- Email: [email protected]
Bypassing Intestinal Sugar Enhancement of Sweet Appetite
Cell Metabolism
Previews Bypassing Intestinal Sugar Enhancement of Sweet Appetite Anthony Sclafani1,* 1Department of Psychology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.12.013
Intestinal sugar sensing has an appetite-stimulating action that enhances preferences for sweets. Han et al. (2016) report that duodenal-jejunal bypass surgery reduces sweet appetite by reducing sugar-induced dopamine release in the dorsal striatum. Bariatric surgery is an effective treatment for obesity that works, in part, by reducing caloric intake and altering food preferences (Mu¨nzberg et al., 2015). The physiological mechanisms responsible for altered appetite are not certain, although most attention has focused on enhancement of food-generated satiation signals. In the paper by Han et al. (2016), a different approach is taken. Here the authors investigated the appetite-stimulating action of sugar in the gut and how duodenal-jejunal bypass (DJB) (or rerouting) modulates this ‘‘appetition’’ effect (Sclafani, 2013). They then examined the role of striatal dopamine systems in mediating the bypass-induced alteration in sugar appetite (de Araujo et al., 2012). The first part of the study introduced a new animal model to investigate appetite conditioning by gastric sugar infusions. Hungry mice were trained (1 hr/day) for 13 days to drink a sweet nonnutritive solution (2 mM sucralose), which was paired with gastric infusions of the same solution (Sucralose group) or infusions of 50% glucose (Glucose group). Not surprisingly, the Glucose mice infused with the hypercaloric/hypertonic sugar self-administered less fluid than did the Sucralose mice. Yet the Glucose mice acquired a stronger appetite for sweet solutions than did the Sucralose mice. This was revealed in satiation tests in which a fixed intragastric (IG) glucose preload reduced the subsequent oral intake of glucose and sucralose less in Glucose mice than in Sucralose mice. The second part of the study investigated how intestinal rerouting affects the sweet appetite conditioned by the IG glucose infusions. This was accomplished by creating a DJB in which the duodenum
was occluded with a pylorus ligation and the jejunum was anastomosed side-toside to the stomach. As a result, ingested food emptied from the stomach into the mid-jejunum, leaving the duodenum unexposed to nutrients. When trained to drink sucralose paired with IG infusions of 50% glucose, the DJB mice self-administered significantly less sugar than did Sham mice with an intact intestinal tract. In subsequent satiation tests, the DJB mice drank substantially less sucralose and glucose than did the Sham mice following glucose preloads; they also drank less glucose following a sucralose preload. The authors concluded that the enhancement in sweet appetite conditioned by IG sugar infusion depends upon duodenal glucose sensing. However, this interpretation can be questioned because of likely differences in gastric emptying. That is, in Sham mice the pyloric sphincter controlled the emptying of the gastric glucose infusions into the duodenum, whereas in the DJB mice the gastric-jejunal anastomosis presumably allowed the hypercaloric/hypertonic glucose infusion to empty rapidly into the jejunum. Gastric dumping of hypertonic glucose may have been discomforting, which could have counteracted any reward action of glucose in the jejunum. Gastric dumping is a common complication of bariatric surgery in humans (Tack and Deloose, 2014). In rats, glucose infusions into the duodenum or jejunum conditioned similar preferences for a flavored saccharin solution; ileal glucose infusions, however, were ineffective (Ackroff et al., 2010). The effectiveness of duodenal versus jejunal glucose infusions to condition flavor preferences in mice requires investigation. The third part of the study analyzed the role of striatal dopamine systems in
