Sleeve Gastrectomy Does Not Cause Hypertrophy and Reprogramming of Intestinal Glucose Metabolism in Rats.

Background: Clinical studies have shown similar rapid improvements in body mass and glycemic control after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG). Evidence suggests that adaptive intestinal tissue growth and reprogramming of intestinal glucose disposal play a key role in the beneficial effects on glucose homeostasis after RYGB, but it is not known whether such adaptive changes also occur after sleeve gastrectomy.

Methods: High-fat diet-induced obese rats were subjected to either VSG or RYGB, and intestinal growth and functional adaptations were assessed by using morphometric, immunohistochemical, and immuno-blot techniques, 3 months after surgery or sham surgery.

Vagal innervation of intestine contributes to weight loss After Roux-en-Y gastric bypass surgery in rats.

Background: It is conceivable that overstimulation of chemo- and mechano-sensors in the Roux and common limbs by uncontrolled influx of undigested nutrients after Roux-en-Y gastric bypass surgery (RYGB) could lead to exaggerated satiety signaling via vagal afferents and contribute to body weight loss. Because previous clinical and preclinical studies using vagotomy came to different conclusions, the aim was to examine the effects of selective and histologically verified celiac branch vagotomy on reduced food intake and body weight loss induced by RYGB.

Methods: Male Sprague-Dawley rats underwent either RYGB + celiac branch vagotomy (RYGB/VgX, n=15), RYGB + sham celiac branch vagotomy (RYGB/Sham VgX; n=6), Sham RYGB + celiac branch vagotomy (Sham/VgX; n=6), or sham RYGB + sham celiac branch vagotomy (Sham/Sham; n=6), and body weight, body composition, and food choice were monitored for 3 months after intervention.

Reversible hyperphagia and obesity in rats with gastric bypass by central MC3/4R blockade.

Objective: To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food.

Methods: Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery.

Results: SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats.

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB.

Longitudinal assessment of food intake, fecal energy loss, and energy expenditure after Roux-en-Y gastric bypass surgery in high-fat-fed obese rats.

Background: The efficacy of Roux-en-Y gastric bypass (RYGB) surgery to produce weight loss has been well-documented, but few studies have measured the key components of energy balance, food intake, and energy expenditure longitudinally.

Methods: Male Sprague-Dawley rats on a high-fat diet underwent either RYGB, sham operation, or pair feeding and were compared to chow-fed lean controls. Body weight and composition, food intake and preference, energy expenditure, fecal output, and gastric emptying were monitored before and up to 4 months after intervention.

"Liking" and "wanting" of sweet and oily food stimuli as affected by high-fat diet-induced obesity, weight loss, leptin, and genetic predisposition.

Cross-sectional studies in both humans and animals have demonstrated associations between obesity and altered reward functions at the behavioral and neural level, but it is unclear whether these alterations are cause or consequence of the obese state. Reward behaviors were quantified in male, outbred Sprague-Dawley (SD) and selected line obesity-prone (OP) and obesity-resistant (OR) rats after induction of obesity by high-fat diet feeding and after subsequent loss of excess body weight by chronic calorie restriction. As measured by the brief access lick and taste-reactivity paradigms, both obese SD and OP rats "liked" low concentrations of sucrose and corn oil less, but "liked" the highest concentrations more, compared with lean rats, and this effect was fully reversed by weight loss in SD rats.

High-fat intake induced by mu-opioid activation of the nucleus accumbens is inhibited by Y1R-blockade and MC3/4R- stimulation.

Nucleus accumbens mu-opioid receptor activation can strongly stimulate intake of high-fat food in satiated rats, and one of the mechanisms involves activation of lateral hypothalamic orexin neurons and orexin receptor-1 signaling in the mesolimbic dopamine system. Here, we tested the potential contribution of NPY/Y1R and alpha-MSH/MC3/4R-signaling to accumbens-induced high-fat feeding. Prior administration of the selective Y1R antagonist 1229U91 or the MC3/4R agonist MTII into the lateral ventricle (LV) dose-dependently decreased high-fat intake induced by nucleus accumbens injection of the mu-opioid receptor agonist DAMGO.

A potential role for hypothalamomedullary POMC projections in leptin-induced suppression of food intake.

Melanocortin-3/4 receptor ligands administered to the caudal brain stem potently modulate food intake by changing meal size. The origin of the endogenous ligands is unclear, because the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract (NTS) harbor populations of proopiomelanocortin (POMC)-expressing neurons. Here we demonstrate that activation of hypothalamic POMC neurons leads to suppression of food intake and that this suppression is prevented by administration of a melanocortin-3/4 receptor antagonist to the NTS and its vicinity.

