Chronic Overeating Research Articles

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC's development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world's population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease's development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.

Compulsive-like eating of high-fat high-sugar food is associated with 'addiction-like' glutamatergic dysfunction in obesity prone rats.

Chronic overeating is a core feature of diet‐induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive‐like eating using a rat model of diet‐induced obesity. A conditioned suppression task demonstrated that diet‐induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet‐induced obese animals. Lastly, both a computed ‘addiction score’ (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet‐induced obesity is associated with compulsive‐like eating of highly palatable food and is accompanied by ‘addiction‐like’ glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction‐like pathology in this model of obesity.

Executive Function performance in patients with obesity: A systematic review

Executive dysfunction is associated with the inability to control aberrant behaviors, such as chronic overeating (Moore, Sabino, Koob, & Cottone, 2017). Obese individuals often report great difficulties controlling eating behaviors, despite a desire to successfully lose weight (Dohle, Diel, & Hofmann, 2018). However, current literature lacks a systematic review about the relationship between executive dysfunction and Obesity. The aim of this study is to present the most important findings about this matter. First, a bibliometric analysis shows the evolution of the topic. Then, the Tree of Science tool is used to show a chronological review that provides a general description of the roots and current perspectives of the state of literature. Finally, clustering analysis of the co-citation network was employed to identify the different perspectives of the topic. The main findings suggest four approaches: (1) effects of body mass index on executive functioning, (2) executive functioning in children with overweight and obesity, (3) physical activity for adult obesity and (4) structural and functional brain changes in obesity. Preliminary data state that in obesity, poor food choices may be associated with frontal cognitive impairments that contribute to reduced orbito-frontal cortex volume.

Molecular Mechanisms of Hypothalamic Insulin Resistance.

Insulin exists in the central nervous system, where it executes two important functions in the hypothalamus: the suppression of food intake and the improvement of glucose metabolism. Recent studies have shown that both are exerted robustly in rodents and humans. If intact, these functions exert beneficial effects on obesity and diabetes, respectively. Disruption of both occurs due to a condition known as hypothalamic insulin resistance, which is caused by obesity and the overconsumption of saturated fat. An enormous volume of literature addresses the molecular mechanisms of hypothalamic insulin resistance. IKKβ and JNK are major players in the inflammation pathway, which is activated by saturated fatty acids that induce hypothalamic insulin resistance. Two major tyrosine phosphatases, PTP-1B and TCPTP, are upregulated in chronic overeating. They dephosphorylate the insulin receptor and insulin receptor substrate proteins, resulting in hypothalamic insulin resistance. Prolonged hyperinsulinemia with excessive nutrition activates the mTOR/S6 kinase pathway, thereby enhancing IRS-1 serine phosphorylation to induce hypothalamic insulin resistance. Other mechanisms associated with this condition include hypothalamic gliosis and disturbed insulin transport into the central nervous system. Unveiling the precise molecular mechanisms involved in hypothalamic insulin resistance is important for developing new ways of treating obesity and type 2 diabetes.

A paradigm shift for the prevention and treatment of individual and global obesity.

The prevalence of obesity and overweight has plateaued in developed countries, although at high levels, but in most parts of the world, it continues to increase. Current recommendations for preventing and treating obesity are based mainly on the notion that overeating results from hedonic eating as a result of unlimited access to palatable foods, particularly those high in sugar and fat, and that hedonic centers are able to “override” the body’s homeostatic mechanisms. This article proposes that the homeostatic mechanisms affecting appetite and satiety are more important in chronic overeating, and that sufficient evidence exists for adopting a new paradigm for controlling individual and global obesity based on controlling energy homeostasis via the enteroendocrine and gut microbiota systems. Many obese children and adolescents have chronic hunger, supporting the notion that they have a homeostatic rather than hedonic abnormality. The effectiveness of weight loss drugs and bariatric surgery suggests that the brain centers controlling energy homeostasis are able to override centers controlling hedonic drives. Energy homeostasis can also be influenced by nutrition, in particular, by avoiding sweetened drinks and consuming whole grains, vegetables, fruits and other foods that are high in dietary fiber, and thereby influence appetite and satiety. New recommendations are outlined for preventing and treating individual and global obesity based on a paradigm that targets appetite and satiety.

