- Email: [email protected]
A Sweet Spot for the Bariatric Surgeon
Cell Metabolism
Previews A Sweet Spot for the Bariatric Surgeon Diego Perez-Tilve,1 David A. D’Alessio,1 and Matthias H. Tscho¨p1,* 1Departments of Psychiatry and Medicine, Obesity Research Centre, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA *Correspondence: [email protected] DOI 10.1016/j.cmet.2008.08.012
While gastric bypass surgery remains popular as the only treatment for morbid obesity with curative potential, the molecular mechanisms underpinning its immediate metabolic benefits remain unclear. New work in this issue (Troy et al., 2008) suggests intestinal glucose production sensed by afferent nerve fibers surrounding the portal vein may be key. Got a sweet tooth? If so, it’s not usually considered a good thing—at least for your metabolic health. But has anyone heard of a sweet duodenum? A few flights further down your digestive tract, right past your stomach, may be a sugar-generating spot that could actually help keep circulating blood glucose levels low and hunger pangs in check. In this issue, Andreelli and colleagues (Troy et al., 2008) present experimental evidence that endogenous glucose production by defined segments of the small intestine regulates food intake and hepatic glucose metabolism via the autonomic nervous system, and may also play a key role in the immediate and substantial metabolic benefits conferred by some bariatric surgeries. Despite a mortality risk of 0.5%–2% (depending on where it is performed), bariatric gastric bypass surgery is an increasingly popular treatment option for obese patients. An estimated 120,000 procedures were performed in the US alone in 2002—twice the number operated 5 years earlier (Couzin, 2008). The typical clinical bypass procedure, Rouxen-Y gastric bypass (RYGB), couples substantial gastric reduction with an intestinal rerouting that excludes the duodenum and proximal jejunum from direct contact with nutrients. Substantial weight loss is the result, at least partly accounted for by a precipitous drop in food intake following surgery. Unexpectedly, gastric bypass surgery also has almost immediate metabolic benefits that precede any substantial weight loss, observations that were initially overlooked by the scientific community (Pories et al., 1987; Pories et al., 1995). Bariatric surgery is estimated to offer the potential to reduce diabetes deaths by more than 90% (Adams et al., 2007), igniting serious discussion as to
whether surgery could be the most efficient treatment for diabetes—even in patients without a great excess of body adiposity. In light of this potential expansion of the indications for bariatric surgery, understanding the physiological and molecular mechanisms underlying its benefits becomes imperative. In their new paper, Mithiuex, Andreelli, and colleagues compare energy and glucose metabolism following two experimental bariatric surgical procedures with sham operations, in high-fat diet-induced obese (HF-DIO) mice (Figure 1). In the first procedure, they used a restrictive prosthetic band around the upper stomach to create a small proximal and a large distal pouch, connected by a narrow lumen (gastric lap band, GLB). Alternatively, they performed an enterogastric anastomosis with pyloric sphincter ligature that excluded duodenum and proximal jejunum from contact with ingested nutrients (entero-gastro anastomosis [EGA]), performed as a surrogate for the clinical RYGB. EGA mice had significantly decreased food intake, and when shamcontrol and GLB mice were pair-fed to the EGA mice, body fat loss was similar in all groups, suggesting that at least in the paradigm used here, changes in weight were a consequence of caloric intake and not differences in energy expenditure. More importantly, the authors observed in EGA mice significant improvements in the ability to clear a glucose load as early as 10 days after surgery. This was due in part to increased insulin secretion, but EGA animals also showed a clear improvement in the sensitivity of hepatic glucose production to suppression by insulin. This enhanced insulin response might be explained by increased secretion of the gastrointestinal hormone
GLP-1, previously implicated as one mediator of bariatric surgery’s immediate metabolic benefits. In EGA mice however, GLP-1 action did not seem to be responsible for improved hepatic insulin sensitivity. The authors also did not see changes in hepatic lipid content in EGA treated mice. Instead, they present compelling tracer dilution and arteriovenous sampling evidence indicating that intestinal gluconeogenesis was directly linked to the improved hepatic glucose metabolism in the EGA mice. In prior studies, the authors have proposed that intestinal gluconeogenesis may regulate afferent nerve fibers that connect with the food intake circuitry of the central nervous system circuitry (Mithieux et al., 2005). In the current work, the EGA procedure increased intestinal glucose production sufficiently to raise portal vein glucose levels as compared to sham-operated controls. This response appeared to be key to improving glucose tolerance and insulin sensitivity. In further studies, mice that lack portal vein glucose sensing (due to tissue-specific deficiency for the glucose transporter GLUT2) did not exhibit decreased food intake and improved glucose metabolism following EGA compared to surgically treated wild-type controls. Consistent with the notion that portal vein glucose sensing signals are relayed to the CNS by visceral nerves, local destruction of sensory fibers in the vicinity of the portal vein attenuated EGA-induced metabolic improvements, including the effects on food intake. These results suggest that intestinal adaptations may underlie the beneficial effects of gastric bypass. Rapid passage of meals into the gut of EGA animals, in the absence of normal gastric, pyloric, and duodenal function to regulate nutrient delivery, increases GLP-1 but also causes
Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc. 177
Cell Metabolism
Previews the small intestine to shift into able. After all, the metabolic a state of higher glucose proderangements associated duction. That this latter effect with obesity tend to appear changes the response of slowly over time. Clearly local neural networks projecchronic negative energy balting to the CNS suggests that ance over time, with concomEGA initiates several actions itant loss of excess fat, will that could mediate metabolic lead to resolution of the metabenefit, as has been probolic syndrome. Since, in posed previously (Berthoud, most patients, gastric bypass 2008; Vincent and le Roux, surgery causes just this sort 2007). of gradual weight loss, are What is the relevance of those unexplained immediate these interesting findings to benefits of RYGB truly clinical bariatric surgeries? needed? Some of the longThe bypass technique used term liabilities of RYGB, such here in mice by Troy and colas reoccurring hypoglycemia leagues differs from RYGB in are plausibly, even likely, that the stomach is fully exa consequence of the same posed to incoming nutrients changes in gut neural and enin the EGA, rather than the docrine function that appear substantial gastric reduction so miraculous in the immediperformed in human patients. ate postoperative period. The exclusion of the duodeTellingly, no one has yet renum and proximal jejunum ported serious and undesired from direct contact with side effects from curing type nutrients may be a key com2 diabetes the old fashioned ponent of the near instant imway—by decreasing food inprovement of diabetic conditake and increasing exercise. tions following RYGB (Rubino Nevertheless, the work et al., 2006). Consistent presented here by Troy and Figure 1. Schematic View of the Mechanistic Model Proposed by with this model, EGA mice colleagues adds a new layer Troy et al. showed distinct improveof complexity and constitutes Glucose produced by defined intestinal segments is secreted directly into the ments in glucose tolerance a novel approach to dissectportal vein, where changes in blood glucose are detected by sensory fibers presumably projecting to central nervous system circuits controlling food compared to GLB animals ing the mechanisms behind intake, insulin secretion, and nutrient partitioning. Enhanced intestinal glucose despite similar amounts of surgically induced metabolic production following bariatric surgeries that bypass duodenum and jejunum food intake (which differed improvement. While it seems may explain some of the immediate metabolic benefits that occur after such surgeries, but not following gastric banding procedures. ANS, autonomic nerlittle even without pair feedunlikely, at least for now, vous system; EGA, entero-gastro anastomosis. ing), body weight, and body that gastric surgery will befat. Unclear, however, is come a primary treatment how these findings will translate into hu- be strengthened by a demonstration that option for diabetes in lean individuals, man (patho-)physiology, for which differ- preventing intestinal gluconeogenesis the role of intestinal glucose production ing effects of banding versus bypass on prevents the effects of EGA. Also of for bariatric success warrants future studbody weight are well documented. interest is whether the GLUT2 knockout ies and may pave the way for new strateOther questions are raised by the stim- or deafferentation experiments would gies to prevent or treat the metabolic synulating data of by Troy and colleagues. worsen glucose tolerance in the GLB or drome. Would devices providing specific While the study of the EGA procedure sham controls. These shortcomings pre- delivery of small amounts of glucose diwas thorough, analysis of the GLB model vent definitive conclusions on the EGA rectly into the portal vein be effective for was limited due to (in some cases fatal) model. Moreover, gastric restriction ap- diabetes? Or would implanted pacegastric obstruction and regurgitation. Al- pears to be much less well tolerated in makers specifically stimulating afferent though the expression of key gluconeo- mice than men, so the rodent work should nerve bundles surrounding the portal genic enzymes were not increased in GLB not dissuade continued clinical use of the vein decrease appetite? Will a well-timed mice (as contrasted with EGA mice), much less invasive and less risky AGB shot of GLP-1 give both approaches an tracer dilution and arteriovenous sam- procedure. additional boost? Clear answers to these pling data would have been useful to conRecently described cases of dramatic questions would undoubtedly put refirm that intestinal glucose production did hypoglycemia in RYGB patients (Service searchers and surgeons in a sweet spot not increase. And while most of the data et al., 2005) raise some doubt as to to solve one of today’s most discussed in this paper is internally consistent, the whether the immediate metabolic bene- biomedical mysteries—but, more impormodel proposed by the authors would fits of bariatric surgery are always desir- tantly, may open up the opportunity to 178 Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc.
