Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3ß and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3ß signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.

A direct effect of the autonomic nervous system on somatic stem cell proliferation?

Regulation of somatic stem cell proliferation is critical for the maintenance of tissue and organ function throughout the body. Modulators of this process include nutrients and peptides, but the role of an autonomic neural influence on stem cell proliferation has been neglected. This article describes the literature in support of autonomic nervous system (ANS) influence on somatic stem cells, with emphasis on intestinal epithelial stem cells (IESCs) as a representative somatic stem cell. Based on the current available data, models for the direct influence of both branches of the ANS (the sympathetic and parasympathetic nervous systems) on IESCs are outlined. Finally, the prospect of treatments derived from ANS influence on somatic stem cells is explored.

Glucose stimulates intestinal epithelial crypt proliferation by modulating cellular energy metabolism.

The intestinal epithelium plays an essential role in nutrient absorption, hormone release, and barrier function. Maintenance of the epithelium is driven by continuous cell renewal by stem cells located in the intestinal crypts. The amount and type of diet influence this process and result in changes in the size and cellular make-up of the tissue. The mechanism underlying the nutrient-driven changes in proliferation is not known, but may involve a shift in intracellular metabolism that allows for more nutrients to be used to manufacture new cells. We hypothesized that nutrient availability drives changes in cellular energy metabolism of small intestinal epithelial crypts that could contribute to increases in crypt proliferation. We utilized primary small intestinal epithelial crypts from C57BL/6J mice to study (1) the effect of glucose on crypt proliferation and (2) the effect of glucose on crypt metabolism using an extracellular flux analyzer for real-time metabolic measurements. We found that glucose increased both crypt proliferation and glycolysis, and the glycolytic pathway inhibitor 2-deoxy-d-glucose (2-DG) attenuated glucose-induced crypt proliferation. Glucose did not enhance glucose oxidation, but did increase the maximum mitochondrial respiratory capacity, which may contribute to glucose-induced increases in proliferation. Glucose activated Akt/HIF-1α signaling pathway, which might be at least in part responsible for glucose-induced glycolysis and cell proliferation. These results suggest that high glucose availability induces an increase in crypt proliferation by inducing an increase in glycolysis with no change in glucose oxidation.

Jejunal Infusion of Glucose Decreases Energy Intake to a Greater Extent than Fructose in Adult Male Rats.

BACKGROUND: Intestinal nutrient infusions result in variable decreases in energy intake and body weight based on nutrient type and specific intestinal infusion site. OBJECTIVE: The objective was to test whether an intrajejunal fructose infusion (FRU) would lower energy intake and body weight and induce similar increases in gut hormones as those found after intrajejunal glucose infusions (GLU). METHODS: Male Sprague-Dawley rats received an intrajejunal infusion of either an equal kilocalorie load of glucose or fructose (11.4 kcal) or saline (SAL) for 5 d while intake of a standard rodent diet was continuously recorded; body weight was measured daily. Immediately after the infusion on the final day, rats were killed and plasma was collected to measure hormones. RESULTS: Daily energy intake was significantly lower in the GLU group than in the SAL group, but the FRU group did not differ from the GLU or SAL groups when the 11.4 kcal of the infusate was included as energy intake. Lower energy intake was due to smaller meal sizes during the infusion period in the GLU group than in the FRU and SAL groups; the FRU and SAL groups did not differ. The percentage of change in body weight was lower in the GLU group than in the FRU and SAL groups. Plasma glucagon-like-peptide 1 (GLP-1) concentrations were greater in the GLU group than in the SAL group; the FRU group did not differ from the GLU or SAL groups. The plasma insulin concentration was greater in the FRU group than in both the GLU and SAL groups. CONCLUSION: These results demonstrate that glucose induces a greater decrease in energy intake and increase in GLP-1 at distal intestinal sites than fructose in rats, which may explain differential effects of these monosaccharides between studies when delivered orally or along the proximal to distal axis of the intestine.

AMP-activated protein kinase is physiologically regulated by inositol polyphosphate multikinase.

