rat pituitaries following adrenalectomy (Estivariz et al, 1988). Desacetyl-a-MSH has also been shown to be a full agonist of a-MSH in stimulating the rat adrenal cortex (Baumann et al, 1986). Desacetyl-a-MSH has also been shown to be a full agonist of a-MSH in stimulating the rat adrenal cortex (Baumann et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…The function of a-MSH in mammals is largely unknown, although recent work has concentrated on its stimulation of the zona glomerulosa (Vinson et al, 1980). Thus, it has been repeatedly shown that a-MSH stimulates release of aldosterone in vitro from the rat adrenal (Szalay & Stark, 1982;Vinson et al, 1983Vinson et al, , 1986Baumann et al, 1986). Experiments performed in vivo have also demonstrated the specific steroidogenic action of a-MSH (Shenker et al, 1985) and in addition have suggested that a-MSH is mitogenic to cells of the rat zona glomerulosa (Robba et al, 1986).…”

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confidence: 99%

Increased Production of Α‐melanocyte‐stimulating Hormone in the Pituitary Gland of Patients With Untreated Addison's Disease

Coates¹,

McNicol²,

Doniach³

et al. 1988

Clinical Endocrinology

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There is evidence that peptides related to alpha-melanocyte-stimulating hormone (alpha-MSH) are involved in regulating the zona glomerulosa of the adrenal cortex in certain species. We have investigated the amount of immunoreactive (IR)-alpha-MSH in the human pituitary gland of patients suffering from Addison's disease. We show increased numbers of cells containing demonstrable IR-alpha-MSH in the anterior lobe in these patients. Using an antiserum with specificity for the acetylated N-terminus of alpha-MSH we suggest that the major form present is desacetyl-alpha-MSH. These findings are in keeping with a role for anterior lobe derived desacetyl-alpha-MSH in the regulation of the human adrenal cortex.

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Steroidogenic activity of highly potent melanotropic peptides in the adrenal cortex of the rat

Cited by 17 publications

References 20 publications

ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans

ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Increased Production of Α‐melanocyte‐stimulating Hormone in the Pituitary Gland of Patients With Untreated Addison's Disease

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