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Autonomic control and bariatric procedures
Autonomic Neuroscience: Basic and Clinical 177 (2013) 81–86
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Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Review
Autonomic control and bariatric procedures Andrea Zsombok ⁎ Department of Physiology, Endocrinology Section, Tulane University, School of Medicine, 1430 Tulane Ave., SL39, New Orleans, LA 70112, United States Department of Medicine, Endocrinology Section, Tulane University, School of Medicine, 1430 Tulane Ave., SL39, New Orleans, LA 70112, United States
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Article history: Received 22 May 2012 Received in revised form 10 October 2012 Accepted 1 March 2013 Keywords: Glucagon-like peptide 1 Brainstem Paraventricular nucleus of the hypothalamus Neuronal properties Autonomic control of the liver
a b s t r a c t The sudden improvement of metabolic profile and the remission of type 2 diabetes after bariatric surgery, well before weight loss, raise important new questions regarding glycemic control. Currently, various types of bariatric procedures target type 2 diabetes in obese and non-obese patients. Nevertheless, the origin of the dramatic metabolic improvements, including glucose homeostasis, is poorly understood, and the role of the gastrointestinal (GI) tract remains relatively speculative, as well as why these procedures are variably effective. One neglected explanation is that such interventions disrupt neural networks mediating GI–brain communication and could alter the autonomic output to the visceral organs, including the liver. Incretins, e.g., glucagon-like peptide 1 (GLP-1), have major influence on the central nervous system. Moreover, the level of GLP-1 is observed to significantly increase after bariatric surgery and could be a key factor in the weight-independent, anti-diabetic effect. Therefore, this review will evaluate the effect of GLP-1 on the central nervous system, with emphasis on the cellular effects of GLP-1, and will provide an overview of the autonomic control of the liver. © 2013 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . GLP-1 action on the central nervous system 2.1. Cellular effects of GLP-1 in the brain 3. Autonomic control of the liver . . . . . . 3.1. The role of PVN . . . . . . . . . . 4. Role of gender . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction Diabetes mellitus (DM) has reached epidemic proportions worldwide, including the United States. The Centers for Disease Control and Prevention estimates that approximately 25.8 million (8.3%) of the US population suffer from DM (CDCP, 2011). Despite the billions of dollars invested to reduce the symptoms and complications, the treatments remain inadequate. Therefore, the positive influence of bariatric procedures on glycemic control requires continued attention and commitment to the search for the underlying mechanisms. The sudden improvement in glycemic and metabolic control within days of bariatric surgery observed in patients subjected to it cannot be ⁎ Tel.: +1 504 988 2597; fax: +1 504 988 2675. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.03.002
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explained with weight loss (Rubino et al., 2010a,b; Spector and Shikora, 2010). Thereby, two leading theories have emerged to explain the weight-independent effect of bariatric surgery (Spector and Shikora, 2010). The “hindgut” theory is based on up-regulation of incretins, including glucagon-like peptide 1 (GLP-1), resulting in increased insulin secretion and improved glucose tolerance. The “foregut” hypothesis, on the other hand, proposes that excluding the duodenum leads to inhibition of signals responsible for insulin resistance and impaired glycemic control (Rubino et al., 2010a,b). However, any type of bariatric operation alters existing gut–brain communication and could alter the neural control of the subdiaphragmatic organs. Furthermore, hormones of the gastrointestinal (GI) tract (e.g., GLP-1, ghrelin) are involved in the regulation of energy homeostasis via the central nervous system (CNS); thus, their altered secretion could significantly impact the neural control of visceral organs including the liver.
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The importance of the central nervous system in the regulation of the visceral organs has long been recognized (Shimazu et al., 1966; Oomura et al., 1969; Swanson and Sawchenko, 1980; Pocai et al., 2005c; Kalsbeek et al., 2010a; Yi et al., 2010) and accumulating experimental evidence indicates that the CNS plays a pivotal role in maintaining glucose regulation and energy balance (Obici et al., 2002a,b,c; Pocai et al., 2005c; Kalsbeek et al., 2010a; Yi et al., 2010). Consequently, it will be important to review the effect of GLP-1 on the brain and the autonomic control of the liver to examine whether the effect could have a major role to play in the rapid improvement of metabolic parameters after bariatric surgery. 2. GLP-1 action on the central nervous system GLP-1 is a gut hormone directly binding to GLP-1 receptors (GLP-1R) (Thorens, 1995). In addition to the enhancement of glucose-induced insulin secretion of pancreatic beta cells, also called “direct route,” GLP-1, through the “gut–brain–periphery” axis, has major effects on insulin secretion and glucose metabolism (Sandoval et al., 2008b; Burcelin et al., 2009). One circuit-mechanism originates from GLP-1R in the gut and/or from enteric glucose sensors of the hepatoportal vein. Ascending information from the GI tract through the afferent sensory branches of the vagus nerve reaches the nucleus of the solitary tract (NTS) (Adachi et al., 1984; Burcelin et al., 2000; Burcelin et al., 2009). The NTS transmits the information to the dorsal motor nucleus of the vagus (DMV), the main parasympathetic output to the visceral organs, and to the hypothalamus (Fig. 1). This neural circuit controls food intake and glucose metabolism (Dardevet et al., 2004; Ionut et al., 2005; Mithieux et al., 2005). Activation of the enteric pathway with infusion of glucose into the stomach without causing hyperglycemia and hyperinsulinemia increases whole-body glucose utilization, muscle glycogen synthesis and neuronal activity in the NTS of mice (Knauf et al., 2008b). Interestingly, it had inhibitory effects on the dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH) and on NPY-positive neurons of the arcuate nucleus (ARC) without affecting the proopiomelanocortin (POMC)-positive neurons, indicating differential regulation of the brainstem and hypothalamus by enteric glucose in rodent models (Knauf et al., 2008b). Activation of this circuit requires functional GLP-1 receptors in the brain, as indicated by the blunted response observed in GLP-1R knockout mice. These observations suggest that augmented GLP-1 levels in the GI tract can significantly