The AMP-activated kinase (AMPK) senses the energy status of cells and regulates fuel availability, whereas hypothalamic AMPK regulates food intake. We report that inositol polyphosphate multikinase (IPMK) regulates glucose signaling to AMPK in a pathway whereby glucose activates phosphorylation of IPMK at tyrosine 174 enabling the enzyme to bind to AMPK and regulate its activation. Thus, refeeding fasted mice rapidly and markedly stimulates transcriptional enhancement of IPMK expression while down-regulating AMPK. Also, AMPK is up-regulated in mice with genetic depletion of hypothalamic IPMK. IPMK physiologically binds AMPK, with binding enhanced by glucose treatment. Regulation by glucose of phospho-AMPK in hypothalamic cell lines is prevented by blocking AMPK-IPMK binding. These findings imply that IPMK inhibitors will be beneficial in treating obesity and diabetes.

Nutrient-specific feeding and endocrine effects of jejunal infusions in obese animals.

Intestinal nutrient infusions result in variable decreases in food intake and body weight based on the nutrient type and the specific intestinal infusion site. We previously found that intrajejunal infusions of a fatty acid and glucose, but not casein hydrolysate, decreases food intake and body weight in lean chow-fed laboratory rats. To test whether obese, high fat-fed animals would show similar decreases in food intake and body weight in response to intrajejunal infusions of the same nutrients, equal kilocalorie loads of these nutrients (11.4 kcal) or vehicle were infused into the jejunum of obese, high fat-fed male Sprague-Dawley rats over 7 h/day for 5 consecutive days. Food intake was continuously monitored, and body weight was measured daily. After the infusion on the final day, rats were killed and plasma was collected. Similar to lean chow-fed rats, intrajejunal infusions of linoleic acid (LA) and glucose (Glu), but not casein hydrolysate (Cas), suppressed food intake with no compensatory increase in food intake after the infusion period. In contrast to lean chow-fed rats, only the LA, and not the Glu or Cas, produced decreases in body weight in the obese high fat-fed rat. There also were no differences in plasma glucagon-like peptide-1 levels in any of the nutrient infusion groups compared with saline infusion. These results suggest that there is a differential response to the same nutrients in lean vs. obese animals.

Inositol polyphosphate multikinase: an emerging player for the central action of AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is an essential enzyme indispensable for energy sensing and metabolic homeostasis at both the cellular and whole-body levels. Phosphorylation of AMPK, a key step for its activation, is known to be regulated by upstream kinases such as liver kinase B1 (LKB1) and calmodulin-dependent protein kinase kinase-beta (CaMKKß). Recent evidence shows that inositol polyphosphate multikinase (IPMK), which possesses both inositol phosphate kinase and lipid inositol kinase activities, can physiologically regulate AMPK signaling in cultured cells and in the arcuate nucleus. IPMK-mediated regulation of AMPK occurs through the dynamic protein interactions of IPMK with AMPK in response to glucose availability. Here we review and discuss a novel role for the hypothalamic IPMK signaling in the control of AMPK and central energy homeostasis.

Jejunal linoleic acid infusions require GLP-1 receptor signaling to inhibit food intake: implications for the effectiveness of Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass surgery results in sustained decreases in food intake and weight loss. A key component is likely the direct delivery of nutrients to the jejunum and resulting changes in levels of gut peptide secretion. Prior work modeling this aspect of the surgery has shown that small-volume, prolonged jejunal infusions of linoleic acid (LA) produce sustained decreases in food intake and weight loss. LA infusions also significantly elevate plasma glucagon-like peptide-1 (GLP-1) levels. To assess a role for the increased circulating GLP-1 in the feeding suppression, we examined the effect of prolonged peripheral minipump administration of the GLP-1 receptor antagonist exendin 9-39 (Ex 9) on the feeding suppression produced by jejunal LA. Using a 2 × 2 design, we infused either saline or LA in the jejunum (7 h/day, 11.4 kcal) for 5 days with a subset of animals from each group receiving either saline or Ex 9 (25 pmol·kg(-1)·min(-1)) continuously via a minipump. The antagonist alone had no effect on food intake. LA reduced daily food intake greatly in excess of the kilocalories infused. Ex 9 completely blocked the feeding suppression produced by the jejunal LA infusion. Ex 9 also attenuated the increase in plasma GLP-1 induced by jejunal LA infusions. These data demonstrate that endogenous GLP-1 receptor signaling is necessary for the reduction in food intake produced by jejunal LA infusions. Whether increased secretion of additional gut peptides is also necessary for such suppressions remains to be determined.

Central sensory-motor crosstalk in the neural gut-brain axis.