Cell Metabolism
Previews put millions of patients in a better place, too. REFERENCES Adams, T.D., Gress, R.E., Smith, S.C., Halverson, R.C., Simper, S.C., Rosamond, W.D., Lamonte, M.J., Stroup, A.M., and Hunt, S.C. (2007). N. Engl. J. Med. 357, 753–761.
Mithieux, G., Misery, P., Magnan, C., Pillot, B., Gautier-Stein, A., Bernard, C., Rajas, F., and Zitoun, C. (2005). Cell Metab. 2, 321–329. Pories, W.J., Caro, J.F., Flickinger, E.G., Meelheim, H.D., and Swanson, M.S. (1987). Ann. Surg. 206, 316–323.
and Marescaux, J. (2006). Ann. Surg. 244, 741–749. Service, G.J., Thompson, G.B., Service, F.J., Andrews, J.C., Collazo-Clavell, M.L., and Lloyd, R.V. (2005). N. Engl. J. Med. 353, 249–254.
Pories, W.J., Swanson, M.S., MacDonald, K.G., Long, S.B., Morris, P.G., Brown, B.M., Barakat, H.A., deRamon, R.A., Israel, G., Dolezal, J.M., et al. (1995). Ann. Surg. 222, 339–350.
Troy, S., Soty, M., Ribeiro, L., Laval, L., Migrenne, S., Fioramonti, X., Pillot, B., Fauveau, V., Aubert, R., Viollet, B., et al. (2008). Cell Metab. 8, this issue, 201–211.
Rubino, F., Forgione, A., Cummings, D.E., Vix, M., Gnuli, D., Mingrone, G., Castagneto, M.,
Vincent, R.P., and le Roux, C.W. (2007). Clin. Endocrinol. (Oxf.) 69, 173–179.
Berthoud, H.R. (2008). Regul. Pept. 149, 15–25. Couzin, J. (2008). Science 320, 438–440.
PI3K Enters Beta-Testing Adam J. Shaywitz,1,2 Kevin D. Courtney,1,3 Akash Patnaik,1,4 and Lewis C. Cantley1,5,* 1Division
of Signal Transduction of Endocrinology Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 4Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] DOI 10.1016/j.cmet.2008.08.011 2Division
Phosphoinositide-3-OH kinases (PI3K) are critical regulators of cell metabolism, growth, and survival. In a recent publication in Nature, Jia et al. (2008) identify specific functions of the p110b isoform of PI3K in glucose metabolism, cellular proliferation, and tumorigenesis. Class IA PI3Ks are members of a conserved family of lipid kinases comprised of a p85 regulatory subunit and a p110 catalytic subunit. There are two ubiquitously expressed class IA catalytic isoforms, p110a and p110b. Class IA PI3Ks are activated by receptor tyrosine kinases (RTKs). The p110b catalytic subunit can also be activated through G protein-coupled receptors (GPCRs) (Hazeki et al., 1998). Activation of PI3K results in the conversion of PI(4,5)P2 to PIP3; the latter binds to pleckstrin homology (PH) domains of various signaling proteins, including the serine/ threonine kinase Akt. Dysregulation of PI3K signaling is implicated in the pathogenesis of diabetes mellitus and cancer (Engelman et al., 2006). The p110a isoform of PI3K has been the most extensively studied to date, and the gene encoding this enzyme is frequently mutated in human cancers. However, in a recent issue of Nature, Jia et al. (2008) identify unique roles for p110b in cellular metabolism and oncogenesis.
