- Email: [email protected]
Enteroendocrine MC4R and Energy Balance: Linking the Long and the Short of It
Cell Metabolism
Previews mutation in the Crygc gene responsible for causing cataracts was achieved by the CRISPR/Cas9 system in mouse zygotes and persisted in the progeny of treated mice (Wu et al., 2013). The second strategy would be to use CRISPR/Cas9 technology to treat DMD postnatally. This approach has the advantage of applicability to all DMD patients, regardless of whether the mutation was inherited or spontaneous. However, the challenges of mosaicism, off-target effects, and immunogenicity would remain. In addition, an efficient mechanism to deliver the Cas9/guide RNA/template to patients requires development, and this is an almost completely unexplored issue in adult mammals. Recent findings showed that successful gene editing with Cas9 could be achieved in hepatocytes after intravascular injections of Cas9/ guide RNA/template into mice carrying a mutation for fumarylacetoacetate hydrolase, which causes a fatal liver disease (Yin et al., 2014). That finding suggests
that postnatal genome editing for DMD may also hold promise for functional recovery. Although muscle fibers are postmitotic and lack proteins required for homologous recombination and are therefore refractory to HDR-mediated correction (Hsu et al., 2014), a population of muscle stem cells (satellite cells) that reside in mature skeletal muscle are viable targets for Cas9-mediated gene editing. The exciting findings and clever experimental design of Dr. Olson and his colleagues have illuminated a path for correction of dystrophin mutations not only in somatic cells to alleviate the disease in individuals, but also for correction in the germline, which could feasibly eliminate the disease in the progeny, though the road to clinical application may be long. REFERENCES Davie, A.M., and Emery, A.E.H. (1978). J. Med. Genet. 15, 339–345.
Hsu, P.D., Lander, E.S., and Zhang, F. (2014). Cell 157, 1262–1278. Kayali, R., Bury, F., Ballard, M., and Bertoni, C. (2010). Hum. Mol. Genet. 19, 3266–3281. Long, C., McAnally, J.R., Shelton, J.M., Mireault, A.A., Bassel-Duby, R., and Olson, E.N. (2014). Science 345, 1184–1188. Rando, T.A., Disatnik, M.H., and Zhou, L.Z. (2000). Proc. Natl. Acad. Sci. USA 97, 5363–5368. Shoukir, Y., Campana, A., Farley, T., and Sakkas, D. (1997). Hum. Reprod. 12, 1531–1536. Wu, Y., Liang, D., Wang, Y., Bai, M., Tang, W., Bao, S., Yan, Z., Li, D., and Li, J. (2013). Cell Stem Cell 13, 659–662. Yen, S.T., Zhang, M., Deng, J.M., Usman, S.J., Smith, C.N., Parker-Thornburg, J., Swinton, P.G., Martin, J.F., and Behringer, R.R. (2014). Dev. Biol. 393, 3–9. Yin, H., Xue, W., Chen, S., Bogorad, R.L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P.A., Jacks, T., and Anderson, D.G. (2014). Nature Biotech. 32, 551–553.
Enteroendocrine MC4R and Energy Balance: Linking the Long and the Short of It Sean Manning1,2 and Rachel L. Batterham1,3,4,* 1Centre
for Obesity Research, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK of Medicine, University College Cork, Cork, Ireland 3UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London NW1 2PG, UK 4National Institute of Health Research University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2014.11.014 2School
Central MC4R pathways are well established as integrators of peripheral signals in the control of energy balance. In this issue, Panaro et al. (2014) identify that MC4Rs expressed on intestinal enteroendocrine L cells regulate PYY and GLP-1 secretion, two gut hormones implicated in the regulation of energy and glucose homeostasis.
