Genetics of obesity

Considerable attention is currently being paid to the secular changes in food intake and physical activity that underlie the increase in the prevalence of obesity that is apparent in many societies. While this is laudable it would be unwise to view these environmental factors in isolation from the biological factors that normally control body weight and composition and the compelling evidence that inter-individual differences in susceptibility to obesity have strong genetic determinants. This is particularly important, as it is only in the past decade that we have begun to obtain substantive information regarding the molecular constituents of pathways controlling mammalian energy balance and therefore, for the first time, are in a position to achieve a better mechanistic understanding of this disease. Population-based association and linkage studies have highlighted a number of loci at which genetic variation is associated with obesity and related phenotypes and the identification and characterization of monogenic obesity syndromes has been particularly fruitful. While there is widespread acceptance that hereditary factors might predispose to human obesity, it is frequently assumed that such factors would influence metabolic rate or the selective partitioning of excess calories into fat. However, it is notable that, thus far, all monogenic defects causing human obesity actually disrupt hypothalamic pathways and have a profound effect on satiety and food intake. To conclude, the evidence we have to date suggests that the major impact of genes on human obesity is just as likely (or perhaps more likely) to directly impact on hunger, satiety and food intake rather than metabolic rate or nutrient partitioning. At the risk of oversimplification, it seems that from an aetiological/genetic standpoint, human obesity appears less a metabolic than a neuro-behavioural disease.     

Fatty acid detection during food consumption and digestion: Associations with ingestive behavior and obesity

The inability of humans to adequately regulate fat consumption is a salient contributor to the development of obesity. The macronutrients, fat, protein and carbohydrate, within foods are detected at various stages of consumption, during which their digestive products, fatty acids, amino acids and sugars, interact with chemosensory cells within the oral epithelium (taste receptor cells) and gastrointestinal (GI) tract (enteroendocrine cells). This chemoreception initiates functional responses, including taste perception, peptide secretion and alterations in GI motility, that play an important role in liking of food, appetite regulation and satiety. This review will summarize the available evidence relating to the oral and GI regulation of fat intake and how chemoreception at both locations is associated with digestive behavior, satiety and weight regulation.     

AMP-activated protein kinase is a key regulator of obesity-associated factors

An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.     

Effect of three different bariatric obesity surgery procedures on nutrient and energy digestibility using a swine experimental model

Morbid obesity is a worldwide health concern that compromises life quality and health status of obese human subjects. Bariatric surgery for treating morbid obesity remains as one of the best alternatives to promote excess weight loss and to reduce co-morbidities. We have not found studies reporting nutrients and energy balance considering digestibility trials in humans following surgery. The purpose of this study was to determine protein, lipid, fiber, energy, calcium, and phosphorous digestibility in a swine model that underwent ileal transposition (IT), sleeve gastrectomy with ileal transposition (SGIT), Roux-en-Y gastric bypass (RYGBP), and with sham operated animals (SHAM). Thirty-two pigs were randomly assigned to four laparoscopic procedures: IT (n = 8), RYGBP (n = 8), SGIT (n = 8), and Sham-operated pigs (n = 8). From day 0 postsurgery to 130, pigs were weighed monthly to determine live weight and weight gain was calculated for each month postsurgery until day 130. Food intake in a metabolic weight basis was calculated by measuring ad libitum food intake at day 130. Swine were fitted into metabolic crates to determine digestibility coefficients of dry matter, protein, fat, fiber, ash, energy, calcium, and phosphorous from day 130. A one-way ANOVA and Student–Newman–Keuls were used to detect differences in weight, food intake, and digestibility coefficients. Digestibility values for dry matter, fiber, phosphorus, and energy showed no differences among groups (P > 0.05). However, significant differences (P ≤ 0.05) were encountered among groups for fat, protein, ash, and calcium digestibilities. The RYGBP procedure, when applied to the pig model, significantly reduced calcium, fat, and ash digestibility, which did not occur with SGIT or IT procedure, when compared with Sham-operated animals.     

The modulatory role of high fat feeding on gastrointestinal signals in obesity

The gastrointestinal (GI) tract is a specialized sensory system that detects and responds to constant changes in nutrient- and bacterial-derived intestinal signals, thus contributing to controls of food intake. Chronic exposure to dietary fat causes morphological, physiological and metabolic changes leading to disruptions in the regulatory feeding pathways promoting more efficient fat absorption and utilization, blunted satiation signals and excess adiposity. Accumulating evidence demonstrates that impaired gastrointestinal signals following long-term high fat consumption are, at least partially, responsible for increased caloric intake. This review focuses on the role of dietary fat in modulating oral and post-oral chemosensory signaling elements responsible for lipid detection and responses, including changes in sensitivity to satiation signals, such as GLP-1, PYY and CCK and their impact on food intake and weight gain. Furthermore, the influence of the gut microbiota on mechanisms controlling energy regulation in the face of excessive fat exposure will be explored. The profound influence of dietary fats on altering complex regulatory feeding pathways can result in dysregulation of body weight and development of obesity, while restoration or manipulation of satiation signaling may prove an effective tool in prevention and treatment of obesity.     