influence the CNS and modulate efferent vagal regulation of the visceral organs. On the other hand, enteric glucose did not alter neuronal activity or whole-body utilization rates in diabetic mice fed with a high-fat diet, thereby suggesting that the “gut–brain–muscle” axis is altered in diabetic conditions (Knauf et al., 2008b). Another circuit regulation involves circulating hormones and nutrients reaching the central nervous system, thereby effecting the neuroendocrine and autonomic nervous system mainly via the brainstem and hypothalamus (Zsombok and Smith, 2009). GLP-1 can directly stimulate neurons in the brainstem and hypothalamus in two ways. One suggested way is through crossing the blood–brain barrier (BBB); however, since the half-life time of GLP-1 is very short, the efficacy of this route can be questioned (Kastin et al., 2002; Banks, 2006). Another route is via direct stimulation of neurons by being synthesized de novo in the brainstem (Merchenthaler et al., 1999). GLP-1 is synthesized in the NTS, and as a result, GLP-1 activates GLP-1 receptors and acts as a neuropeptide (Larsen and Holst, 2005; Wan et al., 2007a,b), modulating synaptic activity, thus influencing metabolism. In in vivo animal studies, intracerebroventricular (ICV) administration of a GLP-1 agonist increased heart rate and blood pressure (Yamamoto et al., 2002). Furthermore, ICV infusion of GLP-1 into the lateral, third and fourth ventricle or to the paraventricular nucleus of the hypothalamus (PVN) decreased food intake (Tang-Christensen et al., 1996; Turton et al., 1996), and infusion into the third ventricle increased neuronal activity determined by c-fos immunoreactivity in the PVN, ARC, NTS and area postrema
Fig. 1. Schematic illustration of GLP-1 effect on gut–brain–digestive system circuits. This model hypothesizes that 1) circulating GLP-1 directly activates GLP-1 receptors by crossing the blood–brain-barrier and thus modulates efferent output. 2) Circulating GLP-1 stimulates the afferent vagus, which in turn triggers the modulation of efferent pathway. 3) It is also possible that stimulation of the afferent vagal nerve will trigger secretion of GLP-1 from NTS, thereby altering neuronal activity and thus influence efferent vagus. Abbreviations: ARC: arcuate nucleus; DMV: dorsal motor nucleus of the vagus; DVC: dorsal vagal complex; GLP-1: glucagon-like peptide 1; HGP: hepatic glucose production; LH: lateral hypothalamus; NTS: nucleus of the solitary tract; PVN: paraventricular nucleus of the hypothalamus; VMH: ventromedial hypothalamus.
(Van Dijk et al., 1996). ICV activation of GLP-1 receptors enhanced glucose-stimulated insulin secretion, and administration of GLP-1 into the ARC but not into the PVN reduced hepatic glucose production (Sandoval et al., 2008b). These observations were consistent with the findings that the GLP-1 receptor mRNA is present in the majority of ARC neurons expressing POMC, suggesting that the hypothalamic ARC neurons are important components of the GLP-1-dependent regulation of glucose production. These data suggest that GLP-1 is involved in the maintenance of glucose homeostasis (Sandoval, 2008; Sandoval et al., 2008b) and GLP-1 receptors in specific nuclei have distinct effects. It is highly likely that the central GLP-1 system is responsible for stimulation of pancreatic insulin secretion and inhibition of glucose production of the liver as suggested by Sandoval and her coworkers. On the other hand, in hyperglycemic hyperinsulinemic clamp studies, central activation of GLP-1 receptors induced insulin resistance, enhanced insulin secretion and stimulated hepatic glycogen storage in mice (Knauf et al., 2005). Blockade of central GLP-1 activation during hyperglycemia increased muscle glycogen deposition. These data indicate that central GLP-1 restricts the amount of glucose taken up by large muscles to allow glycogen storage in the liver to prepare for the next fasting period, as suggested by Knauf et al. (2005). Chronic blockade of brain GLP-1 signaling prevented hyperinsulinemia and insulin resistance and stimulated energy expenditure through thermogenesis in mice fed with a high fat diet (Knauf et al., 2008a). Taken
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together, these studies indicate that GLP-1 acting in the brain has a significant effect on the whole body metabolism and energy balance; however, its effect could be influenced by normoglycemic, hyperglycemic or diabetic conditions. 2.1. Cellular effects of GLP-1 in the brain On the cellular level, GLP-1 modulates synaptic transmission. Electrophysiological recordings from pancreas-projecting DMV neurons indicated that GLP-1 depolarizes the membrane and increases the frequency of action potentials, resulting in excitation of approximately half of pancreas-related brainstem neurons (Wan et al., 2007b). This excitatory effect was mediated both through direct excitations of the recorded DMV neurons (postsynaptic effect) and via inputs arriving from local circuits (presynaptic effect). Regarding presynaptic mechanisms the general understanding is that neurons of the DMV receive both inhibitory and excitatory inputs. Dominance of inhibition leads to suppression of the activity of a DMV neuron, while dominance of excitation results in activation of the DMV cell. Regarding GLP-1 effect, a more detailed cellular investigation found that both the excitatory and inhibitory synaptic inputs to pancreasprojecting vagal motoneurons are increased by GLP-1 (Wan et al., 2007a); however, the integrative net effect of GLP-1 on pancreasprojecting DMV neurons is excitation (Wan et al., 2007b). These cellular studies also elucidated that GLP-1 enhances the excitation in circa 50% of the pancreas-projecting neurons. It is important to note that these GLP-1 excitable neurons are distinct from a neuronal subpopulation responsive to pancreatic polypeptide (Wan et al., 2007b), suggesting separate innervation of endocrine and exocrine pancreatic functions. Since DMV is a parasympathetic motor nucleus, this excitation of pancreas-projecting DMV neurons could result in increased parasympathetic activity stimulating insulin secretion. This hypothesis is further supported by the observation that when direct infusion of GLP-1 into the brainstem is undertaken, the result is insulin release. These data have great importance, showing that GLP-1 can selectively activate a specific subpopulation of brainstem neurons in order to increase insulin secretion without affecting the exocrine function of the pancreas. Another study using cellular investigation of hypocretin/orexin neurons in the lateral hypothalamus revealed that GLP-1 agonists depolarize the neurons, increase their spike frequency through postsynaptic activation of GLP-1 receptors; and enhance glutamate release onto hypocretin neurons through activation of presynaptic GLP-1 receptors on excitatory inputs (Acuna-Goycolea and van den Pol, 2004) as