Abstract 1271: Restricted feeding of a high-fat diet to the dark phase of the day attenuates mammary tumorigenesis in MMTV-PyMT mice

Abstract Obesity is a risk factor for breast cancer. Chronic overeating during the rest phase of the day leads to metabolic dysfunction and obesity. Lifestyle changes including restriction of meal times may be successful weight loss strategies. In the present study, we tested the hypothesis that restricted feeding of a high-fat diet to the dark phase (the active phase) of the day reduces diet-enhanced mammary tumorigenesis in an MMTV-PyMT transgenic mouse model. Mice (female) were fed the AIN93G diet (16% of energy from soybean oil) or the high-fat diet (45% of energy from soybean oil) with or without restricted feeding to the dark phase (12 hours) over eight weeks of the study. The body fat mass of the restricted feeding group was lower than the high-fat group but similar to the AIN93G control group. The mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the control, high-fat and high-fat restricted groups, respectively. Restricted feeding reduced mammary tumor progression by 58% compared to the unrestricted feeding of the high-fat diet. Compared to the AIN93 diet, the high-fat diet significantly increased plasma concentrations of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, resistin, leptin, insulin, angiopoietin-2, hepatocyte growth factor and vascular endothelial growth factor. The restricted feeding reduced concentrations of the aforementioned variables in plasma, except resistin, leptin, and insulin. In summary, restricted feeding of the high-fat diet to the dark phase reduces diet-enhanced mammary tumorigenesis. This protection of the restricted feeding against breast tumorigenesis may be associated with its actions in attenuating adipogenesis and production of related inflammatory cytokines and angiogenic factors. Citation Format: Sneha Sundaram, Lin Yan. Restricted feeding of a high-fat diet to the dark phase of the day attenuates mammary tumorigenesis in MMTV-PyMT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1271.

2125 What genes are involved in the brain food reward circuitry: Findings from a large candidate gene analysis

OBJECTIVES/SPECIFIC AIMS: The food reward circuitry regulates hedonic eating especially in relation to palatable hypercaloric foods, which can lead to chronic overeating and consequent overweight and obesity. Evidence supports that there is considerable overlap within the brain reward circuitry between palatable hypercaloric food intake and substance addiction. The goal of this study was to identify associations between addiction-related genes and body mass index. We hypothesized that addiction-related genes potentially participate in the food reward circuitry if they are associated with obesity traits. METHODS/STUDY POPULATION: A secondary analysis was conducted with 1093 African American adolescents and young adults from the New Mother’s Study. Anthropometric, genetic, demographic and lifestyle measurements were available at the 18-year follow-up assessments. A total of 1350 single nucleotide polymorphisms mapped to 127 addiction-related genes were assessed. A total of 186 ancestry informative markers were used to adjust for population stratification. Generalized estimating equation models were used to identify genetic associations, including additive, dominant, and recessive models, and control for correlations within families. RESULTS/ANTICIPATED RESULTS: The participants ranged from 15 to 23 years of age. Of them, 42.7% were overweight or obese. Significant associations with body mass index were identified for 13 single nucleotide polymorphisms mapped to 11 addiction-related genes, including LEP (p 0.027–<0.001). Most of these genes are involved in dopaminergic, opioidergic, serotonergic pathways, and stress. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results support the role of dopaminergic and opioidergic pathways in the food reward circuitry, and suggest a potential involvement of serotonergic pathways and genes related to stress in the food reward circuitry. Further investigation of the identified genes will facilitate delineation and understanding of the brain food reward system and its relationship with obesity.

Role of Endocannabinoids on Sweet Taste Perception, Food Preference, and Obesity-related Disorders

The prevalence of obesity and obesity-related disorders such as type 2 diabetes (T2D) and metabolic syndrome has increased significantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide. Chronic overeating of highly palatable foods is one of the main responsible aspects behind overweight. Food choice is driven by food preference, which is influenced by environmental and internal factors, from availability to rewarding properties of food. Consequently, the acquisition of a dietary habit that may lead to metabolic alterations is the result of a learning process in which many variables take place. From genetics to socioeconomic status, the response to food and how this food affects energy metabolism is heavily influenced, even before birth. In this work, we review how food preference is acquired and established, particularly as regards sweet taste; towards which flavors and tastes we are positively predisposed by our genetic background, our early experience, further lifestyle, and our surroundings; and, especially, the role that the endocannabinoid system (ECS) plays in all of this. Ultimately, we try to summarize why this system is relevant for health purposes and how this is linked to important aspects of eating behavior, as its function as a modulator of energy homeostasis affects, and is affected by, physiological responses directly associated with obesity.