Neuronal genes for subcutaneous fat thickness in human and pig are identified by local genomic sequencing and combined SNP association study

Obesity represents a major global public health problem that increases the risk for cardiovascular or metabolic disease. The pigs represent an exceptional biomedical model related to energy metabolism and obesity in humans. To pinpoint causal genetic factors for a common form of obesity, we conducted local genomic de novo sequencing, 18.2 Mb, of a porcine QTL region affecting fatness traits, and carried out SNP association studies for backfat thickness and intramuscular fat content in pigs. In order to relate the association studies in pigs to human obesity, we performed a targeted genome wide association study for subcutaneous fat thickness in a cohort population of 8,842 Korean individuals. These combined association studies in human and pig revealed a significant SNP located in a gene family with sequence similarity 73, member A (FAM73A) associated with subscapular skin-fold thickness in humans (rs4121165, GC-corrected p-value  = 0.0000175) and with backfat thickness in pigs (ASGA0029495, p-value  = 0.000031). Our combined association studies also suggest that eight neuronal genes are responsible for subcutaneous fat thickness: NEGR1, SLC44A5, PDE4B, LPHN2, ELTD1, ST6GALNAC3, ST6GALNAC5, and TTLL7. These results provide strong support for a major involvement of the CNS in the genetic predisposition to a common form of obesity.     

Functions of the orbitofrontal and pregenual cingulate cortex in taste, olfaction, appetite and emotion

Complementary neurophysiological recordings in macaques and functional neuroimaging in humans show that the primary taste cortex in the rostral insula and adjoining frontal operculum provides separate and combined representations of the taste, temperature, and texture (including viscosity and fat texture) of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in the orbitofrontal cortex, these sensory inputs are for some neurons combined by learning with olfactory and visual inputs. Different neurons respond to different combinations, providing a rich representation of the sensory properties of food. The representation of taste and other food-related stimuli in the orbitofrontal cortex of macaques is found from its lateral border throughout area 13 to within 7 mm of the midline, and in humans the representation of food-related and other pleasant stimuli is found particularly in the medial orbitofrontal cortex. In the orbitofrontal cortex, feeding to satiety with one food decreases the responses of these neurons to that food, but not to other foods, showing that sensory-specific satiety is computed in the primate (including human) orbitofrontal cortex. Consistently, activation of parts of the human orbitofrontal cortex correlates with subjective ratings of the pleasantness of the taste and smell of food. Cognitive factors, such as a word label presented with an odour, influence the pleasantness of the odour, and the activation produced by the odour in the orbitofrontal cortex. Food intake is thus controlled by building a multimodal representation of the sensory properties of food in the orbitofrontal cortex, and gating this representation by satiety signals to produce a representation of the pleasantness or reward value of food which drives food intake. A neuronal representation of taste is also found in the pregenual cingulate cortex, which receives inputs from the orbitofrontal cortex, and in humans many pleasant stimuli activate the pregenual cingulate cortex, pointing towards this as an important area in motivation and emotion.     

Do Obese Eat Faster Than Lean Subjects? Food Intake Studies in Pima Indian Men

Food intake rate has previously been derived from observation of eating behavior in laboratory settings or in public eating establishments. Although it has been suggested that obese individuals eat faster than lean individuals, observations of such an “obese eating style” have yielded mixed results. In the present study, the relationship between ad-libitum food intake rate and obesity was evaluated over 4 days on a metabolic ward in 28 healthy Pima Indian men (Mean ± SD; 29 ± 7 y, 100.4 ± 27.1 kg, 33 ± 10% body fat) using an automated food selection system containing a large variety of foods . Total energy intake averaged 18829 ± 3299 kJ/d consisting of 47 ± 4,40 ± 3, and 13 ± 1 percent of carbohydrate, fat and protein, respectively. The average meal duration was 25 ± 7 min. Food intake rate was 68 ± 21 g/min while carbohydrate, fat and protein intake rates were 23 ± 6, 9 ± 3 and 6 ± 2 g/min, respectively. Food intake rate correlated negatively with %body fat (1=0.61, P<0.01). Similar relationships were found between the intake rates of carbohydrate, fat and protein and body fatness. Only prospective studies will indicate whether a slow food intake rate may contribute to the etiology of obesity by possibly reducing satiety .     