The neural gut-brain axis consists of viscerosensory and autonomic motor neurons innervating the gastrointestinal (GI) tract. Sensory neurons transmit nutrient-related and non-nutrient-related information to the brain, while motor neurons regulate GI motility and secretion. Previous research provides an incomplete picture of the brain nuclei that are directly connected with the neural gut-brain axis, and no studies have thoroughly assessed sensory-motor overlap in those nuclei. Our goal in this study was to comprehensively characterize the central sensory and motor circuitry associated with the neural gut-brain axis linked to a segment of the small intestine. We injected a retrograde (pseudorabies; PRV) and anterograde (herpes simplex virus 1; HSV) transsynaptic viral tracer into the duodenal wall of adult male rats. Immunohistochemical processing revealed single- and double-labeled cells that were quantified per nucleus. We found that across nearly all brain regions assessed, PRV + HSV immunoreactive neurons comprised the greatest percentage of labeled cells compared with single-labeled PRV or HSV neurons. These results indicate that even though sensory and motor information can be processed by separate neuronal populations, there is neuroanatomical evidence of direct sensory-motor feedback in the neural gut-brain axis throughout the entire caudal-rostral extent of the brain. This is the first study to exhaustively investigate the sensory-motor organization of the neural gut-brain axis, and is a step toward phenotyping the many central neuronal populations involved in GI control.

Insulin/IGF-1 enhances intestinal epithelial crypt proliferation through PI3K/Akt, and not ERK signaling in obese humans.

The intestinal epithelium is continuously regenerated through proliferation and differentiation of stem cells located in the intestinal crypts. Obesity affects this process and results in greater stem cell proliferation and altered tissue growth and function. Obesity-induced high levels of insulin and insulin-like growth factor-1 in the stem cell niche are found to impact proliferation in rodents indicating that insulin and insulin-like growth factor-1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. To determine whether insulin or insulin-like growth factor-1 can induce proliferation in human intestinal epithelial stem cells, and if two downstream insulin and insulin-like growth factor-1 receptor signaling pathways, PI3K/Akt and ERK, are involved, we used primary small intestinal epithelial crypts isolated from obese humans and investigated (1) the effect of insulin or insulin-like growth factor-1 on crypt proliferation, and (2) the effect of insulin and insulin-like growth factor-1 signaling inhibitors on insulin or insulin-like growth factor-1-induced proliferation. We found that insulin and insulin-like growth factor-1 enhanced the proliferation of crypt cells, including intestinal epithelial stem cells. Inhibition of the PI3K/Akt pathway attenuated insulin and insulin-like growth factor-1-induced proliferation, but inhibition of the ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in the insulin/insulin-like growth factor-1-induced increase in crypt proliferation in obese humans, which may contribute to abnormal tissue renewal and function. Impact statement This study investigates if insulin or insulin-like growth factor-1 (IGF-1) induces intestinal epithelial proliferation in humans, and if insulin and IGF-1 receptor signaling is involved in this process in obesity. Although obesity-induced high levels of insulin and IGF-1 in the stem cell niche are found to impact the proliferation of intestinal epithelial stem cells in rodents, we are the first to investigate this effect in humans. We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K/Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation. The imbalance in signaling between PI3K/Akt and ERK pathways may point to a pathway-specific impairment in insulin/IGF-1 receptor signaling. We propose that this may contribute to reciprocal relationships between insulin/IGF-1 receptor resistance and intestinal epithelial proliferation that leads to abnormal tissue renewal and function.

Obesity, independent of diet, drives lasting effects on intestinal epithelial stem cell proliferation in mice.