Eat and Death: Chronic Over-Eating.

Obesity-related co-morbidities decrease life quality, reduce working ability and lead to early death. The total amount of dietary fat consumption may be the most potent food-related risk factor for weight gain. In this respect, dietary intake of high-caloric, high-fat diets due to chronic over-eating and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues . Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance in an inflammation-independent manner. Even in the absence of metabolic disorders, mismatch between fatty acid uptake and utilization leads to the accumulation of toxic lipid species resulting in organ dysfunction. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction may play role in the pathogenesis of lipotoxicity. The hypothalamus senses availability of circulating levels of glucose, lipids and amino acids, thereby modifies feeding according to the levels of those molecules. However, the hypothalamus is also similarly vulnerable to lipotoxicity as the other ectopic lipid accumulated tissues. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B kinase beta subunit/nuclear factor kappa B (IKKβ/NF-κB) in the hypothalamus before the onset of obesity. However, the mechanisms by which high-fat diet induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown. In this chapter, besides lipids and leptin, the role of glucose and insulin on specialized fuel-sensing neurons of hypothalamic neuronal circuits has been debated.

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder characterized by an insatiable appetite, leading to chronic overeating and obesity. Additional features include short stature, intellectual disability, behavioral problems and incomplete sexual development. Although significant progress has been made in understanding the genetic basis of PWS, the mechanisms underlying the pathogenesis of the disorder remain poorly understood. Treatment for PWS consists mainly of palliative therapies; curative therapies are sorely needed. Zebrafish, Danio rerio, represent a promising way forward for elucidating physiological problems such as obesity and identifying new pharmacotherapeutic options for PWS. Over the last decade, an increased appreciation for the highly conserved biology among vertebrates and the ability to perform high-throughput drug screening has seen an explosion in the use of zebrafish for disease modeling and drug discovery. Here, we review recent advances in developing zebrafish models of human disease. Aspects of zebrafish genetics and physiology that are relevant to PWS will be discussed, and the advantages and disadvantages of zebrafish models will be contrasted with current animal models for this syndrome. Finally, we will present a paradigm for drug screening in zebrafish that is potentially the fastest route for identifying and delivering curative pharmacotherapies to PWS patients.

Chronic overeating impairs hepatic glucose uptake and disposition.

Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ≈25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 ± 0.3 and 1.5 ± 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4× basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg(-1)·min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg·kg(-1)·min(-1); P1: 1.7 ± 0.2 vs. 0.3 ± 0.4; P2: 3.6 ± 0.3 vs. 2.3 ± 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism.

Hyperactive hypothalamus, motivated and non‐distractible chronic overeating in ADAR2 transgenic mice

ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [(18) F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased messenger RNA (mRNA) expressions of ADAR2, serotonin 2C receptor (5HT2C R), D1, D2 and mu opioid receptors and no change in corticotropin-releasing hormone mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs and hyperactive brain mesolimbic region.

Sensation and perception of sucrose and fat stimuli predict the reinforcing value of food

Chronic overeating can lead to weight gain and obesity. Sensory system function may play a role in the types of foods people select and the amount of food people eat. Several studies have shown that the orosensory components of eating play a strong role in driving food intake and food selection. In addition, previous work has shown that motivation to get food, or the reinforcing value of food, is a predictor of energy intake. The purpose of this study was to test the hypothesis that higher detection thresholds and lower suprathreshold intensity ratings of sweet and fat stimuli are associated with greater reinforcing value of food. In addition, we sought to determine if the sensory ratings of the stimuli would differ depending on whether they were expectorated or swallowed. The reinforcing value of food was measured by having participants perform operant responses for food on progressive ratio schedules of reinforcement. Taste detection thresholds and suprathresholds for solutions containing varied concentrations of sucrose and fat were also measured in two different Experiments. In Experiment 1, we found that sucrose, but not fat, detection predicted the reinforcing value of food with the reinforcing value of food increasing as sucrose detection threshold increased (indicating poorer detection). In Experiment 2, we found that lower suprathreshold ratings of expectorated fat and sucrose predicted greater reinforcing value of food. In addition, higher detection thresholds for fat stimuli (indicating poorer detection) were associated with greater reinforcing value of food. When taken together, these studies suggest that there is a relationship between taste detection and perception and reinforcing value of food and that these relationships vary based on whether the stimulus is swallowed or expectorated.