glucose-conditioned appetite. Gastric glucose infusions stimulated dorsal striatal dopamine release in Sham mice but not in DJB mice. In addition, direct duodenal glucose infusions stimulated greater dorsal striatal dopamine release then did jejunal infusions in Sham mice. The authors concluded that the duodenum is a critical site for regulating dorsal striatal dopamine. Alternatively, duodenal infusions may be effective because they expose more of the intestinal tract to glucose than do jejunal infusions (see Little et al., 2006). In contrast to the dorsal striatum, dopamine release in the ventral striatum was stimulated by gastric glucose infusions in both Sham and DJB mice. This finding is most interesting and suggests that different glucose sensors and/or pathways influence dorsal and ventral dopamine circuits. Both intestinal and hepatic-portal glucose sensors have been implicated in glucose-conditioned preferences, and perhaps they differentially engage the ventral and dorsal striatal systems (Ackroff et al., 2010; Oliveira-Maia et al., 2011). The last part of the study determined how direct manipulations of dopamine excitable neurons expressing D1 receptors (D1r) influenced sugar seeking in mice. In both Sham and DJB mice, optogenetic activation of dorsal striatal D1r neurons increased sucralose drinking (‘‘seeking’’) following an IG glucose preload, although the effect was less pronounced in DJB mice. Selective ablation of these neurons produced the opposite effect: ablated mice drank less sucralose following an IG glucose preload than did sham-ablated mice. Interestingly, dorsal striatal D1r neuron ablation did not alter glucose selfadministration during the initial training
Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 3
Cell Metabolism
Previews with sucralose paired with IG glucose. Thus, D1r neuron ablation appeared to have a specific effect on sweet appetite following a glucose preload, a form of reward devaluation. In contrast to manipulation of dorsal striatal D1r neurons, activation or ablation of ventral striatal D1r neurons did not alter sweet seeking following glucose preloads. In rats, pharmacological inhibition of D1 receptors in the nucleus accumbens blocked flavor preference conditioning by IG glucose infusions (Touzani et al., 2008). It may be that the dorsal striatal system is critical for stimulating sweet intake in the presence of satiety or other devaluation signals while the ventral striatal system is necessary for glucose-conditioned flavor preferences. The manipulations used by Han and coauthors combined with a conditioned flavor assay could evaluate this notion.
As reviewed by Han et al. (2016), recent animal and human studies have linked bariatric surgery with alterations in striatal dopamine function. What is novel about their study is that it focused on how bariatric surgery may influence striatal dopamine systems to alter the appetite-stimulating actions of nutrients in the intestinal tract. Their combination of behavioral, physiological, and neurochemical techniques can advance our understanding of gut-brain communications related to normal and disordered appetite.
de Araujo, I.E., Ferreira, J.G., Tellez, L.A., Ren, X., and Yeckel, C.W. (2012). Physiol. Behav. 106, 394–399.
ACKNOWLEDGMENTS
Oliveira-Maia, A.J., Roberts, C.D., Walker, Q.D., Luo, B., Kuhn, C., Simon, S.A., and Nicolelis, M.A. (2011). PLoS ONE 6, e24992.
The author’s research was supported by NIH grant RO1 DK031135.
Han, W., Tellez, L.A., Niu, J., Medina, S., Ferreira, T.L., Zhang, X., Su, J., Tong, J., Schwartz, G.J., van den Pol, A., and de Araujo, I.E. (2016). Cell Metab. 23, this issue, 103–112. Little, T.J., Doran, S., Meyer, J.H., Smout, A.J.P.M., O’Donovan, D.G., Wu, K.L., Jones, K.L., Wishart, J., Rayner, C.K., Horowitz, M., and Feinle-Bisset, C. (2006). Am. J. Physiol. Endocrinol. Metab. 291, E647–E655. Mu¨nzberg, H., Laque, A., Yu, S., Rezai-Zadeh, K., and Berthoud, H.R. (2015). Obes. Rev. 16 (Suppl 1 ), 77–90.
Sclafani, A. (2013). Appetite 71, 454–458.
REFERENCES
Tack, J., and Deloose, E. (2014). Best Pract. Res. Clin. Gastroenterol. 28, 741–749.
Ackroff, K., Yiin, Y.M., and Sclafani, A. (2010). Physiol. Behav. 99, 402–411.
Touzani, K., Bodnar, R.J., and Sclafani, A. (2008). Eur. J. Neurosci. 27, 1525–1533.