Chloroplast membranes retard fat digestion and induce satiety: effect of biological membranes on pancreatic lipase/co-lipase

Human obesity is a global epidemic, which causes a rapidly increased frequency of diabetes and cardiovascular disease. One reason for obesity is the ready availability of refined food products with high caloric density, an evolutionarily new event, which makes over-consumption of food inevitable. Fat is a food product with high caloric density. The mechanism for regulation of fat intake has therefore been studied to a great extent. Such studies have shown that, as long as fat stays in the intestine, satiety is promoted. This occurs through the fat-released peptide hormones, the best known being CCK (cholecystokinin), which is released by fatty acids. Hence, retarded fat digestion with prolonged time for delivery of fatty acids promotes satiety. Pancreatic lipase, together with its protein cofactor, co-lipase, is the main enzymatic system responsible for intestinal fat digestion. We found that biological membranes, isolated from plants, animals or bacteria, inhibit the lipase/co-lipase-catalysed hydrolysis of triacylglycerols even in the presence of bile salt. We propose that the inhibition is due to binding of lipase/co-lipase to the membranes and adsorption of the membranes to the aqueous/triacylglycerol interface, thereby hindering lipase/co-lipase from acting on its lipid substrate. We also found that chloroplast membranes (thylakoids), when added to refined food, suppressed food intake in rats, lowered blood lipids and raised the satiety hormones, CCK and enterostatin. Consequently, the mechanism for satiety seems to be retardation of fat digestion allowing the fat products to stay longer in the intestine.     

Review: Effects of fibre,grain starch digestion rate and the ileal brake on voluntary feed intake in pigs

Grains rich in starch constitute the primary source of energy for both pigs and humans, but there is incomplete understanding of physiological mechanisms that determine the extent of digestion of grain starch in monogastric animals including pigs and humans. Slow digestion of starch to produce glucose in the small intestine (SI) leads to undigested starch escaping to the large intestine where it is fermented to produce short-chain fatty acids. Glucose generated from starch provides more energy than short-chain fatty acids for normal metabolism and growth in monogastrics. While incomplete digestion of starch leads to underutilised feed in pigs and economic losses, it is desirable in human nutrition to maintain consistent body weight in adults. Undigested nutrients reaching the ileum may trigger the ileal brake, and fermentation of undigested nutrients or fibre in the large intestine triggers the colonic brake. These intestinal brakes reduce the passage rate in an attempt to maximise nutrient utilisation, and lead to increased satiety that may reduce feed intake. The three physiological mechanisms that control grain digestion and feed intake are: (1) gastric emptying rate; (2) interplay of grain digestion and passage rate in the SI controlling the activation of the ileal brake; and (3) fermentation of undigested nutrients or fibre in the large intestine activating the colonic brake. Fibre plays an important role in influencing these mechanisms and the extent of their effects. In this review, an account of the physiological mechanisms controlling the passage rate, feed intake and enzymatic digestion of grains is presented: (1) to evaluate the merits of recently developed methods of grain/starch digestion for application purposes; and (2) to identify opportunities for future research to advance our understanding of how the combination of controlled grain digestion and fibre content can be manipulated to physiologically influence satiety and food intake.     

Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance

Energy intake and expenditure is a highly conserved and well-controlled system with a bias toward energy intake. In times of abundant food supply, individuals tend to overeat and in consequence to increase body weight, sometimes to the point of clinical obesity. Obesity is a disease that is not only characterized by enormous body weight but also by rising morbidity for diabetes type II and cardiovascular complications. To better understand the critical factors contributing to obesity we performed the present study in which the effects of energy expenditure and energy intake were examined with respect to body weight, localization of fat and insulin resistance in normal Wistar rats. It was found that a diet rich in fat and carbohydrates similar to "fast food" (cafeteria diet) has pronounced implication in the development of obesity, leading to significant body weight gain, fat deposition and also insulin resistance. Furthermore, an irregularly presented cafeteria diet (yoyo diet) has similar effects on body weight and fat deposition. However, these rats were not resistant to insulin, but showed an increased insulin secretion in response to glucose. When rats were fed with a specified high fat/carbohydrate diet (10% fat, 56.7% carbohydrate) ad lib or at the beginning of their activity phase they were able to detect the energy content of the food and compensate this by a lower intake. They, however, failed to compensate when food was given in the resting phase and gained more body weight as controls. Exercise, even of short duration, was able to keep rats on lower body weight and reduced fat deposition. Thus, inappropriate food intake with different levels of energy content is able to induce obesity in normal rats with additional metabolic changes that can be also observed in humans.     