seen in the brainstem (Wan et al., 2007b). GLP-1 activation resulted in excitation of hypocretin neurons but did not alter neurons that synthesize the melanin-concentrating hormone further suggesting that GLP-1 selectively activates specific groups of neurons. Since hypocretin neurons were shown to regulate energy state-dependent arousal (Yamanaka et al., 2003) the GLP-1 agonists-caused excitation of hypocretin cells might enhance hypothalamic arousal. Moreover, GLP-1 effects on hypocretin neurons could have importance in linking gut signals related to energy homeostasis with hypothalamic arousal or increasing arousal signals originating from visceral or cardiac stress as suggested by the authors (Acuna-Goycolea and van den Pol, 2004). Another important observation originating from the cellular studies is that GLP-1 receptors did not show tachyphylaxis. This indicates that GLP-1 receptors will not be desensitized after repeated agonist challenges. These data suggest that GLP-1 receptors could repeatedly respond to elevation of GLP-1 levels; e.g., in the blood during and following a meal or to newly synthesized brain-derived GLP-1. Even more importantly, bariatric surgery elevates the circulating levels of GLP-1 (Laferrere et al., 2008). Based on observations that GLP-1 can penetrate the blood brain barrier and/or simultaneously can activate the afferent vagal nerves, and thus stimulate GLP-1 secretion from the NTS; we can speculate that a greater amount of GLP-1 will be
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available to modulate neuronal activity in the brainstem and hypothalamus. An augmented excitation of the parasympathetic DMV neurons might increase the activity of vagus output to the visceral organs and could reduce hepatic glucose production in addition to enhancement of insulin secretion. Unfortunately, to date, we have information about the excitatory effect of GLP-1 only on a subpopulation of pancreas-related DMV neurons and hypocretin/orexin neurons of the lateral hypothalamus, but it is very likely that another subpopulation of neurons (e.g., liver-related neurons) is also regulated by GLP-1; however, this requires further experimental investigation. In conclusion, these data together highly suggest that brain GLP-1 receptors are pivotal components of the GLP-1 system and that GLP-1 receptors could have a major effect on the whole body metabolism. 3. Autonomic control of the liver The liver has a pivotal role in the regulation of systemic glucose levels through hepatic glucose production (HGP). HGP can be stimulated by hormonal (e.g., increased glucagon release from the pancreas) and by neural signals. Consequently, alteration in central neuronal activity (e.g., due to increased levels of GLP-1) could modulate neural control of the liver and thus, additionally, HGP (Sandoval et al., 2008b), as well as contribute to the beneficial effects of bariatric surgery. The autonomic nervous system, through opposing effects of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), directly regulates the function of the visceral organs, including the glucose production of the liver. The neural innervation of the liver has been the subject of increasingly intense analysis in the context of understanding diabetes and metabolic syndrome (Yi et al., 2010; Shin et al., 2012). Briefly, the sympathetic nerves innervating the liver originate from pre-ganglionic neurons of the intermediolateral column of the spinal cord (IML) and reach the liver through the celiac and superior mesenteric ganglia. The parasympathetic innervation of the liver originates from the dorsal motor nucleus of the vagus (DMV); however, the existence of ganglia connecting the liver and the DMV is still unclear (Berthoud and Powley, 1993; Uyama et al., 2004). Descending inputs from the PVN of the hypothalamus govern both the sympathetic and parasympathetic innervation of the liver. Activation of the SNS increases HGP. On the other hand, activation of the PNS through branches of the vagus nerve decreases HGP (Uyama et al., 2004). Unequal activity of the autonomic nervous system – increased sympathetic and/or decreased parasympathetic activity – is found in many pathophysiological conditions, including diabetes mellitus (Liao et al., 1995; Mori et al., 2008). Indeed, a prospective cohort study revealed a high risk of developing type 2 diabetes if autonomic dysfunction is present (Carnethon et al., 2003). Moreover, unilateral denervation of the liver is more harmful to rhythmic liver metabolism than a complete removal of both branches, implying that an unbalanced autonomic nervous system found in cases of obesity and diabetes is pathological and contributes to the disturbed glucose regulation (Cailotto et al., 2008). This autonomic imbalance is likely due to altered neuronal activity in autonomic centers of the brain. 3.1. The role of PVN The autonomic network is part of what has been called “a single integrated regulatory system” with important centers in the hypothalamus (Swanson and Sawchenko, 1980; Kalsbeek et al., 2010a; Yi et al., 2010). This integrated system incorporates hormonal and neuronal control of the visceral organs and targets (Swanson and Sawchenko, 1980; Sandoval et al., 2008a), indicating that hypothalamic regulation should be viewed as an integrator for both neuroendocrine and neural influences (Kalsbeek et al., 2010a,b). Within the hypothalamus, the PVN is a vital center, integrating both neural and hormonal signals and coordinating neuroendocrine and autonomic outputs (Yi et al.,
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2010). Moreover, the differentiation of preautonomic PVN neurons from the neuroendocrine cells has been a long lasting interest in the field of neuroanatomy and neurophysiology. Due to the limitations of human studies, basic science experiments became critical to evaluate the contribution of the SNS and PNS to the regulation of HGP. With the development of retrograde viral tracers like the pseudorabies virus (PRV), specific neuronal populations could be identified within a functional context (Card et al., 1993; Enquist et al., 1994; Card, 1998; Ch'ng et al., 2007), providing the opportunity to study the cellular function of organ-specific neurons and to differentiate between the SNS and PNS. PRV-152, a viral vector strain isogenic with PRV Bartha that reports enhanced green fluorescent protein or the red fluorescent protein known as PRV-614, is a commonly used tracer to identify liver-related preautonomic neurons in the central nervous system (Buijs et al., 2003; Stanley et al., 2010; Zsombok et al., 2011b). The spread of this virus is strictly retrograde; therefore, the green or red fluorescing neurons are directly and indirectly connected to the inoculated organ; e.g., the liver (Card, 1998). Using this type of identification for neurons, it was found that a subpopulation of liver-related neurons in the PVN expresses