Feeding bouts are regulated by complex, integrated neural and endocrine networks in a process that attempts to optimize use of nutrient availability in the context of changing energy requirements. Hormonal signals of ‘‘long-term’’ energy storage, such as the adipokine leptin, act centrally to modulate food intake (Morton et al.,
2014). Feeding behavior is also modulated centrally by an array of gut-derived hormones that either promote initiation (orexigenic) or termination (anorexigenic) of feeding, thus serving as ‘‘short-term’’ signals of energy availability and regulators of meal size (Morton et al., 2014). For example, secretion of the orexigenic
hormone ghrelin from gastric mucosal endocrine cells progressively increases in the absence of nutrients. In contrast, enteroendocrine L cells release the anorexigenic hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in response to nutrient stimulation. These ‘‘short- and long-term’’ energy signals
Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc. 929
Cell Metabolism
Previews modulate neuronal activity of hypothalamic and brainstem nuclei, midbrain reward areas, and higher cortical regions, leading to integrated regulation of feeding behavior (Morton et al., 2014). Central melanocortin-4 receptor (MC4R) circuits are recognized as key integrators of ‘‘long-term’’ energy signals within the neural networks that regulate energy homeostasis (Girardet and Butler, 2014; Morton et al., 2014). Fine-tuning of the MC4R system has evolved to include the presence of (1) two distinct endogenous agonists (a-MSH and ACTH), (2) an endogenous inverse agonist (AGRP), and (3) a regulatory accessory protein (MRAP2). Central MC4R activation promotes satiety, reduces insulin secretion, increases insulin sensitivity, and increases energy expenditure (Girardet and Butler, 2014). MC4R haploinsufficiency, the most common monogenic cause of severe obesity in humans, results in hyperphagia and hyperinsulinemia, findings that are grossly recapitulated in the Mc4r null mouse and that precede weight gain (Girardet and Butler, 2014). MC4Rs are widely expressed in the brain and have been identified in around 150 brain nuclei. Knockout reexpression studies indicate that MC4Rs in the forebrain, including the paraventricular nucleus of the hypothalamus and the amygdala, regulate feeding, while MC4Rs in preganglionic autonomic neurons regulate body fat content, energy expenditure, and glucose homeostasis (Girardet and Butler, 2014). Importantly, MC4Rs in the dorsomedial nucleus in the brainstem regulate gastrointestinal (GI) function, including meal size, indirectly via parasympathetic vagal efferent nerves. Recently, functional MC4R expression in gastric ghrelin cells was identified, although its physiological relevance remains unclear (Engelstoft et al., 2013). In a new study, Panaro and colleagues (2014) now provide convincing evidence for a direct physiological role of MC4R expressed on enteroendocrine L cells in regulating GI function and enhancing secretion of anorexigenic gut peptides. The study culminates with the finding that an enteroendocrine MC4R system acts as a regulator of PYY and GLP-1 release in vivo. In a series of intestinal MC4R characterization experiments incorporating fluorescence-assisted cell sorting and
immunohistochemistry, Panaro and coworkers (2014) identified that intestinal mucosal MC4R expression is predominantly localized to enteroendocrine L cells. The functionality of L cell MC4R was established using multiple MC4R ligands, across an array of models, including in isolated intestinal cell preparations, in a representative enteroendocrine cell line, in mucosa from mouse intestine or human colon, and in mice in vivo. Importantly, functional studies using the model of L cell regulation of epithelial chloride secretion also established that the effects of L cell MC4R activation are: (1) independent of submucosal neuronal stimulation (tetrodotoxin insensitive), (2) epithelial Y1 receptor dependent (suggestive of a PYY paracrine effect), and (3) mediated by MC4R stimulation on the basolateral but not lumenal membrane of L cells (suggestive of a humoral MC4R ligand). Further in vivo rodent studies confirmed that L cell, but not central, MC4R activation accounts for MC4R agonist effects on PYY secretion and that this enhanced PYY secretion is sufficient to slow colonic motility. This comprehensive body of work has the potential to impact upon multiple overlapping research fields. In the field of bariatric surgery, enhanced postoperative secretion of L cell products is implicated in mediating the beneficial metabolic effects of specific bariatric operations such as Roux-en-Y gastric bypass (RYGBP) (Madsbad et al., 2014) (Figure 1). The work by Panaro et al. (2014) could explain why carriers of a MC4R variant (I251L), which increases basal MC4R activity, experience significantly greater weight loss after RYGBP compared with noncarriers or carriers of other MC4R variants (Mirshahi et al., 2011). In the setting of enhanced PYY/ GLP-1 secretion post-RYGBP, increased basal MC4R activity could further augment this L cell response, promoting greater reductions in food intake in I251L carriers (Figure 1). Interestingly, MC4R signaling is critical for the sustained reductions in food intake and weight loss engendered by RYGBP, as demonstrated by studies undertaken in Mc4r null mice (Hatoum et al., 2012). These studies suggest either that non-MC4R-mediated mechanisms by which RYGBP affects energy balance are not powerful enough
930 Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc.