Meal patterns, satiety, and food choice in a rat model of Roux-en-Y gastric bypass surgery.

Gastric bypass surgery efficiently and lastingly reduces excess body weight and reverses type 2 diabetes in obese patients. Although increased energy expenditure may also play a role, decreased energy intake is thought to be the main reason for weight loss, but the mechanisms involved are poorly understood. Therefore, the aim of this study was to characterize the changes in ingestive behavior in a rat model of Roux-en-Y gastric bypass surgery (RYGB).

Phenotype of neurons in the nucleus of the solitary tract that express CCK-induced activation of the ERK signaling pathway.

The satiating potency of CCK has been well characterized, including its mediation by capsaicin-sensitive vagal primary afferents. We have previously shown that peripherally administered CCK activates the MAPK-signaling cascade in a population of nucleus of the solitary tract (NTS) neurons and that preventing ERK1/2 phosphorylation partly attenuates CCK's satiating potency. The aim of this study was to identify the neurochemical phenotypes of the NTS neurons that exhibit CCK-induced activation of ERK1/2.

Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens.

The overriding of satiety and homeostatic control mechanisms by cognitive, rewarding, and emotional aspects of palatable foods may contribute to the evolving obesity crisis, but little is known about neural pathways and mechanisms responsible for crosstalk between the "cognitive" and "metabolic" brain in the control of appetite. Here we show that neural connections between the nucleus accumbens and hypothalamus might be part of this link. Using the well known model of selective stimulation of high-fat intake induced by intra-accumbens injection of the mu-opioid receptor agonist D-Ala2-N-Me-Phe4-gly5-ol-enkephalin (DAMGO), we demonstrate that orexin signaling in the ventral tegmental area is important for this reward-driven appetite to override metabolic repletion signals in presatiated rats.

Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size.

Ingestive behavior is controlled by a complex interplay between signals conveying availability of (1) potentially ingestible food in the environment, (2) digestible food in the alimentary canal, (3) circulating fuels and (4) stored fuels. Each of these four classes of signals interact with specific sensors and neural circuits whose integrated output determines when food intake is initiated and when it is stopped. Because the final common path responsible for oromotor control is contained within complex neural pattern generators within the brainstem and is intimately linked to sensory information from the alimentary canal, at least part of the integration between the four classes of signals is thought to take place at the level of the caudal brainstem.

Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus.

Signals from the gut and hypothalamus converge in the caudal brainstem to control ingestive behavior. We have previously shown that phosphorylation of ERK1/2 in the solitary nucleus (NTS) is necessary for food intake suppression by exogenous cholecystokinin (CCK). Here we test whether this intracellular signaling cascade is also involved in the integration of melanocortin-receptor (MCR) mediated inputs to the caudal brainstem.

Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function.

Orexin-expressing neurons in the hypothalamus project throughout the neuraxis and are involved in regulation of the sleep/wake cycle, food intake, and autonomic functions. Here we specifically analyze the anatomical organization of orexin projections to the dorsal vagal complex (DVC) and raphe pallidus and effects on ingestive behavior and autonomic functions of local orexin-A administration in nonanesthetized rats. Retrograde tracing experiments revealed that as many as 20% of hypothalamic orexin neurons project to the DVC, where they form straight varicose axon profiles, some of which are in close anatomical apposition with tyrosine hydroxylase (TH)-, glucagon-like peptide-1-, gamma-aminobutyric acid-, and nitric oxide synthase-immunoreactive neurons in a nonselective manner.

Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections.

Metabolic, cognitive, and environmental factors processed in the forebrain modulate food intake by changing the potency of direct controls of meal ingestion in the brain stem. Here, we behaviorally and anatomically test the role of the hypothalamic proopiomelanocortin (POMC) system in mediating some of these descending, indirect controls. Melanotan II (MTII), a stable melanocortin 4 receptor (MC4R) and melanocortin 3 receptor (MC3R) agonist injected into the fourth ventricle near the dorsal vagal complex, potently inhibited 14-h food intake by decreasing meal size but not meal frequency; SHU9119, an antagonist, increased food intake by selectively increasing meal size.

Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation.