corticotrophin-releasing hormone and oxytocin but not vasopressin or thyrotrophin-releasing hormone (Stanley et al., 2010). Furthermore, the majority of liver-related PVN neurons also express insulin receptor substrate 2, a functional component of the insulin signaling pathway, indicating a possible interaction between insulin signaling and liver-related neurons (Zsombok et al., 2011b). The use of PRV-labeling also allows the electrophysiological (thereby functional) investigation of these liver-related PVN neurons (Gao et al., 2012). Recent findings from our laboratory using patchclamp recordings demonstrated that the normal excitatory regulation of liver-related PVN neurons impaired in type 1 diabetic conditions (Gao et al., 2012) indicates that preautonomic PVN neurons could be good candidates for the origin of the autonomic imbalance in diabetes. In these experiments, the sympathetic and parasympathetic liverrelated PVN neurons were not distinguished; however, the study revealed two populations of liver-related PVN neurons that could indicate differential regulation of the SNS and PNS, although this requires further investigation (Gao et al., 2012). Neuroanatomical studies conducted in rodents also revealed that preautonomic PVN neurons are either pre-sympathetic or preparasympathetic (Buijs et al., 2001, 2003). This is a very important observation that could suggest that hormones, nutrients and peptides could be effective on one of the autonomic systems but ineffective on the other, providing the possibility to enhance or reduce specific autonomic functions. For example, selective stimulation of preparasympathetic liver-related PVN neurons could activate the hepatic branch of the PNS, resulting in decreased gluconeogenesis (Pocai et al., 2005a). If this is true, pharmacological manipulation of the PNS or SNS could be used as a novel therapeutic approach to treat autonomic imbalance and decrease the elevated glucose production of the liver in diabetic patients. Increased gluconeogenesis is known both in type 1 and type 2 diabetic patients (Magnusson et al., 1992; Petersen et al., 2004). Animal studies conducted on rodents indicate that decreased PNS stimulation of the liver leads to enhanced hepatic gluconeogenesis (Pocai et al., 2005a,b,c; Lam et al., 2010), leading to increased HGP. Despite the importance of the SNS and the PNS regarding control of HGP, very little is known about the mechanisms participating in the control of liver-related PVN neurons. Recent data demonstrated that liver-related PVN neurons are regulated by TRPV1 (transient receptor potential vanilloid type 1). TRPV1 is a ligand-gated, nonselective cation channel, widely expressed in the brain, including the PVN (Cavanaugh et al., 2011). Furthermore, the majority of liver-related PVN neurons express TRPV1, providing anatomical settings for TRPV1 action. TRPV1dependent stimulation of liver-related PVN neurons diminished in experiments involving the type 1 diabetic mouse model, while both in vitro and in vivo insulin replacement rescued the TRPV1-dependent excitation (Gao et al., 2012). This insulin-dependent reinstatement of
TRPV1 action was also observed in the DMV (Zsombok et al., 2011a), indicating that insulin has a critical role in the central control of autonomic function. Based on our current knowledge that GI hormones (e.g., cholecystokinin, ghrelin, GLP-1) and nutrients (glucose, lipids) have known effects on food intake and energy balance, it is more than likely that the beneficial effects observed after bariatric surgery are not due to a single mechanism. Most likely, it is due to a more complex change in the “gut–brain–periphery” axis as suggested by Berthoud's group (Shin et al., 2012). To investigate this theory, Berthoud's group used a rat model for Roux-En-Y gastric bypass (RYGB) to determine the contribution of vagal innervation of the hepatic portal vein and the liver to the surgery-induced weight loss, food intake and energy expenditure (Shin et al., 2012). Their results indicate that both RYGB and RYGB with common hepatic branch vagotomy significantly reduced body weight, meal size, adiposity and increased satiety and energy expenditure compared to sham-operated rats. Their data indicate that the vagal nerve supply to the liver, hepatic portal vein and the proximal duodenum originated from the common hepatic branch is not necessary to decrease food intake, body weight and increase energy expenditure (Shin et al., 2012). The outcome of the study clearly indicates that none of the sensory and/or motor functions are critical for the beneficial effect of RYGB to lower body weight. However, the contribution of the common hepatic branch to the beneficial effect of RYGB on glucose homeostasis has not been determined in this study. Therefore, it is possible that the common hepatic branch has a more important role in the glucose metabolism than in feeding-related changes as suggested by Troy et al. (2008); however, further studies are necessary for clarification. 4. Role of gender The overwhelming majority of weight loss surgeries have been performed on female patients; however, the majority of animal studies have been conducted on male rodents, making it challenging to analyze questions regarding the role of gender. Sleeve gastrectomy on female rats indicated significant weight loss, lower leptin and higher adiponectin levels compared to sham-operated rats, indicating similar improvements seen in male animals (Brinckerhoff et al., 2011). On the other hand, a recent retrospective study on patients who have undergone RYGB or adjustable gastric bypass investigated the age and gender effects on blood lipids (Pohle-Krauza et al., 2011). The authors found that the improvements of blood lipid profile, mainly high-density lipoprotein cholesterol, after surgery could be modulated by gender. Furthermore, proximal pouch distension (PPD), the most common condition requiring attention after gastric banding surgery, clearly showed that young women are at a greater risk for developing PPD compared to men (Dixon and Cobourn, 2013). Even more interestingly, in men the risk for developing PPD is low in all age groups and in women the risk significantly decreases with age, especially after menopause (Dixon and Cobourn, 2013). The increased risk in premenopausal women suggests that sex hormones, most likely progesterone, may be involved; however, genderdependent conclusions require further investigation. In conclusion, the mechanisms behind the weight-independent improvement of glycemic and metabolic parameters following different forms of bariatric surgery remain unresolved; however, there is a growing body of evidence suggesting the involvement of more than one system, including the gastrointestinal tract and the autonomic nervous system. Acknowledgments The author acknowledges funding support from the American Heart Association (10GRNT4540000) and the Tulane BIRCWH Program (NIH 2K12HD043451).