Can Insulin Production Suppress b Cell Growth? Matias De Vas1 and Jorge Ferrer1,2,* 1Section
of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
2Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d’Investigacions Biomediques
August Pi
I Sunyer (IDIBAPS), Barcelona, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.12.016
While insulin has mitogenic effects in many cell types, its effects on b cells remain elusive. In this issue of Cell Metabolism, Szabat et al. (2015) genetically block insulin production in adult b cells and show that this leads to a relief of ER stress, AKT activation, and increased b cell proliferation. Insulin is a major regulator of cellular survival and proliferation in many cell types, but its effects on insulin-producing b cells are still unclear. There are numerous indications that insulin might exert mitogenic effects in b cells, as it does in other cell types. For example, the inactivation of the insulin receptor gene in b cells leads to a partial reduction of postnatal b cell proliferation, and this effect is accentuated with simultaneous inactivation of the receptor for IGF1 (insulin-like growth factor 1) (Ueki et al., 2006). Furthermore, genetic perturbations of known downstream insulin signaling mediators, such as IRS2, AKT, and PDK1, also show pro-
found b cell growth phenotypes (Withers et al., 1998; Hashimoto et al., 2006; Bernal-Mizrachi et al., 2001). Paradoxically, mice that harbor homozygous germline mutations of the two non-allelic mouse insulin genes show increased, rather than decreased, islet cell proliferation (Duvillie´ et al., 2002). However, since these effects could theoretically be indirect, involving for instance increased islet vascularization, it is currently not possible to draw any firm conclusion regarding the direct effects of insulin on b cells (Duvillie´ et al., 2002). Given that insulin production can vary substantially throughout the lifetime of an individual, and across populations,
4 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.
the notion that insulin production could affect b cell growth has significant potential implications for human diabetes. Szabat et al. (2015) have now addressed this conundrum by using a conditional insulin gene knockout approach. They bred mice carrying three genetic modifications: homozygous germline loss-of-function mutations in the Ins1 gene, homozygous ‘‘floxed’’ Ins2 alleles, and a Pdx1CreER tamoxifen-inducible Cre recombinase transgene. When these mice were treated with tamoxifen at 6 weeks of age, both Ins2 alleles were recombined in most cells, and this led to a complete abrogation of insulin
Previews Bypassing Intestinal Sugar Enhancement of Sweet Appetite Anthony Sclafani1,* 1Department of Psychology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.12.013
Intestinal sugar sensing has an appetite-stimulating action that enhances preferences for sweets. Han et al. (2016) report that duodenal-jejunal bypass surgery reduces sweet appetite by reducing sugar-induced dopamine release in the dorsal striatum. Bariatric surgery is an effective treatment for obesity that works, in part, by reducing caloric intake and altering food preferences (Mu¨nzberg et al., 2015). The physiological mechanisms responsible for altered appetite are not certain, although most attention has focused on enhancement of food-generated satiation signals. In the paper by Han et al. (2016), a different approach is taken. Here the authors investigated the appetite-stimulating action of sugar in the gut and how duodenal-jejunal bypass (DJB) (or rerouting) modulates this ‘‘appetition’’ effect (Sclafani, 2013). They then examined the role of striatal dopamine systems in mediating the bypass-induced alteration in sugar appetite (de Araujo et al., 2012). The first part of the study introduced a new animal model to investigate appetite conditioning by gastric sugar infusions. Hungry mice were trained (1 hr/day) for 13 days to drink a sweet nonnutritive solution (2 mM sucralose), which was paired with gastric infusions of the same solution (Sucralose group) or infusions of 50% glucose (Glucose group). Not surprisingly, the Glucose mice infused with the hypercaloric/hypertonic sugar self-administered less fluid than did the Sucralose mice. Yet the Glucose mice acquired a stronger appetite for sweet solutions than did the Sucralose mice. This was revealed in satiation tests in which a fixed intragastric (IG) glucose preload reduced the subsequent oral intake of glucose and sucralose less in Glucose mice than in Sucralose mice. The second part of the study investigated how intestinal rerouting affects the sweet appetite conditioned by the IG glucose infusions. This was accomplished by creating a DJB in which the duodenum