The polymorphisms of UCP1 genes associated with fat metabolism,obesity and diabetes

Uncoupling protein 1 (UCP1), a 32-kDa protein located in the inner mitochondrial membrane, is abundant in brown adipose tissue, as a proton transporter in mitochondria inner membrane which uncouples oxidative metabolism from ATP synthesis and dissipates energy through the heat. UCP1 has been reported to play important roles for energy homeostasis in rodents and neonate of larger mammals including human. Recently, numerous candidate genes were searched to determine the genetic factors implicated in the pathogenesis of obesity, related metabolic disorders and diabetes. UCP-1, which plays a major role in thermogenesis, was suggested to be one of the candidates. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans, and the genetic variety association with the fat metabolism, obesity and diabetes.     

Genetics of fat tissue accumulation in pigs: a comparative approach

Fatness traits are important in pig production since they influence meat quality and fattening efficiency. On the other hand, excessive fat accumulation in humans has become a serious health problem due to worldwide spread of obesity. Since the pig is also considered as an animal model for numerous human diseases, including obesity and metabolic syndrome, comparative genomic studies may bring new insights into genetics of fatness/obesity. Input of genetic factors into phenotypic variability of these traits is rather high and the heritability coefficient (h ²) of these traits oscillates around 0.5. Genome scanning revealed the presence of more than 500 QTLs for fatness in the pig genome. In addition to QTL studies, many candidate gene polymorphisms have been analyzed in terms of their associations with pig fatness, including genes encoding leptin (LEP) and its receptor (LEPR), insulin-like growth factor 2 (IGF-2), fatty acid-binding proteins (FABP3 andFABP4), melanocortin receptor type 4 (MC4R), and theFTO (fat mass and obesity-associated) gene. Among them, a confirmed effect on pig fatness was found for a well-known polymorphism of theIGF-2 gene. In humans the strongest association with predisposition to obesity was shown for polymorphism of theFTO gene, while in pigs such an association seems to be doubtful. The development of functional genomics has revealed a large number of genes whose expression is associated with fat accumulation and lipid metabolism, so far not studied extensively in terms of the association of their polymorphism with pig fatness. Recently, epigenomic mechanisms, mainly RNA interference, have been considered as a potential source of information on genetic input into the fat accumulation process. The rather limited progress in studies focused on the identification of gene polymorphism related with fatness traits shows that their genetic background is highly complex.     

Identification of Sphingolipid Metabolites That Induce Obesity via Misregulation of Appetite,Caloric Intake and Fat Storage in Drosophila

Obesity is defined by excessive lipid accumulation. However, the active mechanistic roles that lipids play in its progression are not understood. Accumulation of ceramide, the metabolic hub of sphingolipid metabolism, has been associated with metabolic syndrome and obesity in humans and model systems. Here, we use Drosophila genetic manipulations to cause accumulation or depletion of ceramide and sphingosine-1-phosphate (S1P) intermediates. Sphingolipidomic profiles were characterized across mutants for various sphingolipid metabolic genes using liquid chromatography electrospray ionization tandem mass spectroscopy. Biochemical assays and microscopy were used to assess classic hallmarks of obesity including elevated fat stores, increased body weight, resistance to starvation induced death, increased adiposity, and fat cell hypertrophy. Multiple behavioral assays were used to assess appetite, caloric intake, meal size and meal frequency. Additionally, we utilized DNA microarrays to profile differential gene expression between these flies, which mapped to changes in lipid metabolic pathways. Our results show that accumulation of ceramides is sufficient to induce obesity phenotypes by two distinct mechanisms: 1) Dihydroceramide (C_14:0) and ceramide diene (C_14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) Modulating the S1P: ceramide (C_14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity.     

Effect of a protein preload on food intake and satiety feelings in response to duodenal fat perfusions in healthy male subjects

The control of food intake and satiety requires a coordinated interplay. Oral protein and duodenal fat inhibit food intake and induce satiety, but their interactive potential is unclear. Our aim was therefore to investigate the interactions between an oral protein preload and intraduodenal (ID) fat on food intake and satiety feelings. Twenty healthy male volunteers were studied in a randomized, double-blind, four-period crossover design. On each study day, subjects underwent one of the following treatments: 1) water preload plus ID saline perfusion, 2) water preload plus ID fat perfusion, 3) protein preload plus ID saline perfusion, or 4) protein preload plus ID fat perfusion. Subjects were free to eat and drink as much as they wished. An oral protein preload significantly reduced caloric intake (19%, P < 0.01). Simultaneous administration of an oral protein preload and ID fat did not result in a positive synergistic effect with respect to caloric consumption, rejecting the initial hypothesis that the two nutrients exert a positive synergistic effect on food intake. An oral protein preload but not ID fat altered the feelings of hunger and fullness. These data indicate that the satiety effect of an oral protein preload is not amplified by ID fat; indeed, the effect of a protein preload does not seem to be mediated by cholecystokinin, glucagon-like peptide-1, or peptide YY. Much more information is necessary to understand the basic physiological mechanisms that control food intake and satiety.     