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Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Review
Autonomic control and bariatric procedures Andrea Zsombok ⁎ Department of Physiology, Endocrinology Section, Tulane University, School of Medicine, 1430 Tulane Ave., SL39, New Orleans, LA 70112, United States Department of Medicine, Endocrinology Section, Tulane University, School of Medicine, 1430 Tulane Ave., SL39, New Orleans, LA 70112, United States
a r t i c l e
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Article history: Received 22 May 2012 Received in revised form 10 October 2012 Accepted 1 March 2013 Keywords: Glucagon-like peptide 1 Brainstem Paraventricular nucleus of the hypothalamus Neuronal properties Autonomic control of the liver
a b s t r a c t The sudden improvement of metabolic profile and the remission of type 2 diabetes after bariatric surgery, well before weight loss, raise important new questions regarding glycemic control. Currently, various types of bariatric procedures target type 2 diabetes in obese and non-obese patients. Nevertheless, the origin of the dramatic metabolic improvements, including glucose homeostasis, is poorly understood, and the role of the gastrointestinal (GI) tract remains relatively speculative, as well as why these procedures are variably effective. One neglected explanation is that such interventions disrupt neural networks mediating GI–brain communication and could alter the autonomic output to the visceral organs, including the liver. Incretins, e.g., glucagon-like peptide 1 (GLP-1), have major influence on the central nervous system. Moreover, the level of GLP-1 is observed to significantly increase after bariatric surgery and could be a key factor in the weight-independent, anti-diabetic effect. Therefore, this review will evaluate the effect of GLP-1 on the central nervous system, with emphasis on the cellular effects of GLP-1, and will provide an overview of the autonomic control of the liver. © 2013 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . GLP-1 action on the central nervous system 2.1. Cellular effects of GLP-1 in the brain 3. Autonomic control of the liver . . . . . . 3.1. The role of PVN . . . . . . . . . . 4. Role of gender . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction Diabetes mellitus (DM) has reached epidemic proportions worldwide, including the United States. The Centers for Disease Control and Prevention estimates that approximately 25.8 million (8.3%) of the US population suffer from DM (CDCP, 2011). Despite the billions of dollars invested to reduce the symptoms and complications, the treatments remain inadequate. Therefore, the positive influence of bariatric procedures on glycemic control requires continued attention and commitment to the search for the underlying mechanisms. The sudden improvement in glycemic and metabolic control within days of bariatric surgery observed in patients subjected to it cannot be ⁎ Tel.: +1 504 988 2597; fax: +1 504 988 2675. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.03.002
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explained with weight loss (Rubino et al., 2010a,b; Spector and Shikora, 2010). Thereby, two leading theories have emerged to explain the weight-independent effect of bariatric surgery (Spector and Shikora, 2010). The “hindgut” theory is based on up-regulation of incretins, including glucagon-like peptide 1 (GLP-1), resulting in increased insulin secretion and improved glucose tolerance. The “foregut” hypothesis, on the other hand, proposes that excluding the duodenum leads to inhibition of signals responsible for insulin resistance and impaired glycemic control (Rubino et al., 2010a,b). However, any type of bariatric operation alters existing gut–brain communication and could alter the neural control of the subdiaphragmatic organs. Furthermore, hormones of the gastrointestinal (GI) tract (e.g., GLP-1, ghrelin) are involved in the regulation of energy homeostasis via the central nervous system (CNS); thus, their altered secretion could significantly impact the neural control of visceral organs including the liver.
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The importance of the central nervous system in the regulation of the visceral organs has long been recognized (Shimazu et al., 1966; Oomura et al., 1969; Swanson and Sawchenko, 1980; Pocai et al., 2005c; Kalsbeek et al., 2010a; Yi et al., 2010) and accumulating experimental evidence indicates that the CNS plays a pivotal role in maintaining glucose regulation and energy balance (Obici et al., 2002a,b,c; Pocai et al., 2005c; Kalsbeek et al., 2010a; Yi et al., 2010). Consequently, it will be important to review the effect of GLP-1 on the brain and the autonomic control of the liver to examine whether the effect could have a major role to play in the rapid improvement of metabolic parameters after bariatric surgery. 2. GLP-1 action on the central nervous system GLP-1 is a gut hormone directly binding to GLP-1 receptors (GLP-1R) (Thorens, 1995). In addition to the enhancement of glucose-induced insulin secretion of pancreatic beta cells, also called “direct route,” GLP-1, through the “gut–brain–periphery” axis, has major effects on insulin secretion and glucose metabolism (Sandoval et al., 2008b; Burcelin et al., 2009). One circuit-mechanism originates from GLP-1R in the gut and/or from enteric glucose sensors of the hepatoportal vein. Ascending information from the GI tract through the afferent sensory branches of the vagus nerve reaches the nucleus of the solitary tract (NTS) (Adachi et al., 1984; Burcelin et al., 2000; Burcelin et al., 2009). The NTS transmits the information to the dorsal motor nucleus of the vagus (DMV), the main parasympathetic output to the visceral organs, and to the hypothalamus (Fig. 1). This neural circuit controls food intake and glucose metabolism (Dardevet et al., 2004; Ionut et al., 2005; Mithieux et al., 2005). Activation of the enteric pathway with infusion of glucose into the stomach without causing hyperglycemia and hyperinsulinemia increases whole-body glucose utilization, muscle glycogen synthesis and neuronal activity in the NTS of mice (Knauf et al., 2008b). Interestingly, it had inhibitory effects on the dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH) and on NPY-positive neurons of the arcuate nucleus (ARC) without affecting the proopiomelanocortin (POMC)-positive neurons, indicating differential regulation of the brainstem and hypothalamus by enteric glucose in rodent models (Knauf et al., 2008b). Activation of this circuit requires functional GLP-1 receptors in the brain, as indicated by the blunted response observed in GLP-1R knockout mice. These observations suggest that augmented GLP-1 levels in the GI tract can significantly influence the CNS and modulate efferent vagal regulation of the visceral organs. On the other hand, enteric glucose