The intestinal epithelium plays an essential role in nutrient absorption, hormone release, and barrier function. Maintenance of the epithelium is driven by continuous cell renewal by intestinal epithelial stem cells located in the intestinal crypts. Obesity affects this process and results in changes in the size and function of the tissue. Because both the amount of food intake and the composition of the diet are contributing factors to developing and maintaining obesity, it is necessary to tease apart the separate contributions of obesity versus the type/amount of diet in driving the epithelial changes. C57BL/6J mice were fed a 60% high-fat diet versus a 10% low-fat diet for three months. A pair fed group was included (mice were fed with high-fat diet, but in equal kcal as that eaten by the low-fat diet- fed mice to keep them lean). We investigated the differences in (1) crypt-villus morphology in vivo, (2) the number and function of differentiated epithelial cell types in vivo, and (3) lasting effects on intestinal epithelial stem cell proliferation and growth in vitro. We found that high-fat diet-induced obesity, independent of the high-fat diet, increased crypt depth, villus height, the number of intestinal epithelial stem cells and goblet cells in vivo, and enhanced the size of the enterospheres developed from isolated IESCs in vitro. In addition, there is an interaction of obesity, type of diet, and availability of the diet (pair fed versus ad libitum) on protein and mRNA expression of alkaline phosphatase (an enzyme of enterocytes). These results suggest that high-fat diet-induced obesity, independent of the high-fat diet, induces lasting effects on intestinal epithelial stem cell proliferation, and drives the differentiation into goblet cells, but an interaction of obesity and diet drives alterations in the function of the enterocytes. Impact statement This study investigates whether obesity or the type/amount of diet differentially alters the proliferation, differentiation, growth, and function of the intestinal epithelial tissue. Although diet-induced obesity is known to alter the growth and function of the epithelium in vivo and cause lasting effects in intestinal epithelial stem cells (IESCs) in vitro, we are the first to tease apart the separate contributions of obesity versus the type/amount of diet in these processes. We found that high-fat diet (HFD)-induced obesity, independent of the HFD, drives lasting effects on IESC proliferation and differentiation into goblet cells, which may contribute to the growth of the epithelium. In addition, there is an interaction of obesity, type of diet, and availability of the diet (PF versus ad libitum) on the function of enterocytes. Identification of the factors driving the epithelial changes may provide new therapeutic strategies to control altered tissue growth and function associated with obesity.

Evidence for a direct effect of the autonomic nervous system on intestinal epithelial stem cell proliferation.

The sympathetic (SNS) and parasympathetic (PNS) branches of the autonomic nervous system have been implicated in the modulation of the renewal of many tissues, including the intestinal epithelium. However, it is not known whether these mechanisms are direct, requiring an interaction between autonomic neurotransmitters and receptors on proliferating epithelial cells. To evaluate the existence of a molecular framework for a direct effect of the SNS or PNS on intestinal epithelial renewal, we measured gene expression for the main autonomic neurotransmitter receptors in this tissue. We separately evaluated intestinal epithelial regions comprised of the stem, progenitor, and mature cells, which allowed us to investigate the distinct contributions of each cell population to this proposed autonomic effect. Notably, we found that the stem cells expressed the receptors for the SNS-associated alpha2A adrenoreceptor and the PNS-associated muscarinic acetylcholine receptors (M1 and M3). In a separate experiment, we found that the application of norepinephrine or acetylcholine decreases the expression of cyclin D1, a gene necessary for cell cycle progression, in intestinal epithelial organoids compared with controls (P < 0.05). Together, these results provide evidence of a direct mechanism for the autonomic nervous system influence on intestinal epithelial stem cell proliferation.

Sex differences influence intestinal epithelial stem cell proliferation independent of obesity.

The intestinal epithelium is continuously regenerated by cell renewal of intestinal epithelial stem cells (IESCs) located in the intestinal crypts. Obesity affects this process and results in changes in the size and cellular make-up of the tissue, but it remains unknown if there are sex differences in obesity-induced alterations in IESC proliferation and differentiation. We fed male and female mice a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 3 months and investigated the differences in (1) the expression of markers of different intestinal epithelial cell types in vivo, and (2) lasting effects on IESC growth in vitro. We found that the growth of IESCs in vitro were enhanced in females compared with males. HFD induced similar in vivo changes and in vitro early growth of IESCs in males and females. The IESCs isolated and grown in vitro from females, though, showed an enhanced growth that was independent of obesity. To determine whether this effect was driven by sex steroid hormones, we used primary intestinal crypts isolated from male and female mice and investigated the differences in (1) the expression of steroid hormone receptors, and (2) cell proliferation in response to steroid hormones. We found that estrogen receptor α was expressed in crypts from both sexes, but estrogen had no effect on proliferation in either sex. These results suggest that obesity similarly effects IESCs in males and females, but IESCs in females have greater proliferation ability than males, but this is not driven by a direct effect of sex steroid hormones on IESCs or other crypt cells that provide essential niche support for IESCs.

LKB1-AMPK modulates nutrient-induced changes in the mode of division of intestinal epithelial crypt cells in mice.