Obesogenic diets may differentially alter dopamine control of sucrose and fructose intake in rats

Chronic overeating of obesogenic diets can lead to obesity, reduced dopamine signaling, and increased consumption of added sugars to compensate for blunted reward. However, the specific role of diet composition yet remains unknown. To study this, Sprague–Dawley male rats were fed a high-energy diet with high fat and low carbohydrate content (HFHE), a fat-sugar combination high-energy diet (FCHE), or standard chow for 24 weeks. We found that both high-energy diets produced substantial body weight gain compared to chow-fed controls. To investigate dopamine control of short (2-h) intake of palatable sucrose or fructose solutions, rats were pretreated peripherally (IP) with equimolar doses (0–600 nmol/kg) of the dopamine D1 (SCH23390) and D2 (raclopride) subtype-specific receptor antagonists. The results showed an overall increase in the efficacy of D1 and D2 receptor antagonists on suppression of intake in obese rats compared to lean rats, with effects differing based on diets and test solutions. Specifically, SCH23390 potently reduced both sucrose and fructose intake in all groups; however, lower doses were more effective in HFHE rats. In contrast, raclopride was most effective at reducing fructose intake in the obese FCHE rats. Thus, it appears that obesity due to the consumption of combinations of dietary fat and sugar rather than extra calories from dietary fat alone may result in reduced D2 receptor signaling. Furthermore, such deficits seem to preferentially affect the control of fructose intake. These findings demonstrate for the first time a plausible interaction between diet composition and dopamine control of carbohydrate intake in diet-induced obese rats. It also provides additional evidence that sucrose and fructose intake is regulated differentially by the dopamine system.

Relation of dietary restraint scores to cognitive biases and reward sensitivity

This study tested the hypotheses that dietary restraint scores are associated with greater reward sensitivity and cognitive bias for food-related cues, which might result in chronic overeating and efforts to curb this tendency through dietary restriction. Participants (N=63) with high versus low scores on the DEBQ-R did not differ on attentional bias for pictorial food-related cues on a visual probe task, or approach tendencies elicited by food cues, as assessed with a stimulus–response compatibility (SRC) task. Restraint was also unrelated to performance on an operant task that assessed how hard participants would work for snacks, or responding during a taste habituation paradigm. Dietary restraint scores were correlated with self-reported appetitive response to food, sensitivity to reward, and sensitivity to punishment. Results provide limited support for the hypothesis that individuals with elevated dietary restraint scores show greater reward sensitivity and cognitive bias for food stimuli, though it is possible that the null findings on the behavioral task resulted because of an approach-avoidance conflict to food cues in which heightened appetitive responses to food are inhibited by food-related anxiety.

Food addiction: true or false?

Food addiction has been implicated as a putative causal factor in chronic overeating, binge eating, and obesity. The concept of food addiction has been controversial historically due to definitional and conceptual difficulties and to a lack of rigorous scientific data. Support for the food addiction hypothesis comes from alterations in neurochemistry (dopamine, endogenous opioids), neuroanatomy (limbic system), and self-medication behaviors. Foods identified as having potential addictive properties include sweets, carbohydrates, fats, sweet/fat combinations, and possibly processed and/or high salt foods. Eating topography has been identified as a necessary factor in neural pathway changes that promote addiction-like properties in response to some foods. A recently developed food addiction scale shows promise in identifying food addiction. Recent findings have strengthened the case for food addiction. These findings may serve to validate the perception of food addiction in patients and inform psychoeducational, cognitive-behavioral, and/or pharmacological treatment for chronic food cravings, compulsive overeating, and binge eating that may represent a phenotype of obesity. Screening for food addiction has the potential to identify people with eating difficulties that seriously compromise weight management efforts. Future research should include a focus on human food addiction research; evaluating the impact of treatment on underlying neurochemistry; and prevention or reversal of food addiction in humans.