Brain mechanisms underlying flavour and appetite

Complementary neurophysiological recordings in macaques and functional neuroimaging in humans show that the primary taste cortex in the rostral insula and adjoining frontal operculum provides separate and combined representations of the taste, temperature and texture (including viscosity and fat texture) of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in the orbitofrontal cortex, these sensory inputs are for some neurons combined by learning with olfactory and visual inputs. Different neurons respond to different combinations, providing a rich representation of the sensory properties of food. In the orbitofrontal cortex, feeding to satiety with one food decreases the responses of these neurons to that food, but not to other foods, showing that sensory-specific satiety is computed in the primate (including human) orbitofrontal cortex. Consistently, activation of parts of the human orbitofrontal cortex correlates with subjective ratings of the pleasantness of the taste and smell of food. Cognitive factors, such as a word label presented with an odour, influence the pleasantness of the odour and the activation produced by the odour in the orbitofrontal cortex. These findings provide a basis for understanding how what is in the mouth is represented by independent information channels in the brain; how the information from these channels is combined; and how and where the reward and subjective affective value of food is represented and is influenced by satiety signals. Activation of these representations in the orbitofrontal cortex may provide the goal for eating, and understanding them helps to provide a basis for understanding appetite and its disorders.     

Nutrigenomics: integrating genomic approaches into nutrition research

It has been suggested that the supermarket of today will be the pharmacy of tomorrow. Such statements have been derived from recognition of our increasing ability to optimize nutrition, and maintain a state of good health through longer periods of life. The new field of nutrigenomics, which focuses on the interaction between bioactive dietary components and the genome, recognizes that current nutritional guidelines may be ideal for only a relatively small proportion of the population. There is good evidence that nutrition has significant influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-protective dietary factors. For example, a significant number of human studies in various areas are increasing the evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various foods, will profoundly influence the effects of these genes. Identifying key SNPs that are likely to influence the health of an individual provides an approach to understanding and, ultimately, to optimizing nutrition at the population or individual level. Traditional methods for identification of SNPs may involve consideration of individual variants, using methodologies such as restriction fragment length polymorphisms or quantitative real-time PCR assays. New developments allow identification of up to 500,000 SNPs in an individual, and with increasingly lowered pricings these developments may explode the population-level potential for dietary optimization based on nutrigenomic approaches.     

Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety

Despite the prevalence of obesity and its related diseases, the signaling pathways for appetite control and satiety are not clearly understood. Here we report C. elegans quiescence behavior, a cessation of food intake and movement that is possibly a result of satiety. C. elegans quiescence shares several characteristics of satiety in mammals. It is induced by high-quality food, it requires nutritional signals from the intestine, and it depends on prior feeding history: fasting enhances quiescence after refeeding. During refeeding after fasting, quiescence is evoked, causing gradual inhibition of food intake and movement, mimicking the behavioral sequence of satiety in mammals. Based on these similarities, we propose that quiescence results from satiety. This hypothesized satiety-induced quiescence is regulated by peptide signals such as insulin and TGF-beta. The EGL-4 cGMP-dependent protein kinase functions downstream of insulin and TGF-beta in sensory neurons including ASI to control quiescence in response to food intake.     

Critical role for peptide YY in protein-mediated satiation and body-weight regulation

Dietary protein enhances satiety and promotes weight loss, but the mechanisms by which appetite is affected remain unclear. We investigated the role of gut hormones, key regulators of ingestive behavior, in mediating the satiating effects of different macronutrients. In normal-weight and obese human subjects, high-protein intake induced the greatest release of the anorectic hormone peptide YY (PYY) and the most pronounced satiety. Long-term augmentation of dietary protein in mice increased plasma PYY levels, decreased food intake, and reduced adiposity. To directly determine the role of PYY in mediating the satiating effects of protein, we generated Pyy null mice, which were selectively resistant to the satiating and weight-reducing effects of protein and developed marked obesity that was reversed by exogenous PYY treatment. Our findings suggest that modulating the release of endogenous satiety factors, such as PYY, through alteration of specific diet constituents could provide a rational therapy for obesity.