to overcome complete absence of MC4R signaling or that the MC4R system is intrinsic to the biological response to RYGBP (Figure 1). However, a study employing intracerebroventricular administration of a specific MC4R antagonist in RYGBP and sham-operated rats demonstrated that, while central MC4R blockade led to doubling of food intake and weight regain, the RYGBP-driven reduction in meal size was unaffected (Mumphrey et al., 2014). These findings suggested that peripheral MC4R pathways govern meal size, a concept now supported by the work of Panaro et al. (2014). A further intriguing corollary of the study is the potential for host-gut microbiota interactions impacting on the enteroendocrine MC4R system. The dynamic between ‘‘healthy’’ and ‘‘harmful’’ microbiota is now thought to regulate multiple host metabolic effects, although the mechanisms underlying these effects remain to be fully elucidated. A recent study demonstrated evidence for molecular mimicry involving a gut bacterial ClpB heat-shock protein and the MC4R agonist a-MSH (Tennoune et al., 2014). While the study (Tennoune et al., 2014) focused on the relevance of the findings for patients with eating disorders, the possibility of local modulation of enteroendocrine MC4R function by a microbiota-derived a-MSH mimetic (Figure 1) now has potentially far-reaching implications in the fields of type 2 diabetes, obesity, and irritable bowel syndrome. Finally, the study by Panaro and colleagues poses the question of whether enteric neurons, originating outside of the brain, could directly regulate enteroendocrine cells via the MC4R system. Exciting research describing neuronallike features and direct innervation of enteroendocrine cells has recently emerged (Boho´rquez et al., 2014). Enteroendocrine cells exhibit a prominent basal cytoplasmic process, termed a ‘‘neuropod,’’ containing neurofilaments, which are the typical structural proteins of axons. These ‘‘neuropods’’ are escorted by enteric glia, and their development is enhanced by glial-derived neurotrophic factors. Our understanding of neural interactions with the enteroendocrine system is thus rapidly advancing. The work by Panaro et al. (2014) firmly places the enteroendocrine MC4R
Cell Metabolism
Previews
Figure 1. A Schematic Overview of Integration of Central and Enteroendocrine MC4R Pathways during Dieting and after RYGBP In Roux-en-Y gastric bypass (RYGBP), a small gastric pouch is created and connected with the mid-jejunum, thereby allowing nutrients to bypass the majority of the stomach, the duodenum, and the proximal jejunum. Reductions in circulating leptin occur with dieting and after RYGBP and lead to lower hypothalamic/ brainstem a-MSH (a-melanocyte stimulating hormone) production from pro-opiomelancortin (POMC), resulting in reduced activation of central MC4R, thus promoting increased appetite. Circulating adrenocorticotrphic hormone (ACTH), a POMC product secreted from the pituitary gland, is increased after dieting but not after RYGBP. Long-term gut hormonal adaptations occur after dieting, including increased secretion of the orexigenic hormone ghrelin and reduced secretion of the anorexigenic L cell products peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). MC4R activation in gastric ghrelin cells stimulates ghrelin secretion. The release of PYY and GLP-1 secretion is markedly enhanced after RYGBP, due to expedited exposure of distal intestinal L cells to nutrients. GLP-1 (directly) and PYY (indirectly) act on POMC-expressing neurons, increasing central a-MSH production and reducing appetite. Panaro et al. (2014) show that L cell MC4R activation enhances GLP-1 and PYY secretion. Candidate physiologic ligands for L cell MC4R include a-MSH, ACTH, and autoantibodies produced in response to gut microbiota-derived ClpB heat shock protein. Enhanced L cell secretion of PYY and/or GLP-1 could promote greater reductions in appetite in carriers of the I251L MC4R allele compared to noncarriers among patients undergoing RYGBP. Dashed black lines indicate a relatively lower level of signaling. Solid red lines indicate a relatively higher level of signaling.
pathway at the center of an increasingly more complex model of energy balance regulation (Figure 1).
Engelstoft, M.S., Park, W.M., Sakata, I., Kristensen, L.V., Husted, A.S., Osborne-Lawrence, S., Piper, P.K., Walker, A.K., Pedersen, M.H., Nøhr, M.K., et al. (2013). Mol Metab 2, 376–392.