Orexin-expressing neurons in the lateral hypothalamus with their wide projections throughout the brain are important for the regulation of sleep and wakefulness, ingestive behavior, and the coordination of these behaviors in the environmental context. To further identify downstream effector targets of the orexin system, we examined in detail orexin-A innervation of the caudal raphe nuclei in the medulla, known to harbor sympathetic preganglionic motor neurons involved in thermal, cardiovascular, and gastrointestinal regulation. All three components of the caudal raphe nuclei, raphe pallidus, raphe obscurus, and parapyramidal nucleus, are innervated by orexin-A-immunoreactive fibers.

Extracellular signal-regulated kinase 1/2 signaling pathway in solitary nucleus mediates cholecystokinin-induced suppression of food intake in rats.

Increased food intake is a major factor in the development of obesity, and the control of meal size is a valid approach to reduce food intake in humans. Meal termination, or satiety, is thought to be organized within the caudal brainstem where direct signals from the food handling alimentary canal and long-term signals from the forebrain converge in the solitary nucleus. Cholecystokinin (CCK) released from the gut after ingestion of food has been strongly implicated in nucleus tractus solitarius (NTS)-mediated satiation, but the exact cellular and intracellular signaling events are not understood.

Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons.

Corticolimbic circuits involving the prefrontal cortex, amygdala, and ventral striatum determine the reward value of food and might play a role in environmentally induced obesity. Chemical manipulation of the nucleus accumbens shell (AcbSh) has been shown to elicit robust feeding and Fos expression in the hypothalamus and other brain areas of satiated rats. To determine the neurochemical phenotype of hypothalamic neurons receiving input from the AcbSh, we carried out c-Fos/peptide double-labeling immunohistochemistry in various hypothalamic areas known to contain feeding peptides, from rats that exhibited a significant feeding response after AcbSh microinjection of the GABA(A) agonist muscimol.

Vanilloid receptor (VR1) expression in vagal afferent neurons innervating the gastrointestinal tract.

The vanilloid receptor VR1 is a nonselective cation channel activated by capsaicin as well as increases in temperature and acidity, and can be viewed as molecular integrator of chemical and physical stimuli that elicit pain. The distribution of VR1 receptors in peripheral and central processes of rat primary vagal afferent neurons innervating the gastrointestinal tract was investigated by immunohistochemistry. Forty-two percent of neurons in the nodose ganglia retrogradely labeled from the stomach wall expressed low to moderate VR1 immunoreactivity (VR1-IR).

CART in the dorsal vagal complex: sources of immunoreactivity and effects on Fos expression and food intake.

CART-peptide (CARTp) has been shown to suppress food intake, particularly when injected into the 4th ventricle of rats, and the presence of CART in nodose ganglia suggested a role in satiation. Based on retrograde tracing from the DVC combined with CART immunohistochemistry and supranodose vagotomy, we found that CART immunoreactivity in varicose fibers of the dorsal vagal complex originates from vagal afferents, sparse projections from the medullary reticular formation and the arcuate/retrochiasmatic nucleus of the hypothalamus, and most likely also from local CART neurons in the area postrema and NTS. In the nodose ganglia, 17% of neurons with projections to the stomach and 41% to the duodenum express CART-IR.

Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP.

Agouti-related protein (AgRP) is coexpressed with neuropeptide Y (NPY) in a population of neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulates food intake for up to 7 days if injected intracerebroventricularly. The prolonged food intake stimulation does not seem to depend on continued competition at the melanocortin-4 receptor (MC4R), because the relatively specific MC4R agonist MTII regains its ability to suppress food intake 24 h after AgRP injection. Intracerebroventricular AgRP also stimulates c-Fos expression 24 h after injection in several brain areas, so the neurons exhibiting delayed Fos expression might be particularly important in feeding behavior.

Vagal afferents innervating the gastrointestinal tract and CCKA-receptor immunoreactivity.

A large body of evidence derived from electrophysiological recording and pharmacological/behavioral experiments suggests the presence of CCKA-receptors on vagal primary afferent fibers innervating the gastrointestinal tract. With the availability of antibodies specific for the CCKA-receptor, we wanted to demonstrate its presence and distribution on identified vagal afferent fibers and different types of terminals in the mucosa, myenteric plexus, and external muscle layers of the stomach and duodenum. In the duodenal mucosa, neither a C-terminal (Ab-1) nor an N-terminal (Ab-2) specific antibody produced any specific staining; in the myenteric plexus, non-vagal enteric neurons and their processes, but not vagal intraganglionic laminar endings (IGLEs), exhibited CCKAR-immunoreactivity.