Nutrient availability influences intestinal epithelial stem cell proliferation and tissue growth. Increases in food result in a greater number of epithelial cells, villi height and crypt depth. We investigated whether this nutrient-driven expansion of the tissue is the result of a change in the mode of intestinal epithelial stem cell division and if LKB1-AMPK signaling plays a role. We utilized in vivo and in vitro experiments to test this hypothesis. C57BL/6J mice were separated into four groups and fed varying amounts of chow for 18 h: (1) ad libitum, (2) 50% of their average daily intake (3) fasted or (4) fasted for 12 h and refed. Mice were sacrificed, intestinal sections excised and immunohistochemically processed to determine the mitotic spindle orientation. Epithelial organoids in vitro were treated with no (0 mM), low (5 mM) or high (20 mM) amounts of glucose with or without an activator (Metformin) or inhibitor (Compound C) of LKB1-AMPK signaling. Cells were then processed to determine the mode of stem cell division. Fasted mice show a greater % of asymmetrically dividing cells compared with the other feeding groups. Organoids incubated with 0 mM glucose resulted in a greater % of asymmetrically dividing cells compared with the low or high-glucose conditions. In addition, LKB1-AMPK activation attenuated the % of symmetric division normally seen in high-glucose conditions. In contrast, LKB1-AMPK inhibition attenuated the % of asymmetric division normally seen in no glucose conditions. These data suggest that nutrient availability dictates the mode of division and that LKB1-AMPK mediates this nutrient-driven effect on intestinal epithelial stem cell proliferation. Impact statement The underlying cell biology of changes in the polarity of mitotic spindles and its relevance to tissue growth is a new concept and, thus, these data provide novel findings to begin to explain how this process contributes to the regeneration and growth of tissues. We find that short-term changes in food intake in vivo or glucose availability in vitro dictate the mode of division of crypt cells. In addition, we find that LKB1-AMPK signaling modulates the glucose-induced changes in the mode of division in vitro. Identifying mechanisms involved in the mode of division may provide new targets to control tissue growth.

Alterations in circadian and meal-induced gut peptide levels in lean and obese rats.

Alterations in gut hormone signaling are a likely contributing factor to the metabolic disturbances associated with overweight/obesity as they coordinate the timing of feeding behavior, absorption, and utilization of nutrients. These hormones are released in response to food intake, or follow a circadian or anticipatory pattern of secretion that is independent of nutrient stimulation. The aim of this study was to identify the degree to which high-fat diet-induced obesity would alter the daily rhythm of gut peptide plasma levels (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], insulin or amylin [AMY]) or meal-induced levels in the middle of the light or dark cycle. Male Sprague-Dawley rats were fed a high-fat diet (OBESE) or chow (LEAN), implanted with jugular catheters, and blood samples were taken every 2 h throughout the light/dark cycle while freely feeding or after an Ensure liquid meal. We found that even when OBESE and LEAN animals ate the same kcals and have a similar pattern of food intake, there is a difference in both the levels and rhythm of plasma gut peptides. GLP-1 and PYY are higher during the light cycle in LEAN animals and AMY is higher in the OBESE group throughout the light/dark cycle. There was also a differential response of plasma gut signals after the Ensure meal, even though the composition and amount of intake of the meal were the same in both groups. These changes occur prior to the high-fat diet induced loss of glycemic control and may be a target for early intervention. Impact statement The aim of this study was to test if obesity would alter the daily rhythm of gut peptides or meal-induced levels in the middle of the light or dark cycle. We found that even when animals are eating the same amount (in kcal) of food that the obese animals have altered daily rhythms and meal-induced gut peptide levels. In particular, we are the first to show that obesity induces increases in peptide YY levels during the light cycle and amylin remains high throughout the light and dark cycle in obese animals. These changes occurred prior to a loss of glycemic control. Thus, the rhythm of gut peptides could be used as an early indicator of later and more serious metabolic disturbances and may be a target for early intervention.

Long-term effect of parasympathetic or sympathetic denervation on intestinal epithelial cell proliferation and apoptosis.