ACKNOWLEDGMENTS
Girardet, C., and Butler, A.A. (2014). Biochim. Biophys. Acta 1842, 482–494.
R.L.B. receives funding from the Rosetrees Trust and is supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre.
Hatoum, I.J., Stylopoulos, N., Vanhoose, A.M., Boyd, K.L., Yin, D.P., Ellacott, K.L., Ma, L.L., Blaszczyk, K., Keogh, J.M., Cone, R.D., et al. (2012). J. Clin. Endocrinol. Metab. 97, E1023– E1031.
REFERENCES
Madsbad, S., Dirksen, C., and Holst, J.J. (2014). Lancet Diabetes Endocrinol 2, 152–164.
Boho´rquez, D.V., Samsa, L.A., Roholt, A., Medicetty, S., Chandra, R., and Liddle, R.A. (2014). PLoS ONE 9, e89881.
Mirshahi, U.L., Still, C.D., Masker, K.K., Gerhard, G.S., Carey, D.J., and Mirshahi, T. (2011). J. Clin. Endocrinol. Metab. 96, E2088–E2096.
Morton, G.J., Meek, T.H., and Schwartz, M.W. (2014). Nat. Rev. Neurosci. 15, 367–378. Mumphrey, M.B., Hao, Z., Townsend, R.L., Patterson, L.M., Morrison, C.D., Mu¨nzberg, H., Stylopoulos, N., Ye, J., and Berthoud, H.R. (2014). Obesity (Silver Spring) 22, 1847–1853. Panaro, B.L., Tough, I.R., Engelstoft, M.S., Matthews, R.T., Digby, G.J., Møller, C.L., Svendsen, B., Gribble, F., Reimann, F., Holst, J.J., et al. (2014). Cell Metab. 20, this issue, 1018–1029. Tennoune, N., Chan, P., Breton, J., Legrand, R., Chabane, Y.N., Akkermann, K., Ja¨rv, A., Ouelaa, W., Takagi, K., Ghouzali, I., et al. (2014). Transcult. Psychiatry 4, e458.
Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc. 931
Previews mutation in the Crygc gene responsible for causing cataracts was achieved by the CRISPR/Cas9 system in mouse zygotes and persisted in the progeny of treated mice (Wu et al., 2013). The second strategy would be to use CRISPR/Cas9 technology to treat DMD postnatally. This approach has the advantage of applicability to all DMD patients, regardless of whether the mutation was inherited or spontaneous. However, the challenges of mosaicism, off-target effects, and immunogenicity would remain. In addition, an efficient mechanism to deliver the Cas9/guide RNA/template to patients requires development, and this is an almost completely unexplored issue in adult mammals. Recent findings showed that successful gene editing with Cas9 could be achieved in hepatocytes after intravascular injections of Cas9/ guide RNA/template into mice carrying a mutation for fumarylacetoacetate hydrolase, which causes a fatal liver disease (Yin et al., 2014). That finding suggests
that postnatal genome editing for DMD may also hold promise for functional recovery. Although muscle fibers are postmitotic and lack proteins required for homologous recombination and are therefore refractory to HDR-mediated correction (Hsu et al., 2014), a population of muscle stem cells (satellite cells) that reside in mature skeletal muscle are viable targets for Cas9-mediated gene editing. The exciting findings and clever experimental design of Dr. Olson and his colleagues have illuminated a path for correction of dystrophin mutations not only in somatic cells to alleviate the disease in individuals, but also for correction in the germline, which could feasibly eliminate the disease in the progeny, though the road to clinical application may be long. REFERENCES Davie, A.M., and Emery, A.E.H. (1978). J. Med. Genet. 15, 339–345.