In the liver, p110a appears to be the predominant PI3K isoform activated following insulin receptor stimulation (Foukas et al., 2006). Indeed, Jia et al. (2008) show that deletion of p110b does not affect the ability of insulin to activate Akt in the liver, which supports the results of prior pharmacologic studies showing that p110b does not play a significant role in insulin-stimulated Akt activation (Knight et al., 2006). However, Jia et al. (2008) found that the absence of p110b impairs insulin repression of gluconeogenic genes and leads to glucose intolerance. Many insulin-repressed genes in the liver contain binding sites for FOXO transcription factors, and expression of constitutively active FOXO leads to increased gluconeogenic gene expression (Zhang et al., 2006). Notably, mice heterozygous for both p110a and p110b exhibit glucose intolerance despite intact insulinstimulated AKT activity, suggesting that factors in addition to Akt are required for insulin signaling in the liver (Brachmann
et al., 2005). Jia et al. (2008) did not examine FOXO phosphorylation, and other kinases, in addition to Akt, can phosphorylate FOXO. However, FOXO is one of many transcription factors contributing to PEPCK expression; therefore, full repression in the presence of insulin may require activation of an as-yet-unidentified signaling complex by p110b and may occur in a PIP3-independent manner (see Figure 1A). Alternatively, p110b catalytic activity and PIP3 production might be required for repression of PEPCK by insulin. It is known that pharmacologic inhibition of p110b does not block acute Akt phosphorylation, but it does significantly inhibit PIP3 generation. This observation raises the possibility that while p110a activation alone produces more than sufficient PIP3 for acute AKT activation, additional PIP3dependent responses that require higher levels of this lipid or that require PIP3 production at a unique location by p110b play additional roles in suppression of gluconeogenesis.
Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc. 179
Previews A Sweet Spot for the Bariatric Surgeon Diego Perez-Tilve,1 David A. D’Alessio,1 and Matthias H. Tscho¨p1,* 1Departments of Psychiatry and Medicine, Obesity Research Centre, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA *Correspondence: [email protected] DOI 10.1016/j.cmet.2008.08.012
While gastric bypass surgery remains popular as the only treatment for morbid obesity with curative potential, the molecular mechanisms underpinning its immediate metabolic benefits remain unclear. New work in this issue (Troy et al., 2008) suggests intestinal glucose production sensed by afferent nerve fibers surrounding the portal vein may be key. Got a sweet tooth? If so, it’s not usually considered a good thing—at least for your metabolic health. But has anyone heard of a sweet duodenum? A few flights further down your digestive tract, right past your stomach, may be a sugar-generating spot that could actually help keep circulating blood glucose levels low and hunger pangs in check. In this issue, Andreelli and colleagues (Troy et al., 2008) present experimental evidence that endogenous glucose production by defined segments of the small intestine regulates food intake and hepatic glucose metabolism via the autonomic nervous system, and may also play a key role in the immediate and substantial metabolic benefits conferred by some bariatric surgeries. Despite a mortality risk of 0.5%–2% (depending on where it is performed), bariatric gastric bypass surgery is an increasingly popular treatment option for obese patients. An estimated 120,000 procedures were performed in the US alone in 2002—twice the number operated 5 years earlier (Couzin, 2008). The typical clinical bypass procedure, Rouxen-Y gastric bypass (RYGB), couples substantial gastric reduction with an intestinal rerouting that excludes the duodenum and proximal jejunum from direct contact with nutrients. Substantial weight loss is the result, at least partly accounted for by a precipitous drop in food intake following surgery. Unexpectedly, gastric bypass surgery also has almost immediate metabolic benefits that precede any substantial weight loss, observations that were initially overlooked by the scientific community (Pories et al., 1987; Pories et al., 1995). Bariatric surgery is estimated to offer the potential to reduce diabetes deaths by more than 90% (Adams et al., 2007), igniting serious discussion as to
