New aspects of melanocortin signaling: A role for PRCP in α-MSH degradation

Diano, Sabrina

doi:10.1016/j.yfrne.2010.09.001

Cited by 49 publications

(31 citation statements)

References 236 publications

(323 reference statements)

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“…Observations linking PRCP to hypertension, preeclampsia and the metabolic syndrome are consistent with its reported effects on the renin-angiotensin and kallikrein-kinin systems [38–40], and indicate that PRCP might be an attractive target for treating cardiovascular or inflammatory disorders. More recently, PRCP has been implicated in the regulation of food intake in mice [15, 41]. PRCP activity appears to lead to increased food intake by converting α-MSH (also referred to as α-MSH 1–13 ) to α-MSH 1–12 .…”

Section: Discussionmentioning

confidence: 99%

Influence of a Novel Inhibitor (UM8190) of Prolylcarboxypeptidase (PRCP) on Appetite and Thrombosis

Rabey¹,

Gadepalli²,

Diano³

et al. 2012

CMC

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Preclinical pharmacological characterization of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) was investigated. We synthesized and evaluated a library of proline-based analogs as prospective recombinant PRCP (rPRCP) inhibitors and inhibitors of PRCP-dependent prekallikrein (PK) activation on human pulmonary artery endothelial cells (HPAEC). Among the newly synthesized compounds, UM8190 was further characterized in vivo using methods that encompassed a mouse carotid artery thrombosis model and animal model of food consumption. (S)-N-dodecyl-1-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide [Compound 3 (UM8190)] was selected for further evaluation from the initial assessment of its PRCP inhibitory action (Ki= 43 µM) coupled with its ability to block PRCP-dependent PK activation on HPAEC (Ki= 34 µM). UM8190 demonstrated excellent selectivity against a panel of carboxypeptidases and serine proteases and blocked bradykinin (BK) generation and BK-induced permeability by 100%, suggesting that it may be useful in preventing the local production of large amounts of BK. Furthermore, UM8190 showed an anorexigenic effect when systemically administered to fasted mice, reducing food intake in a dose- and time-dependent manner. In a mouse carotid artery thrombosis model, it also demonstrated an antithrombotic effect. UM8190 is a selective PRCP inhibitor and it may represent a new anorexigenic, and antithrombotic drug, that works by inhibiting PRCP–mediated mechanisms.

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Section: Discussionmentioning

confidence: 99%

Influence of a Novel Inhibitor (UM8190) of Prolylcarboxypeptidase (PRCP) on Appetite and Thrombosis

Rabey¹,

Gadepalli²,

Diano³

et al. 2012

CMC

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“…POMC mRNA is expressed not only in the hypothalamic arcuate nucleus but also in other brain areas, including the brainstem and pituitary (4). This gene encodes a polypeptide hormone precursor that undergoes tissue-specific proteolysis, thus generating a specific repertoire of biologically active peptides and hormones, including adrenocorticotropin (ACTH), α-, β- and γ-MSHs, and β-endorphin (Figure 2b), all of which can modulate food consumption and energy balance.…”

Section: Pomc Processingmentioning

confidence: 99%

“…The arcuate melanocortin neurons consist of two distinct neuronal populations: the pro-opiomelanocortin (POMC)-expressing neurons and the neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing neurons. More recent studies using pharmacogenetic and optogenetic techniques (2, 3) have further proved that although POMC neuronal activation reduces food intake and increases energy expenditure, NPY/AgRP neuronal activation induces increased food intake and decreased energy expenditure (4, 5). These opposite functions in metabolism regulation are accomplished by the opposite effects on their target neurons, the melanocortin 4 receptor (MC4R)-expressing neurons, in several brain areas.…”

Section: Introductionmentioning

confidence: 99%

“…POMC cells activate MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH) and in other brain regions, including the brainstem, thus inhibiting food intake and increasing energy expenditure. Conversely, NPY/AgRP neurons antagonize these effects (4). Furthermore, the NPY/AgRP neurons, containing the inhibitory neurotransmitter GABA, project onto POMC neurons (1).…”

Section: Introductionmentioning

confidence: 99%

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POMC Neurons: From Birth to Death

Toda

Santoro

Kim

et al. 2017

Annu. Rev. Physiol.

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132

121

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The hypothalamus is an evolutionarily conserved brain structure that regulates an organism’s basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.

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“…In the short term, central administration of MSH analogs decreases feeding and improves glucose metabolism (McMinn et al 2000, Obici et al 2001, Petervari et al 2011. In the long term, melanocortin activation leads to reduced body weight and improved glucose tolerance in obese animal models (Savontaus et al 2004, Lee et al 2008, Wallingford et al 2009, Diano 2011, Jeong et al 2012a. On the other hand, the disruption of the melanocortin pathways leads to obesity in genetically modified mice and in humans.…”

Section: Introductionmentioning

confidence: 99%

α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

Eerola¹,

Rinne²,

Penttinen³

et al. 2014

Journal of Endocrinology

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The POMC pathway is involved in the regulation of energy and cardiovascular homeostasis in the hypothalamus and the brain stem. Although the acute effects of POMC-derived peptides in different brain locations have been elucidated, the chronic site-specific effects of distinct peptides remain to be studied. To this end, we used a lentiviral gene delivery vector to study the long-term effects of a-MSH in the nucleus tractus solitarius (NTS) of the brain stem. The a-MSH vector (LVi-a-MSH-EGFP) based on the N-terminal POMC sequence and a control vector (LVi-EGFP) were delivered into the NTS of C57BL/6N male mice fed on a western diet. Effects on body weight and composition, feeding, glucose metabolism, and hemodynamics by telemetric analyses were studied during the 12-week follow-up. The LVi-a-MSH-EGFP-treated mice had a significantly smaller gain in the fat mass compared with LVi-EGFP-injected mice. There was a small initial decrease in food intake and no differences in the physical activity. Glucose metabolism was not changed compared with the control. LVi-a-MSH-EGFP increased the heart rate (HR), which was attenuated by adrenergic blockade suggesting an increased sympathetic activity. Reduced response to muscarinic blockade suggested a decreased parasympathetic activity. Fitting with sympathetic activation, LVi-a-MSH-EGFP treatment reduced urine secretion. Thus, the results demonstrate that long-term a-MSH overexpression in the NTS attenuates diet-induced obesity. Modulation of autonomic nervous system tone increased the HR and most probably contributed to an anti-obesity effect. The results underline the key role of NTS in the a-MSH-induced long-term effects on adiposity and in regulation of sympathetic and parasympathetic activities.

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New aspects of melanocortin signaling: A role for PRCP in α-MSH degradation

Cited by 49 publications

References 236 publications

Influence of a Novel Inhibitor (UM8190) of Prolylcarboxypeptidase (PRCP) on Appetite and Thrombosis

Influence of a Novel Inhibitor (UM8190) of Prolylcarboxypeptidase (PRCP) on Appetite and Thrombosis

POMC Neurons: From Birth to Death

α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

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