did not alter neuronal activity or whole-body utilization rates in diabetic mice fed with a high-fat diet, thereby suggesting that the “gut–brain–muscle” axis is altered in diabetic conditions (Knauf et al., 2008b). Another circuit regulation involves circulating hormones and nutrients reaching the central nervous system, thereby effecting the neuroendocrine and autonomic nervous system mainly via the brainstem and hypothalamus (Zsombok and Smith, 2009). GLP-1 can directly stimulate neurons in the brainstem and hypothalamus in two ways. One suggested way is through crossing the blood–brain barrier (BBB); however, since the half-life time of GLP-1 is very short, the efficacy of this route can be questioned (Kastin et al., 2002; Banks, 2006). Another route is via direct stimulation of neurons by being synthesized de novo in the brainstem (Merchenthaler et al., 1999). GLP-1 is synthesized in the NTS, and as a result, GLP-1 activates GLP-1 receptors and acts as a neuropeptide (Larsen and Holst, 2005; Wan et al., 2007a,b), modulating synaptic activity, thus influencing metabolism. In in vivo animal studies, intracerebroventricular (ICV) administration of a GLP-1 agonist increased heart rate and blood pressure (Yamamoto et al., 2002). Furthermore, ICV infusion of GLP-1 into the lateral, third and fourth ventricle or to the paraventricular nucleus of the hypothalamus (PVN) decreased food intake (Tang-Christensen et al., 1996; Turton et al., 1996), and infusion into the third ventricle increased neuronal activity determined by c-fos immunoreactivity in the PVN, ARC, NTS and area postrema
Fig. 1. Schematic illustration of GLP-1 effect on gut–brain–digestive system circuits. This model hypothesizes that 1) circulating GLP-1 directly activates GLP-1 receptors by crossing the blood–brain-barrier and thus modulates efferent output. 2) Circulating GLP-1 stimulates the afferent vagus, which in turn triggers the modulation of efferent pathway. 3) It is also possible that stimulation of the afferent vagal nerve will trigger secretion of GLP-1 from NTS, thereby altering neuronal activity and thus influence efferent vagus. Abbreviations: ARC: arcuate nucleus; DMV: dorsal motor nucleus of the vagus; DVC: dorsal vagal complex; GLP-1: glucagon-like peptide 1; HGP: hepatic glucose production; LH: lateral hypothalamus; NTS: nucleus of the solitary tract; PVN: paraventricular nucleus of the hypothalamus; VMH: ventromedial hypothalamus.
(Van Dijk et al., 1996). ICV activation of GLP-1 receptors enhanced glucose-stimulated insulin secretion, and administration of GLP-1 into the ARC but not into the PVN reduced hepatic glucose production (Sandoval et al., 2008b). These observations were consistent with the findings that the GLP-1 receptor mRNA is present in the majority of ARC neurons expressing POMC, suggesting that the hypothalamic ARC neurons are important components of the GLP-1-dependent regulation of glucose production. These data suggest that GLP-1 is involved in the maintenance of glucose homeostasis (Sandoval, 2008; Sandoval et al., 2008b) and GLP-1 receptors in specific nuclei have distinct effects. It is highly likely that the central GLP-1 system is responsible for stimulation of pancreatic insulin secretion and inhibition of glucose production of the liver as suggested by Sandoval and her coworkers. On the other hand, in hyperglycemic hyperinsulinemic clamp studies, central activation of GLP-1 receptors induced insulin resistance, enhanced insulin secretion and stimulated hepatic glycogen storage in mice (Knauf et al., 2005). Blockade of central GLP-1 activation during hyperglycemia increased muscle glycogen deposition. These data indicate that central GLP-1 restricts the amount of glucose taken up by large muscles to allow glycogen storage in the liver to prepare for the next fasting period, as suggested by Knauf et al. (2005). Chronic blockade of brain GLP-1 signaling prevented hyperinsulinemia and insulin resistance and stimulated energy expenditure through thermogenesis in mice fed with a high fat diet (Knauf et al., 2008a). Taken
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together, these studies indicate that GLP-1 acting in the brain has a significant effect on the whole body metabolism and energy balance; however, its effect could be influenced by normoglycemic, hyperglycemic or diabetic conditions. 2.1. Cellular effects of GLP-1 in the brain On the cellular level, GLP-1 modulates synaptic transmission. Electrophysiological recordings from pancreas-projecting DMV neurons indicated that GLP-1 depolarizes the membrane and increases the frequency of action potentials, resulting in excitation of approximately half of pancreas-related brainstem neurons (Wan et al., 2007b). This excitatory effect was mediated both through direct excitations of the recorded DMV neurons (postsynaptic effect) and via inputs arriving from local circuits (presynaptic effect). Regarding presynaptic mechanisms the general understanding is that neurons of the DMV receive both inhibitory and excitatory inputs. Dominance of inhibition leads to suppression of the activity of a DMV neuron, while dominance of excitation results in activation of the DMV cell. Regarding GLP-1 effect, a more detailed cellular investigation found that both the excitatory and inhibitory synaptic inputs to pancreasprojecting vagal motoneurons are increased by GLP-1 (Wan et al., 2007a); however, the integrative net effect of GLP-1 on pancreasprojecting DMV neurons is excitation (Wan et al., 2007b). These cellular studies also elucidated that GLP-1 enhances the excitation in circa 50% of the pancreas-projecting neurons. It is important to note that these GLP-1 excitable neurons are distinct from a neuronal subpopulation responsive to pancreatic polypeptide (Wan et al., 2007b), suggesting separate innervation of endocrine and exocrine pancreatic functions. Since DMV is a parasympathetic motor nucleus, this excitation of pancreas-projecting DMV neurons could result in increased parasympathetic activity stimulating insulin secretion. This hypothesis is further supported by the observation that when direct infusion of GLP-1 into the brainstem is undertaken, the result is insulin release. These data have great importance, showing that GLP-1 can selectively activate a specific subpopulation of brainstem neurons in order to increase insulin secretion without affecting the exocrine function of the pancreas. Another study using cellular investigation of hypocretin/orexin neurons in the lateral hypothalamus revealed that GLP-1 agonists depolarize the neurons, increase their spike frequency through postsynaptic activation of GLP-1 receptors; and enhance glutamate release onto hypocretin neurons through activation of presynaptic GLP-1 receptors on excitatory inputs (Acuna-Goycolea and van den Pol, 2004) as seen in the brainstem (Wan et al., 2007b). GLP-1 activation resulted in excitation of hypocretin