Hsu, P.D., Lander, E.S., and Zhang, F. (2014). Cell 157, 1262–1278. Kayali, R., Bury, F., Ballard, M., and Bertoni, C. (2010). Hum. Mol. Genet. 19, 3266–3281. Long, C., McAnally, J.R., Shelton, J.M., Mireault, A.A., Bassel-Duby, R., and Olson, E.N. (2014). Science 345, 1184–1188. Rando, T.A., Disatnik, M.H., and Zhou, L.Z. (2000). Proc. Natl. Acad. Sci. USA 97, 5363–5368. Shoukir, Y., Campana, A., Farley, T., and Sakkas, D. (1997). Hum. Reprod. 12, 1531–1536. Wu, Y., Liang, D., Wang, Y., Bai, M., Tang, W., Bao, S., Yan, Z., Li, D., and Li, J. (2013). Cell Stem Cell 13, 659–662. Yen, S.T., Zhang, M., Deng, J.M., Usman, S.J., Smith, C.N., Parker-Thornburg, J., Swinton, P.G., Martin, J.F., and Behringer, R.R. (2014). Dev. Biol. 393, 3–9. Yin, H., Xue, W., Chen, S., Bogorad, R.L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P.A., Jacks, T., and Anderson, D.G. (2014). Nature Biotech. 32, 551–553.
Enteroendocrine MC4R and Energy Balance: Linking the Long and the Short of It Sean Manning1,2 and Rachel L. Batterham1,3,4,* 1Centre
for Obesity Research, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK of Medicine, University College Cork, Cork, Ireland 3UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London NW1 2PG, UK 4National Institute of Health Research University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2014.11.014 2School
Central MC4R pathways are well established as integrators of peripheral signals in the control of energy balance. In this issue, Panaro et al. (2014) identify that MC4Rs expressed on intestinal enteroendocrine L cells regulate PYY and GLP-1 secretion, two gut hormones implicated in the regulation of energy and glucose homeostasis.
Feeding bouts are regulated by complex, integrated neural and endocrine networks in a process that attempts to optimize use of nutrient availability in the context of changing energy requirements. Hormonal signals of ‘‘long-term’’ energy storage, such as the adipokine leptin, act centrally to modulate food intake (Morton et al.,
2014). Feeding behavior is also modulated centrally by an array of gut-derived hormones that either promote initiation (orexigenic) or termination (anorexigenic) of feeding, thus serving as ‘‘short-term’’ signals of energy availability and regulators of meal size (Morton et al., 2014). For example, secretion of the orexigenic
hormone ghrelin from gastric mucosal endocrine cells progressively increases in the absence of nutrients. In contrast, enteroendocrine L cells release the anorexigenic hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in response to nutrient stimulation. These ‘‘short- and long-term’’ energy signals
Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc. 929
Cell Metabolism
Previews modulate neuronal activity of hypothalamic and brainstem nuclei, midbrain reward areas, and higher cortical regions, leading to integrated regulation of feeding behavior (Morton et al., 2014). Central melanocortin-4 receptor (MC4R) circuits are recognized as key integrators of ‘‘long-term’’ energy signals within the neural networks that regulate energy homeostasis (Girardet and Butler, 2014; Morton et al., 2014). Fine-tuning of the MC4R system has evolved to include the presence of (1) two distinct endogenous agonists (a-MSH and ACTH), (2) an endogenous inverse agonist (AGRP), and (3) a regulatory accessory protein (MRAP2). Central MC4R activation promotes satiety, reduces insulin secretion, increases insulin sensitivity, and increases energy expenditure (Girardet and Butler, 2014). MC4R haploinsufficiency, the most common monogenic cause of severe obesity in humans, results in hyperphagia and hyperinsulinemia, findings that are grossly recapitulated in the Mc4r null mouse and that precede weight gain (Girardet and Butler, 2014). MC4Rs are widely expressed in the brain and have been identified in around 150 brain nuclei. Knockout reexpression studies indicate that MC4Rs in the forebrain, including the paraventricular nucleus of the hypothalamus and the amygdala, regulate feeding, while MC4Rs in preganglionic autonomic neurons regulate body fat content, energy expenditure, and glucose homeostasis (Girardet and Butler, 2014). Importantly, MC4Rs in the dorsomedial nucleus in the brainstem regulate gastrointestinal (GI) function, including meal size, indirectly via parasympathetic vagal efferent nerves. Recently, functional MC4R expression in gastric ghrelin cells was identified, although its physiological relevance remains unclear (Engelstoft et al., 2013). In a new study, Panaro and colleagues (2014) now provide convincing evidence for a direct physiological role of MC4R expressed on enteroendocrine L cells in regulating GI function and enhancing secretion of anorexigenic gut peptides. The study culminates with the finding that an enteroendocrine MC4R system acts as a regulator of PYY and GLP-1 release in vivo. In a series of intestinal MC4R characterization experiments incorporating fluorescence-assisted cell sorting and
