The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo

Panaro, Brandon L.; Tough, Iain R.; Engelstoft, Maja S.; Matthews, Robert T.; Digby, Gregory J.; Møller, Cleide Oliveira de Almeida; Svendsen, Berit; Gribble, Fiona M.; Reimann, Frank; Holst, Jens J.; Holst, Birgitte; Schwartz, Thue W.; Cox, Helen; Cone, Roger D.

doi:10.1016/j.cmet.2014.10.004

Cited by 147 publications

(143 citation statements)

References 42 publications

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“…In contrast, exendin(9-39) did not alter Cpd 1 responses, confirming that GLP-1 receptors are not involved. Notably, Cpd 1 responses were inhibited when apical glucose was removed; thus, FFA2 agonism exhibited glucose sensitivity as observed for other L cell-specific G-protein-coupled receptors (35,44). FFA2 2/2 mice had significantly faster distal colon motility and UGIT compared with WT mice, revealing a role for FFA2 in both colonic and ileal brakes.…”

Section: Discussionmentioning

confidence: 73%

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models

et al. 2015

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Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by shortchain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2 2/2 tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2 2/2 mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2 2/2 mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes.

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Section: Discussionmentioning

confidence: 73%

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models

et al. 2015

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“…cDNA from the purified cell populations was analysed for bombesin receptor expression by a qPCR array targeting 379 non-odorant 7TM receptors (Fig. 5) as previously reported (Panaro et al 2014). None of the three bombesin receptors was expressed above background levels in GIP cells (Fig.…”

Section: Expressionmentioning

confidence: 92%

GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness

Svendsen¹,

Pais²,

Engelstoft³

et al. 2015

Journal of Endocrinology

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The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L-and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1-and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (w5%). KCl, glucose and forskolinCIBMX increased the secretion of both GLP1 and GIP, whereas bombesin/ neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'.

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“…Disruption of this gene in knockout mouse models generate a nonhyperphagic increase in adiposity that is associated with reduced lean body mass and increased feed efficiency (Butler et al 2000, Chen et al 2000). The MC4R is widely expressed throughout the CNS (Mountjoy et al 1994) as well as peripheral nervous system (Gautron et al 2010), and in intestinal L cells (Panaro et al 2014). MC4R functions to regulate food intake and energy expenditure, and this role for the receptor has been shown to be evolutionarily conserved in vertebrates from fish to human.…”

Section: Cloning Of the Melanocortin Receptorsmentioning

confidence: 99%

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

Anderson

Çakır

Carrington

et al. 2016

Journal of Molecular Endocrinology

130

117

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The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.

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The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo

Cited by 147 publications

References 42 publications

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models

GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

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