was occluded with a pylorus ligation and the jejunum was anastomosed side-toside to the stomach. As a result, ingested food emptied from the stomach into the mid-jejunum, leaving the duodenum unexposed to nutrients. When trained to drink sucralose paired with IG infusions of 50% glucose, the DJB mice self-administered significantly less sugar than did Sham mice with an intact intestinal tract. In subsequent satiation tests, the DJB mice drank substantially less sucralose and glucose than did the Sham mice following glucose preloads; they also drank less glucose following a sucralose preload. The authors concluded that the enhancement in sweet appetite conditioned by IG sugar infusion depends upon duodenal glucose sensing. However, this interpretation can be questioned because of likely differences in gastric emptying. That is, in Sham mice the pyloric sphincter controlled the emptying of the gastric glucose infusions into the duodenum, whereas in the DJB mice the gastric-jejunal anastomosis presumably allowed the hypercaloric/hypertonic glucose infusion to empty rapidly into the jejunum. Gastric dumping of hypertonic glucose may have been discomforting, which could have counteracted any reward action of glucose in the jejunum. Gastric dumping is a common complication of bariatric surgery in humans (Tack and Deloose, 2014). In rats, glucose infusions into the duodenum or jejunum conditioned similar preferences for a flavored saccharin solution; ileal glucose infusions, however, were ineffective (Ackroff et al., 2010). The effectiveness of duodenal versus jejunal glucose infusions to condition flavor preferences in mice requires investigation. The third part of the study analyzed the role of striatal dopamine systems in
glucose-conditioned appetite. Gastric glucose infusions stimulated dorsal striatal dopamine release in Sham mice but not in DJB mice. In addition, direct duodenal glucose infusions stimulated greater dorsal striatal dopamine release then did jejunal infusions in Sham mice. The authors concluded that the duodenum is a critical site for regulating dorsal striatal dopamine. Alternatively, duodenal infusions may be effective because they expose more of the intestinal tract to glucose than do jejunal infusions (see Little et al., 2006). In contrast to the dorsal striatum, dopamine release in the ventral striatum was stimulated by gastric glucose infusions in both Sham and DJB mice. This finding is most interesting and suggests that different glucose sensors and/or pathways influence dorsal and ventral dopamine circuits. Both intestinal and hepatic-portal glucose sensors have been implicated in glucose-conditioned preferences, and perhaps they differentially engage the ventral and dorsal striatal systems (Ackroff et al., 2010; Oliveira-Maia et al., 2011). The last part of the study determined how direct manipulations of dopamine excitable neurons expressing D1 receptors (D1r) influenced sugar seeking in mice. In both Sham and DJB mice, optogenetic activation of dorsal striatal D1r neurons increased sucralose drinking (‘‘seeking’’) following an IG glucose preload, although the effect was less pronounced in DJB mice. Selective ablation of these neurons produced the opposite effect: ablated mice drank less sucralose following an IG glucose preload than did sham-ablated mice. Interestingly, dorsal striatal D1r neuron ablation did not alter glucose selfadministration during the initial training
Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 3
Cell Metabolism
Previews with sucralose paired with IG glucose. Thus, D1r neuron ablation appeared to have a specific effect on sweet appetite following a glucose preload, a form of reward devaluation. In contrast to manipulation of dorsal striatal D1r neurons, activation or ablation of ventral striatal D1r neurons did not alter sweet seeking following glucose preloads. In rats, pharmacological inhibition of D1 receptors in the nucleus accumbens blocked flavor preference conditioning by IG glucose infusions (Touzani et al., 2008). It may be that the dorsal striatal system is critical for stimulating sweet intake in the presence of satiety or other devaluation signals while the ventral striatal system is necessary for glucose-conditioned flavor preferences. The manipulations used by Han and coauthors combined with a conditioned flavor assay could evaluate this notion.
As reviewed by Han et al. (2016), recent animal and human studies have linked bariatric surgery with alterations in striatal dopamine function. What is novel about their study is that it focused on how bariatric surgery may influence striatal dopamine systems to alter the appetite-stimulating actions of nutrients in the intestinal tract. Their combination of behavioral, physiological, and neurochemical techniques can advance our understanding of gut-brain communications related to normal and disordered appetite.
de Araujo, I.E., Ferreira, J.G., Tellez, L.A., Ren, X., and Yeckel, C.W. (2012). Physiol. Behav. 106, 394–399.