whether surgery could be the most efficient treatment for diabetes—even in patients without a great excess of body adiposity. In light of this potential expansion of the indications for bariatric surgery, understanding the physiological and molecular mechanisms underlying its benefits becomes imperative. In their new paper, Mithiuex, Andreelli, and colleagues compare energy and glucose metabolism following two experimental bariatric surgical procedures with sham operations, in high-fat diet-induced obese (HF-DIO) mice (Figure 1). In the first procedure, they used a restrictive prosthetic band around the upper stomach to create a small proximal and a large distal pouch, connected by a narrow lumen (gastric lap band, GLB). Alternatively, they performed an enterogastric anastomosis with pyloric sphincter ligature that excluded duodenum and proximal jejunum from contact with ingested nutrients (entero-gastro anastomosis [EGA]), performed as a surrogate for the clinical RYGB. EGA mice had significantly decreased food intake, and when shamcontrol and GLB mice were pair-fed to the EGA mice, body fat loss was similar in all groups, suggesting that at least in the paradigm used here, changes in weight were a consequence of caloric intake and not differences in energy expenditure. More importantly, the authors observed in EGA mice significant improvements in the ability to clear a glucose load as early as 10 days after surgery. This was due in part to increased insulin secretion, but EGA animals also showed a clear improvement in the sensitivity of hepatic glucose production to suppression by insulin. This enhanced insulin response might be explained by increased secretion of the gastrointestinal hormone
GLP-1, previously implicated as one mediator of bariatric surgery’s immediate metabolic benefits. In EGA mice however, GLP-1 action did not seem to be responsible for improved hepatic insulin sensitivity. The authors also did not see changes in hepatic lipid content in EGA treated mice. Instead, they present compelling tracer dilution and arteriovenous sampling evidence indicating that intestinal gluconeogenesis was directly linked to the improved hepatic glucose metabolism in the EGA mice. In prior studies, the authors have proposed that intestinal gluconeogenesis may regulate afferent nerve fibers that connect with the food intake circuitry of the central nervous system circuitry (Mithieux et al., 2005). In the current work, the EGA procedure increased intestinal glucose production sufficiently to raise portal vein glucose levels as compared to sham-operated controls. This response appeared to be key to improving glucose tolerance and insulin sensitivity. In further studies, mice that lack portal vein glucose sensing (due to tissue-specific deficiency for the glucose transporter GLUT2) did not exhibit decreased food intake and improved glucose metabolism following EGA compared to surgically treated wild-type controls. Consistent with the notion that portal vein glucose sensing signals are relayed to the CNS by visceral nerves, local destruction of sensory fibers in the vicinity of the portal vein attenuated EGA-induced metabolic improvements, including the effects on food intake. These results suggest that intestinal adaptations may underlie the beneficial effects of gastric bypass. Rapid passage of meals into the gut of EGA animals, in the absence of normal gastric, pyloric, and duodenal function to regulate nutrient delivery, increases GLP-1 but also causes
Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc. 177
Cell Metabolism
Previews the small intestine to shift into able. After all, the metabolic a state of higher glucose proderangements associated duction. That this latter effect with obesity tend to appear changes the response of slowly over time. Clearly local neural networks projecchronic negative energy balting to the CNS suggests that ance over time, with concomEGA initiates several actions itant loss of excess fat, will that could mediate metabolic lead to resolution of the metabenefit, as has been probolic syndrome. Since, in posed previously (Berthoud, most patients, gastric bypass 2008; Vincent and le Roux, surgery causes just this sort 2007). of gradual weight loss, are What is the relevance of those unexplained immediate these interesting findings to benefits of RYGB truly clinical bariatric surgeries? needed? Some of the longThe bypass technique used term liabilities of RYGB, such here in mice by Troy and colas reoccurring hypoglycemia leagues differs from RYGB in are plausibly, even likely, that the stomach is fully exa consequence of the same posed to incoming nutrients changes in gut neural and enin the EGA, rather than the docrine function that appear substantial gastric reduction