Intestinal epithelial tissue is constantly regenerated as a means to maintain proper tissue function. Previous studies have demonstrated that denervation of the parasympathetic or sympathetic nervous system to the intestine alters this process. However, results are inconsistent between studies, showing both increases and decreases in proliferation after denervation of the parasympathetic or sympathetic. The effect appears to correlate with (1) the timing post-denervation, (2) denervation-induced changes in food intake, (3) the denervation technique used, and (4) which intestinal segment is investigated. Thus, we proposed that parasympathetic or sympathetic denervation does not have an effect on intestinal epithelial regeneration when you (1) evaluate denervation after long-term denervation, (2) control for post-surgical changes in food intake, (3) use minimally invasive surgical techniques and (4) include a segmental analysis. To test this, adult male Sprague Dawley rats underwent parasympathetic denervation via subdiaphragmatic vagotomy, sympathetic denervation via celiacomesenteric ganglionectomy, a parasympathetic denervation sham surgery, or a sympathetic denervation sham surgery. Sham surgery ad libitum-fed groups and sham surgery pair-fed groups were used to control for surgically induced changes in food intake. Three weeks post-surgery, animals were sacrificed and tissue from the duodenum, jejunum, and ileum was excised and immunohistochemically processed to visualize indicators of proliferation (bromodeoxyuridine-positive cells) and apoptosis (caspase-3-positive cells). Results showed no differences between groups in proliferation, apoptosis, or total cell number in any intestinal segment. These results suggest that parasympathetic or sympathetic denervation does not have a significant long-term effect on intestinal epithelial turnover. Thus, intestinal epithelial regeneration is able to recover after autonomic nervous system injury. Impact statement This study investigates the long-term effect of autonomic denervation on intestinal epithelial cell turnover, as measured by proliferation, apoptosis, and total cell number. Although previous research has established that autonomic denervation can alter intestinal epithelial turnover under short-term conditions, here we establish for the first time that these changes do not persist long-term when you control for surgical-induced changes in food intake and use targeted denervation procedures. These findings add to the base of knowledge on autonomic control of tissue turnover, highlight the ability of the intestinal epithelium to recover after autonomic injury and reveal possible implications of the use of ANS denervation for disease treatment in humans.

The antagonism of ghrelin alters the appetitive response to learned cues associated with food.

The rapid increase in obesity may be partly mediated by an increase in the exposure to cues for food. Food-paired cues play a role in food procurement and intake under conditions of satiety. The mechanism by which this occurs requires characterization, but may involve ghrelin. This orexigenic peptide alters the response to food-paired conditioned stimuli, and neural responses to food images in reward nuclei. Therefore, we tested whether a ghrelin receptor antagonist alters the influence of food-paired cues on the performance of instrumental responses that earn food and the consumption of food itself using tests of Pavlovian-to-instrumental transfer (PIT) and cue potentiated feeding (CPF), respectively. Food-deprived rats received Pavlovian conditioning where an auditory cue was paired with delivery of sucrose solution followed by instrumental conditioning to lever press for sucrose. Following training, rats were given ad libitum access to chow. On test day, rats were injected with the ghrelin receptor antagonist GHRP-6 [D-Lys3] and then tested for PIT or CPF. Disrupting ghrelin signaling enhanced expression of PIT. In addition, GHRP-6 [D-Lys3] impaired the initiation of feeding behavior in CPF without influencing overall intake of sucrose. Finally, in PIT tested rats, enhanced FOS immunoreactivity was revealed following the antagonist in regions thought to underlie PIT; however, the antagonist had no effect on FOS immunoreactivity in CPF tested rats.

Nutrient-induced intestinal adaption and its effect in obesity.

Obese and lean individuals respond differently to nutrients with changes in digestion, absorption and hormone release. This may be a result of differences in intestinal epithelial morphology and function driven by the hyperphagia or the type of diet associated with obesity. It is well known that the maintenance and growth of the intestine is driven by the amount of luminal nutrients, with high nutrient content resulting in increases in cell number, villi length and crypt depth. In addition, the type of nutrient appears to contribute to alterations in the morphology and function of the epithelial cells. This intestinal adaptation may be what is driving the differences in nutrient processing in lean versus obese individuals. This review describes how nutrients may be able to induce changes in intestinal epithelial cell proliferation, differentiation and function and the link between intestinal adaptation and obesity.

Glucagon-like peptide 1 and appetite.

Glucagon-like peptide 1 (GLP-1) and GLP-1 analogs have received much recent attention due to the success of GLP-1 mimetics in treating type II diabetes mellitus (T2DM), but these compounds may also have the potential to treat obesity. The satiety effect of GLP-1 may involve both within-meal enteroenteric reflexes, and across-meal central signaling mechanisms, that mediate changes in appetite and promote satiety. Here, we review data supporting the role of both peripheral and central GLP-1 signaling in the control of gastrointestinal motility and food intake. Understanding the mechanisms underlying the appetite-suppressive effects of GLP-1 may help in developing targeted treatments for obesity.