ACKNOWLEDGMENTS
Oliveira-Maia, A.J., Roberts, C.D., Walker, Q.D., Luo, B., Kuhn, C., Simon, S.A., and Nicolelis, M.A. (2011). PLoS ONE 6, e24992.
The author’s research was supported by NIH grant RO1 DK031135.
Han, W., Tellez, L.A., Niu, J., Medina, S., Ferreira, T.L., Zhang, X., Su, J., Tong, J., Schwartz, G.J., van den Pol, A., and de Araujo, I.E. (2016). Cell Metab. 23, this issue, 103–112. Little, T.J., Doran, S., Meyer, J.H., Smout, A.J.P.M., O’Donovan, D.G., Wu, K.L., Jones, K.L., Wishart, J., Rayner, C.K., Horowitz, M., and Feinle-Bisset, C. (2006). Am. J. Physiol. Endocrinol. Metab. 291, E647–E655. Mu¨nzberg, H., Laque, A., Yu, S., Rezai-Zadeh, K., and Berthoud, H.R. (2015). Obes. Rev. 16 (Suppl 1 ), 77–90.
Sclafani, A. (2013). Appetite 71, 454–458.
REFERENCES
Tack, J., and Deloose, E. (2014). Best Pract. Res. Clin. Gastroenterol. 28, 741–749.
Ackroff, K., Yiin, Y.M., and Sclafani, A. (2010). Physiol. Behav. 99, 402–411.
Touzani, K., Bodnar, R.J., and Sclafani, A. (2008). Eur. J. Neurosci. 27, 1525–1533.
Can Insulin Production Suppress b Cell Growth? Matias De Vas1 and Jorge Ferrer1,2,* 1Section
of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
2Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d’Investigacions Biomediques
August Pi
I Sunyer (IDIBAPS), Barcelona, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.12.016
While insulin has mitogenic effects in many cell types, its effects on b cells remain elusive. In this issue of Cell Metabolism, Szabat et al. (2015) genetically block insulin production in adult b cells and show that this leads to a relief of ER stress, AKT activation, and increased b cell proliferation. Insulin is a major regulator of cellular survival and proliferation in many cell types, but its effects on insulin-producing b cells are still unclear. There are numerous indications that insulin might exert mitogenic effects in b cells, as it does in other cell types. For example, the inactivation of the insulin receptor gene in b cells leads to a partial reduction of postnatal b cell proliferation, and this effect is accentuated with simultaneous inactivation of the receptor for IGF1 (insulin-like growth factor 1) (Ueki et al., 2006). Furthermore, genetic perturbations of known downstream insulin signaling mediators, such as IRS2, AKT, and PDK1, also show pro-
found b cell growth phenotypes (Withers et al., 1998; Hashimoto et al., 2006; Bernal-Mizrachi et al., 2001). Paradoxically, mice that harbor homozygous germline mutations of the two non-allelic mouse insulin genes show increased, rather than decreased, islet cell proliferation (Duvillie´ et al., 2002). However, since these effects could theoretically be indirect, involving for instance increased islet vascularization, it is currently not possible to draw any firm conclusion regarding the direct effects of insulin on b cells (Duvillie´ et al., 2002). Given that insulin production can vary substantially throughout the lifetime of an individual, and across populations,
4 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.
the notion that insulin production could affect b cell growth has significant potential implications for human diabetes. Szabat et al. (2015) have now addressed this conundrum by using a conditional insulin gene knockout approach. They bred mice carrying three genetic modifications: homozygous germline loss-of-function mutations in the Ins1 gene, homozygous ‘‘floxed’’ Ins2 alleles, and a Pdx1CreER tamoxifen-inducible Cre recombinase transgene. When these mice were treated with tamoxifen at 6 weeks of age, both Ins2 alleles were recombined in most cells, and this led to a complete abrogation of insulin