so miraculous in the immediperformed in human patients. ate postoperative period. The exclusion of the duodeTellingly, no one has yet renum and proximal jejunum ported serious and undesired from direct contact with side effects from curing type nutrients may be a key com2 diabetes the old fashioned ponent of the near instant imway—by decreasing food inprovement of diabetic conditake and increasing exercise. tions following RYGB (Rubino Nevertheless, the work et al., 2006). Consistent presented here by Troy and Figure 1. Schematic View of the Mechanistic Model Proposed by with this model, EGA mice colleagues adds a new layer Troy et al. showed distinct improveof complexity and constitutes Glucose produced by defined intestinal segments is secreted directly into the ments in glucose tolerance a novel approach to dissectportal vein, where changes in blood glucose are detected by sensory fibers presumably projecting to central nervous system circuits controlling food compared to GLB animals ing the mechanisms behind intake, insulin secretion, and nutrient partitioning. Enhanced intestinal glucose despite similar amounts of surgically induced metabolic production following bariatric surgeries that bypass duodenum and jejunum food intake (which differed improvement. While it seems may explain some of the immediate metabolic benefits that occur after such surgeries, but not following gastric banding procedures. ANS, autonomic nerlittle even without pair feedunlikely, at least for now, vous system; EGA, entero-gastro anastomosis. ing), body weight, and body that gastric surgery will befat. Unclear, however, is come a primary treatment how these findings will translate into hu- be strengthened by a demonstration that option for diabetes in lean individuals, man (patho-)physiology, for which differ- preventing intestinal gluconeogenesis the role of intestinal glucose production ing effects of banding versus bypass on prevents the effects of EGA. Also of for bariatric success warrants future studbody weight are well documented. interest is whether the GLUT2 knockout ies and may pave the way for new strateOther questions are raised by the stim- or deafferentation experiments would gies to prevent or treat the metabolic synulating data of by Troy and colleagues. worsen glucose tolerance in the GLB or drome. Would devices providing specific While the study of the EGA procedure sham controls. These shortcomings pre- delivery of small amounts of glucose diwas thorough, analysis of the GLB model vent definitive conclusions on the EGA rectly into the portal vein be effective for was limited due to (in some cases fatal) model. Moreover, gastric restriction ap- diabetes? Or would implanted pacegastric obstruction and regurgitation. Al- pears to be much less well tolerated in makers specifically stimulating afferent though the expression of key gluconeo- mice than men, so the rodent work should nerve bundles surrounding the portal genic enzymes were not increased in GLB not dissuade continued clinical use of the vein decrease appetite? Will a well-timed mice (as contrasted with EGA mice), much less invasive and less risky AGB shot of GLP-1 give both approaches an tracer dilution and arteriovenous sam- procedure. additional boost? Clear answers to these pling data would have been useful to conRecently described cases of dramatic questions would undoubtedly put refirm that intestinal glucose production did hypoglycemia in RYGB patients (Service searchers and surgeons in a sweet spot not increase. And while most of the data et al., 2005) raise some doubt as to to solve one of today’s most discussed in this paper is internally consistent, the whether the immediate metabolic bene- biomedical mysteries—but, more impormodel proposed by the authors would fits of bariatric surgery are always desir- tantly, may open up the opportunity to 178 Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc.
Cell Metabolism
Previews put millions of patients in a better place, too. REFERENCES Adams, T.D., Gress, R.E., Smith, S.C., Halverson, R.C., Simper, S.C., Rosamond, W.D., Lamonte, M.J., Stroup, A.M., and Hunt, S.C. (2007). N. Engl. J. Med. 357, 753–761.
Mithieux, G., Misery, P., Magnan, C., Pillot, B., Gautier-Stein, A., Bernard, C., Rajas, F., and Zitoun, C. (2005). Cell Metab. 2, 321–329. Pories, W.J., Caro, J.F., Flickinger, E.G., Meelheim, H.D., and Swanson, M.S. (1987). Ann. Surg. 206, 316–323.
and Marescaux, J. (2006). Ann. Surg. 244, 741–749. Service, G.J., Thompson, G.B., Service, F.J., Andrews, J.C., Collazo-Clavell, M.L., and Lloyd, R.V. (2005). N. Engl. J. Med. 353, 249–254.