neurons but did not alter neurons that synthesize the melanin-concentrating hormone further suggesting that GLP-1 selectively activates specific groups of neurons. Since hypocretin neurons were shown to regulate energy state-dependent arousal (Yamanaka et al., 2003) the GLP-1 agonists-caused excitation of hypocretin cells might enhance hypothalamic arousal. Moreover, GLP-1 effects on hypocretin neurons could have importance in linking gut signals related to energy homeostasis with hypothalamic arousal or increasing arousal signals originating from visceral or cardiac stress as suggested by the authors (Acuna-Goycolea and van den Pol, 2004). Another important observation originating from the cellular studies is that GLP-1 receptors did not show tachyphylaxis. This indicates that GLP-1 receptors will not be desensitized after repeated agonist challenges. These data suggest that GLP-1 receptors could repeatedly respond to elevation of GLP-1 levels; e.g., in the blood during and following a meal or to newly synthesized brain-derived GLP-1. Even more importantly, bariatric surgery elevates the circulating levels of GLP-1 (Laferrere et al., 2008). Based on observations that GLP-1 can penetrate the blood brain barrier and/or simultaneously can activate the afferent vagal nerves, and thus stimulate GLP-1 secretion from the NTS; we can speculate that a greater amount of GLP-1 will be
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available to modulate neuronal activity in the brainstem and hypothalamus. An augmented excitation of the parasympathetic DMV neurons might increase the activity of vagus output to the visceral organs and could reduce hepatic glucose production in addition to enhancement of insulin secretion. Unfortunately, to date, we have information about the excitatory effect of GLP-1 only on a subpopulation of pancreas-related DMV neurons and hypocretin/orexin neurons of the lateral hypothalamus, but it is very likely that another subpopulation of neurons (e.g., liver-related neurons) is also regulated by GLP-1; however, this requires further experimental investigation. In conclusion, these data together highly suggest that brain GLP-1 receptors are pivotal components of the GLP-1 system and that GLP-1 receptors could have a major effect on the whole body metabolism. 3. Autonomic control of the liver The liver has a pivotal role in the regulation of systemic glucose levels through hepatic glucose production (HGP). HGP can be stimulated by hormonal (e.g., increased glucagon release from the pancreas) and by neural signals. Consequently, alteration in central neuronal activity (e.g., due to increased levels of GLP-1) could modulate neural control of the liver and thus, additionally, HGP (Sandoval et al., 2008b), as well as contribute to the beneficial effects of bariatric surgery. The autonomic nervous system, through opposing effects of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), directly regulates the function of the visceral organs, including the glucose production of the liver. The neural innervation of the liver has been the subject of increasingly intense analysis in the context of understanding diabetes and metabolic syndrome (Yi et al., 2010; Shin et al., 2012). Briefly, the sympathetic nerves innervating the liver originate from pre-ganglionic neurons of the intermediolateral column of the spinal cord (IML) and reach the liver through the celiac and superior mesenteric ganglia. The parasympathetic innervation of the liver originates from the dorsal motor nucleus of the vagus (DMV); however, the existence of ganglia connecting the liver and the DMV is still unclear (Berthoud and Powley, 1993; Uyama et al., 2004). Descending inputs from the PVN of the hypothalamus govern both the sympathetic and parasympathetic innervation of the liver. Activation of the SNS increases HGP. On the other hand, activation of the PNS through branches of the vagus nerve decreases HGP (Uyama et al., 2004). Unequal activity of the autonomic nervous system – increased sympathetic and/or decreased parasympathetic activity – is found in many pathophysiological conditions, including diabetes mellitus (Liao et al., 1995; Mori et al., 2008). Indeed, a prospective cohort study revealed a high risk of developing type 2 diabetes if autonomic dysfunction is present (Carnethon et al., 2003). Moreover, unilateral denervation of the liver is more harmful to rhythmic liver metabolism than a complete removal of both branches, implying that an unbalanced autonomic nervous system found in cases of obesity and diabetes is pathological and contributes to the disturbed glucose regulation (Cailotto et al., 2008). This autonomic imbalance is likely due to altered neuronal activity in autonomic centers of the brain. 3.1. The role of PVN The autonomic network is part of what has been called “a single integrated regulatory system” with important centers in the hypothalamus (Swanson and Sawchenko, 1980; Kalsbeek et al., 2010a; Yi et al., 2010). This integrated system incorporates hormonal and neuronal control of the visceral organs and targets (Swanson and Sawchenko, 1980; Sandoval et al., 2008a), indicating that hypothalamic regulation should be viewed as an integrator for both neuroendocrine and neural influences (Kalsbeek et al., 2010a,b). Within the hypothalamus, the PVN is a vital center, integrating both neural and hormonal signals and coordinating neuroendocrine and autonomic outputs (Yi et al.,
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2010). Moreover, the differentiation of preautonomic PVN neurons from the neuroendocrine cells has been a long lasting interest in the field of neuroanatomy and neurophysiology. Due to the limitations of human studies, basic science experiments became critical to evaluate the contribution of the SNS and PNS to the regulation of HGP. With the development of retrograde viral tracers like the pseudorabies virus (PRV), specific neuronal populations could be identified within a functional context (Card et al., 1993; Enquist et al., 1994; Card, 1998; Ch'ng et al., 2007), providing the opportunity to study the cellular function of organ-specific neurons and to differentiate between the SNS and PNS. PRV-152, a viral vector strain isogenic with PRV Bartha that reports enhanced green fluorescent protein or the red fluorescent protein known as PRV-614, is a commonly used tracer to identify liver-related preautonomic neurons in the central nervous system (Buijs et al., 2003; Stanley et al., 2010; Zsombok et al., 2011b). The spread of this virus is strictly retrograde; therefore, the green or red fluorescing neurons are directly and indirectly connected to the inoculated organ; e.g., the liver (Card, 1998). Using this type of identification for neurons, it was found that a subpopulation of liver-related neurons in the PVN expresses corticotrophin-releasing hormone and oxytocin but not vasopressin or thyrotrophin-releasing