immunohistochemistry, Panaro and coworkers (2014) identified that intestinal mucosal MC4R expression is predominantly localized to enteroendocrine L cells. The functionality of L cell MC4R was established using multiple MC4R ligands, across an array of models, including in isolated intestinal cell preparations, in a representative enteroendocrine cell line, in mucosa from mouse intestine or human colon, and in mice in vivo. Importantly, functional studies using the model of L cell regulation of epithelial chloride secretion also established that the effects of L cell MC4R activation are: (1) independent of submucosal neuronal stimulation (tetrodotoxin insensitive), (2) epithelial Y1 receptor dependent (suggestive of a PYY paracrine effect), and (3) mediated by MC4R stimulation on the basolateral but not lumenal membrane of L cells (suggestive of a humoral MC4R ligand). Further in vivo rodent studies confirmed that L cell, but not central, MC4R activation accounts for MC4R agonist effects on PYY secretion and that this enhanced PYY secretion is sufficient to slow colonic motility. This comprehensive body of work has the potential to impact upon multiple overlapping research fields. In the field of bariatric surgery, enhanced postoperative secretion of L cell products is implicated in mediating the beneficial metabolic effects of specific bariatric operations such as Roux-en-Y gastric bypass (RYGBP) (Madsbad et al., 2014) (Figure 1). The work by Panaro et al. (2014) could explain why carriers of a MC4R variant (I251L), which increases basal MC4R activity, experience significantly greater weight loss after RYGBP compared with noncarriers or carriers of other MC4R variants (Mirshahi et al., 2011). In the setting of enhanced PYY/ GLP-1 secretion post-RYGBP, increased basal MC4R activity could further augment this L cell response, promoting greater reductions in food intake in I251L carriers (Figure 1). Interestingly, MC4R signaling is critical for the sustained reductions in food intake and weight loss engendered by RYGBP, as demonstrated by studies undertaken in Mc4r null mice (Hatoum et al., 2012). These studies suggest either that non-MC4R-mediated mechanisms by which RYGBP affects energy balance are not powerful enough
930 Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc.
to overcome complete absence of MC4R signaling or that the MC4R system is intrinsic to the biological response to RYGBP (Figure 1). However, a study employing intracerebroventricular administration of a specific MC4R antagonist in RYGBP and sham-operated rats demonstrated that, while central MC4R blockade led to doubling of food intake and weight regain, the RYGBP-driven reduction in meal size was unaffected (Mumphrey et al., 2014). These findings suggested that peripheral MC4R pathways govern meal size, a concept now supported by the work of Panaro et al. (2014). A further intriguing corollary of the study is the potential for host-gut microbiota interactions impacting on the enteroendocrine MC4R system. The dynamic between ‘‘healthy’’ and ‘‘harmful’’ microbiota is now thought to regulate multiple host metabolic effects, although the mechanisms underlying these effects remain to be fully elucidated. A recent study demonstrated evidence for molecular mimicry involving a gut bacterial ClpB heat-shock protein and the MC4R agonist a-MSH (Tennoune et al., 2014). While the study (Tennoune et al., 2014) focused on the relevance of the findings for patients with eating disorders, the possibility of local modulation of enteroendocrine MC4R function by a microbiota-derived a-MSH mimetic (Figure 1) now has potentially far-reaching implications in the fields of type 2 diabetes, obesity, and irritable bowel syndrome. Finally, the study by Panaro and colleagues poses the question of