Pories, W.J., Swanson, M.S., MacDonald, K.G., Long, S.B., Morris, P.G., Brown, B.M., Barakat, H.A., deRamon, R.A., Israel, G., Dolezal, J.M., et al. (1995). Ann. Surg. 222, 339–350.
Troy, S., Soty, M., Ribeiro, L., Laval, L., Migrenne, S., Fioramonti, X., Pillot, B., Fauveau, V., Aubert, R., Viollet, B., et al. (2008). Cell Metab. 8, this issue, 201–211.
Rubino, F., Forgione, A., Cummings, D.E., Vix, M., Gnuli, D., Mingrone, G., Castagneto, M.,
Vincent, R.P., and le Roux, C.W. (2007). Clin. Endocrinol. (Oxf.) 69, 173–179.
Berthoud, H.R. (2008). Regul. Pept. 149, 15–25. Couzin, J. (2008). Science 320, 438–440.
PI3K Enters Beta-Testing Adam J. Shaywitz,1,2 Kevin D. Courtney,1,3 Akash Patnaik,1,4 and Lewis C. Cantley1,5,* 1Division
of Signal Transduction of Endocrinology Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 4Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] DOI 10.1016/j.cmet.2008.08.011 2Division
Phosphoinositide-3-OH kinases (PI3K) are critical regulators of cell metabolism, growth, and survival. In a recent publication in Nature, Jia et al. (2008) identify specific functions of the p110b isoform of PI3K in glucose metabolism, cellular proliferation, and tumorigenesis. Class IA PI3Ks are members of a conserved family of lipid kinases comprised of a p85 regulatory subunit and a p110 catalytic subunit. There are two ubiquitously expressed class IA catalytic isoforms, p110a and p110b. Class IA PI3Ks are activated by receptor tyrosine kinases (RTKs). The p110b catalytic subunit can also be activated through G protein-coupled receptors (GPCRs) (Hazeki et al., 1998). Activation of PI3K results in the conversion of PI(4,5)P2 to PIP3; the latter binds to pleckstrin homology (PH) domains of various signaling proteins, including the serine/ threonine kinase Akt. Dysregulation of PI3K signaling is implicated in the pathogenesis of diabetes mellitus and cancer (Engelman et al., 2006). The p110a isoform of PI3K has been the most extensively studied to date, and the gene encoding this enzyme is frequently mutated in human cancers. However, in a recent issue of Nature, Jia et al. (2008) identify unique roles for p110b in cellular metabolism and oncogenesis.
In the liver, p110a appears to be the predominant PI3K isoform activated following insulin receptor stimulation (Foukas et al., 2006). Indeed, Jia et al. (2008) show that deletion of p110b does not affect the ability of insulin to activate Akt in the liver, which supports the results of prior pharmacologic studies showing that p110b does not play a significant role in insulin-stimulated Akt activation (Knight et al., 2006). However, Jia et al. (2008) found that the absence of p110b impairs insulin repression of gluconeogenic genes and leads to glucose intolerance. Many insulin-repressed genes in the liver contain binding sites for FOXO transcription factors, and expression of constitutively active FOXO leads to increased gluconeogenic gene expression (Zhang et al., 2006). Notably, mice heterozygous for both p110a and p110b exhibit glucose intolerance despite intact insulinstimulated AKT activity, suggesting that factors in addition to Akt are required for insulin signaling in the liver (Brachmann
et al., 2005). Jia et al. (2008) did not examine FOXO phosphorylation, and other kinases, in addition to Akt, can phosphorylate FOXO. However, FOXO is one of many transcription factors contributing to PEPCK expression; therefore, full repression in the presence of insulin may require activation of an as-yet-unidentified signaling complex by p110b and may occur in a PIP3-independent manner (see Figure 1A). Alternatively, p110b catalytic activity and PIP3 production might be required for repression of PEPCK by insulin. It is known that pharmacologic inhibition of p110b does not block acute Akt phosphorylation, but it does significantly inhibit PIP3 generation. This observation raises the possibility that while p110a activation alone produces more than sufficient PIP3 for acute AKT activation, additional PIP3dependent responses that require higher levels of this lipid or that require PIP3 production at a unique location by p110b play additional roles in suppression of gluconeogenesis.
Cell Metabolism 8, September 3, 2008 ª2008 Elsevier Inc. 179