hormone (Stanley et al., 2010). Furthermore, the majority of liver-related PVN neurons also express insulin receptor substrate 2, a functional component of the insulin signaling pathway, indicating a possible interaction between insulin signaling and liver-related neurons (Zsombok et al., 2011b). The use of PRV-labeling also allows the electrophysiological (thereby functional) investigation of these liver-related PVN neurons (Gao et al., 2012). Recent findings from our laboratory using patchclamp recordings demonstrated that the normal excitatory regulation of liver-related PVN neurons impaired in type 1 diabetic conditions (Gao et al., 2012) indicates that preautonomic PVN neurons could be good candidates for the origin of the autonomic imbalance in diabetes. In these experiments, the sympathetic and parasympathetic liverrelated PVN neurons were not distinguished; however, the study revealed two populations of liver-related PVN neurons that could indicate differential regulation of the SNS and PNS, although this requires further investigation (Gao et al., 2012). Neuroanatomical studies conducted in rodents also revealed that preautonomic PVN neurons are either pre-sympathetic or preparasympathetic (Buijs et al., 2001, 2003). This is a very important observation that could suggest that hormones, nutrients and peptides could be effective on one of the autonomic systems but ineffective on the other, providing the possibility to enhance or reduce specific autonomic functions. For example, selective stimulation of preparasympathetic liver-related PVN neurons could activate the hepatic branch of the PNS, resulting in decreased gluconeogenesis (Pocai et al., 2005a). If this is true, pharmacological manipulation of the PNS or SNS could be used as a novel therapeutic approach to treat autonomic imbalance and decrease the elevated glucose production of the liver in diabetic patients. Increased gluconeogenesis is known both in type 1 and type 2 diabetic patients (Magnusson et al., 1992; Petersen et al., 2004). Animal studies conducted on rodents indicate that decreased PNS stimulation of the liver leads to enhanced hepatic gluconeogenesis (Pocai et al., 2005a,b,c; Lam et al., 2010), leading to increased HGP. Despite the importance of the SNS and the PNS regarding control of HGP, very little is known about the mechanisms participating in the control of liver-related PVN neurons. Recent data demonstrated that liver-related PVN neurons are regulated by TRPV1 (transient receptor potential vanilloid type 1). TRPV1 is a ligand-gated, nonselective cation channel, widely expressed in the brain, including the PVN (Cavanaugh et al., 2011). Furthermore, the majority of liver-related PVN neurons express TRPV1, providing anatomical settings for TRPV1 action. TRPV1dependent stimulation of liver-related PVN neurons diminished in experiments involving the type 1 diabetic mouse model, while both in vitro and in vivo insulin replacement rescued the TRPV1-dependent excitation (Gao et al., 2012). This insulin-dependent reinstatement of
TRPV1 action was also observed in the DMV (Zsombok et al., 2011a), indicating that insulin has a critical role in the central control of autonomic function. Based on our current knowledge that GI hormones (e.g., cholecystokinin, ghrelin, GLP-1) and nutrients (glucose, lipids) have known effects on food intake and energy balance, it is more than likely that the beneficial effects observed after bariatric surgery are not due to a single mechanism. Most likely, it is due to a more complex change in the “gut–brain–periphery” axis as suggested by Berthoud's group (Shin et al., 2012). To investigate this theory, Berthoud's group used a rat model for Roux-En-Y gastric bypass (RYGB) to determine the contribution of vagal innervation of the hepatic portal vein and the liver to the surgery-induced weight loss, food intake and energy expenditure (Shin et al., 2012). Their results indicate that both RYGB and RYGB with common hepatic branch vagotomy significantly reduced body weight, meal size, adiposity and increased satiety and energy expenditure compared to sham-operated rats. Their data indicate that the vagal nerve supply to the liver, hepatic portal vein and the proximal duodenum originated from the common hepatic branch is not necessary to decrease food intake, body weight and increase energy expenditure (Shin et al., 2012). The outcome of the study clearly indicates that none of the sensory and/or motor functions are critical for the beneficial effect of RYGB to lower body weight. However, the contribution of the common hepatic branch to the beneficial effect of RYGB on glucose homeostasis has not been determined in this study. Therefore, it is possible that the common hepatic branch has a more important role in the glucose metabolism than in feeding-related changes as suggested by Troy et al. (2008); however, further studies are necessary for clarification. 4. Role of gender The overwhelming majority of weight loss surgeries have been performed on female patients; however, the majority of animal studies have been conducted on male rodents, making it challenging to analyze questions regarding the role of gender. Sleeve gastrectomy on female rats indicated significant weight loss, lower leptin and higher adiponectin levels compared to sham-operated rats, indicating similar improvements seen in male animals (Brinckerhoff et al., 2011). On the other hand, a recent retrospective study on patients who have undergone RYGB or adjustable gastric bypass investigated the age and gender effects on blood lipids (Pohle-Krauza et al., 2011). The authors found that the improvements of blood lipid profile, mainly high-density lipoprotein cholesterol, after surgery could be modulated by gender. Furthermore, proximal pouch distension (PPD), the most common condition requiring attention after gastric banding surgery, clearly showed that young women are at a greater risk for developing PPD compared to men (Dixon and Cobourn, 2013). Even more interestingly, in men the risk for developing PPD is low in all age groups and in women the risk significantly decreases with age, especially after menopause (Dixon and Cobourn, 2013). The increased risk in premenopausal women suggests that sex hormones, most likely progesterone, may be involved; however, genderdependent conclusions require further investigation. In conclusion, the mechanisms behind the weight-independent improvement of glycemic and metabolic parameters following different forms of bariatric surgery remain unresolved; however, there is a growing body of evidence suggesting the involvement of more than one system, including the gastrointestinal tract and the autonomic nervous system. Acknowledgments The author acknowledges funding support from the American Heart Association (10GRNT4540000) and the Tulane BIRCWH Program (NIH 2K12HD043451).
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