Parabrachial Coding of Sapid Sucrose:

Cumulative evidence in rats suggests that the pontine parabrachial nuclei (PBN) are necessary for assigning hedonic value to taste stimuli. In a series of studies, our laboratory has investigated the parabrachial coding of sapid sucrose in normal and obese rats. First, using chronic microdialysis, we demonstrated that sucrose intake increases dopamine release in the nucleus accumbens, an effect that is dependent on oral stimulation and on concentration. The dopamine response was independent of the thalamocortical gustatory system but was blunted substantially by lesions of the PBN. Similar lesions of the PBN but not the thalamic taste relay diminished cFos activation in the nucleus accumbens caused by sucrose ingestion. Recent single-neuron recording studies have demonstrated that processing of sucrose-evoked activity in the PBN is altered in Otsuka Long Evans Tokushima Fatty (OLETF) rats, which develop obesity due to chronic overeating and express increased avidity to sweet. Compared with lean controls, taste neurons in OLETF rats had reduced overall sensitivity to sucrose and altered concentration responses, with decreased responses to lower concentrations and augmented responses to higher concentrations. The decreased sensitivity to sucrose was specific to NaCl-best neurons that also responded to sucrose, but the concentration effects were carried by the sucrose-specific neurons. Collectively, these findings support the hypothesis that the PBN enables taste stimuli to engage the reward system and, in doing so, influences food intake and body weight regulation. Obesity, in turn, may further alter the gustatory code via forebrain connections to the taste relays or hormonal changes consequent to weight gain.

Your brain on fat: dietary-induced obesity impairs central nutrient sensing

the past decade has witnessed a rejuvenated interest in the ability of the central nervous system (CNS) to sense and respond to changes in nutrient availability. This interest has been driven in part by a conceptual framework where the CNS receives signals regarding nutrient availability that are

Association Between Body Size and Colorectal Adenoma Recurrence

Obesity has been associated with increased risk for colorectal adenoma, although its role as a risk factor after polypectomy for recurrence is unclear. Therefore, we sought to evaluate the effect of anthropometric measures of obesity on adenoma after polypectomy. Subjects with baseline adenomas (n = 2465) and follow-up colonoscopy data were drawn from 2 randomized trials designed to prevent adenoma recurrence. Over a mean follow-up period of 3.1 years presence of a body mass index (BMI) > or = 30 kg/m2 was associated with a nonsignificant 17% increase in the odds for any adenoma recurrence among all subjects (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.92-1.48). This result was confined to men (OR, 1.36; 95% CI, 1.01-1.83) and not observed for women (OR, 0.90; 95% CI, 0.60-1.33). Results for waist circumference did not reach statistical significance, although trends were similar to those for BMI. Analyses of the effects of obesity on more clinically significant lesions demonstrated that high BMI was a slightly stronger risk factor for advanced adenoma recurrences in men (OR, 1.62; 95% CI, 1.04-2.53) when compared with non-advanced lesions (OR, 1.26; 95% CI, 0.91-1.75). In addition, we observed an association for obesity and odds of adenoma recurrence among participants reporting a family history of colorectal cancer (OR, 2.25; 95% CI, 1.32-3.84) but not for those without (OR, 1.00; 95% CI, 0.77 to 1.31; P(int) = P = .008). Our results support obesity as a risk factor for subsequent short-interval (mean follow-up time 3.1 years) development of colorectal adenomas, particularly among men and persons with a family history of colorectal cancer. Furthermore, obesity in men appears to be strongly associated with the development of clinically advanced lesions.

Obesity and eating disorders

The presence of fat in the small intestine slows gastric emptying, stimulates the release of many gastrointestinal hormones, and suppresses appetite and energy intake as a result of the digestion of fats into free fatty acids; the effects of free fatty acids are, in turn, dependent on their chain length. Given these effects of fat, it is paradoxical that high dietary fat intakes have been linked to increased energy intake and body weight and are considered to play a significant role in the pathogenesis of obesity. However, increasing evidence indicates that a chronic increase in dietary fat is associated with an attenuation of the feedback signals arising from the small intestine induced by fat, with a consequent relative acceleration of gastric emptying, modulation of gastrointestinal hormone secretion, and attenuation of the suppression of energy intake. This review addresses the gastrointestinal factors involved in the regulation of appetite and energy intake, with a particular focus on 1) the gastrointestinal mechanisms triggered by small intestinal fat that modulate energy intake, 2) the potential role of a high dietary fat intake in the development of obesity, and 3) implications for the prevention and management of obesity. Am J Clin Nutr 2007;86:531–41.