whether enteric neurons, originating outside of the brain, could directly regulate enteroendocrine cells via the MC4R system. Exciting research describing neuronallike features and direct innervation of enteroendocrine cells has recently emerged (Boho´rquez et al., 2014). Enteroendocrine cells exhibit a prominent basal cytoplasmic process, termed a ‘‘neuropod,’’ containing neurofilaments, which are the typical structural proteins of axons. These ‘‘neuropods’’ are escorted by enteric glia, and their development is enhanced by glial-derived neurotrophic factors. Our understanding of neural interactions with the enteroendocrine system is thus rapidly advancing. The work by Panaro et al. (2014) firmly places the enteroendocrine MC4R
Cell Metabolism
Previews
Figure 1. A Schematic Overview of Integration of Central and Enteroendocrine MC4R Pathways during Dieting and after RYGBP In Roux-en-Y gastric bypass (RYGBP), a small gastric pouch is created and connected with the mid-jejunum, thereby allowing nutrients to bypass the majority of the stomach, the duodenum, and the proximal jejunum. Reductions in circulating leptin occur with dieting and after RYGBP and lead to lower hypothalamic/ brainstem a-MSH (a-melanocyte stimulating hormone) production from pro-opiomelancortin (POMC), resulting in reduced activation of central MC4R, thus promoting increased appetite. Circulating adrenocorticotrphic hormone (ACTH), a POMC product secreted from the pituitary gland, is increased after dieting but not after RYGBP. Long-term gut hormonal adaptations occur after dieting, including increased secretion of the orexigenic hormone ghrelin and reduced secretion of the anorexigenic L cell products peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). MC4R activation in gastric ghrelin cells stimulates ghrelin secretion. The release of PYY and GLP-1 secretion is markedly enhanced after RYGBP, due to expedited exposure of distal intestinal L cells to nutrients. GLP-1 (directly) and PYY (indirectly) act on POMC-expressing neurons, increasing central a-MSH production and reducing appetite. Panaro et al. (2014) show that L cell MC4R activation enhances GLP-1 and PYY secretion. Candidate physiologic ligands for L cell MC4R include a-MSH, ACTH, and autoantibodies produced in response to gut microbiota-derived ClpB heat shock protein. Enhanced L cell secretion of PYY and/or GLP-1 could promote greater reductions in appetite in carriers of the I251L MC4R allele compared to noncarriers among patients undergoing RYGBP. Dashed black lines indicate a relatively lower level of signaling. Solid red lines indicate a relatively higher level of signaling.
pathway at the center of an increasingly more complex model of energy balance regulation (Figure 1).
Engelstoft, M.S., Park, W.M., Sakata, I., Kristensen, L.V., Husted, A.S., Osborne-Lawrence, S., Piper, P.K., Walker, A.K., Pedersen, M.H., Nøhr, M.K., et al. (2013). Mol Metab 2, 376–392.
ACKNOWLEDGMENTS
Girardet, C., and Butler, A.A. (2014). Biochim. Biophys. Acta 1842, 482–494.
R.L.B. receives funding from the Rosetrees Trust and is supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre.
Hatoum, I.J., Stylopoulos, N., Vanhoose, A.M., Boyd, K.L., Yin, D.P., Ellacott, K.L., Ma, L.L., Blaszczyk, K., Keogh, J.M., Cone, R.D., et al. (2012). J. Clin. Endocrinol. Metab. 97, E1023– E1031.
REFERENCES
Madsbad, S., Dirksen, C., and Holst, J.J. (2014). Lancet Diabetes Endocrinol 2, 152–164.
Boho´rquez, D.V., Samsa, L.A., Roholt, A., Medicetty, S., Chandra, R., and Liddle, R.A. (2014). PLoS ONE 9, e89881.
Mirshahi, U.L., Still, C.D., Masker, K.K., Gerhard, G.S., Carey, D.J., and Mirshahi, T. (2011). J. Clin. Endocrinol. Metab. 96, E2088–E2096.
Morton, G.J., Meek, T.H., and Schwartz, M.W. (2014). Nat. Rev. Neurosci. 15, 367–378. Mumphrey, M.B., Hao, Z., Townsend, R.L., Patterson, L.M., Morrison, C.D., Mu¨nzberg, H., Stylopoulos, N., Ye, J., and Berthoud, H.R. (2014). Obesity (Silver Spring) 22, 1847–1853. Panaro, B.L., Tough, I.R., Engelstoft, M.S., Matthews, R.T., Digby, G.J., Møller, C.L., Svendsen, B., Gribble, F., Reimann, F., Holst, J.J., et al. (2014). Cell Metab. 20, this issue, 1018–1029. Tennoune, N., Chan, P., Breton, J., Legrand, R., Chabane, Y.N., Akkermann, K., Ja¨rv, A., Ouelaa, W., Takagi, K., Ghouzali, I., et al. (2014). Transcult. Psychiatry 4, e458.
Cell Metabolism 20, December 2, 2014 ª2014 Elsevier Inc. 931