The Effects of Overfeeding on the Neuronal Response to Visual Food Cues in Thin and Reduced-Obese Individuals

Background

The regulation of energy intake is a complex process involving the integration of homeostatic signals and both internal and external sensory inputs. The objective of this study was to examine the effects of short-term overfeeding on the neuronal response to food-related visual stimuli in individuals prone and resistant to weight gain.

Methodology/Principal Findings

22 thin and 19 reduced-obese (RO) individuals were studied. Functional magnetic resonance imaging (fMRI) was performed in the fasted state after two days of eucaloric energy intake and after two days of 30% overfeeding in a counterbalanced design. fMRI was performed while subjects viewed images of foods of high hedonic value and neutral non-food objects. In the eucaloric state, food as compared to non-food images elicited significantly greater activation of insula and inferior visual cortex in thin as compared to RO individuals. Two days of overfeeding led to significant attenuation of not only insula and visual cortex responses but also of hypothalamus response in thin as compared to RO individuals.

Conclusions/Significance

These findings emphasize the important role of food-related visual cues in ingestive behavior and suggest that there are important phenotypic differences in the interactions between external visual sensory inputs, energy balance status, and brain regions involved in the regulation of energy intake. Furthermore, alterations in the neuronal response to food cues may relate to the propensity to gain weight.     

Serum Leptin Levels in Obese Males During Over‐ and Underfeeding

Leptin levels in lean adults vary in response to short‐term alterations in energy balance. We tested whether leptin responded to short‐term changes in energy balance in obese males in a similar manner to lean individuals. We enrolled eight obese, healthy males in a 12‐day study composed of four consecutive dietary treatment periods of 3 days each: baseline eucaloric feeding followed by randomized crossover periods of overfeeding (130% of total energy expenditure (TEE)) or underfeeding (70% of TEE), separated by a eucaloric (100% of TEE) washout period. We measured TEE with doubly labeled water prior to baseline. Leptin levels were measured throughout the third day of each treatment and 24‐h weighted averaged were calculated. Subjects' ad libitum intake during a breakfast buffet following each treatment period was recorded. During underfeeding, leptin levels decreased by 21 ± 6% (P < 0.01) from the previous eucaloric period. During overfeeding, leptin levels increased by 25 ± 11% (P < 0.01) when subjects were underfed first, but did not increase (5 ± 8%, nonsignificant (n.s.)) when subjects were overfed first. Changes in ad libitum intake from baseline were calculated for each subject after over‐, under‐, and eucaloric feeding and did not to correlate with the changes in mesor leptin levels from baseline (R² = 0.006, n.s). Leptin levels in obese males were acutely responsive to negative energy balance, but not to positive energy balance unless subjects were previously underfed. Consequently, leptin levels in obese males do not respond to changes in energy intake in a manner that would protect against weight gain.     

Spatially Distributed Effects of Mental Exhaustion on Resting-State FMRI Networks

Brain activity during rest is spatially coherent over functional connectivity networks called resting-state networks. In resting-state functional magnetic resonance imaging, independent component analysis yields spatially distributed network representations reflecting distinct mental processes, such as intrinsic (default) or extrinsic (executive) attention, and sensory inhibition or excitation. These aspects can be related to different treatments or subjective experiences. Among these, exhaustion is a common psychological state induced by prolonged mental performance. Using repeated functional magnetic resonance imaging sessions and spatial independent component analysis, we explored the effect of several hours of sustained cognitive performances on the resting human brain. Resting-state functional magnetic resonance imaging was performed on the same healthy volunteers in two days, with and without, and before, during and after, an intensive psychological treatment (skill training and sustained practice with a flight simulator). After each scan, subjects rated their level of exhaustion and performed an N-back task to evaluate eventual decrease in cognitive performance. Spatial maps of selected resting-state network components were statistically evaluated across time points to detect possible changes induced by the sustained mental performance. The intensive treatment had a significant effect on exhaustion and effort ratings, but no effects on N-back performances. Significant changes in the most exhausted state were observed in the early visual processing and the anterior default mode networks (enhancement) and in the fronto-parietal executive networks (suppression), suggesting that mental exhaustion is associated with a more idling brain state and that internal attention processes are facilitated to the detriment of more extrinsic processes. The described application may inspire future indicators of the level of fatigue in the neural attention system.     

The Effects of Overfeeding on Spontaneous Physical Activity in Obesity Prone and Obesity Resistant Humans

Despite living in an environment that promotes weight gain in many individuals, some individuals maintain a thin phenotype while self‐reporting expending little or no effort to control their weight. When compared with obesity prone (OP) individuals, we wondered if obesity resistant (OR) individuals would have higher levels of spontaneous physical activity (SPA) or respond to short‐term overfeeding by increasing their level of SPA in a manner that could potentially limit future weight gain. SPA was measured in 55 subjects (23 OP and 32 OR) using a novel physical activity monitoring system (PAMS) that measured body position and movement while subjects were awake for 6 days, either in a controlled eucaloric condition or during 3 days of overfeeding (1.4× basal energy) and for the subsequent 3 days (ad libitum recovery period). Pedometers were also used before and during use of the PAMS to provide an independent measure of SPA. SPA was quantified by the PAMS as fraction of recording time spent lying, sitting, or in an upright posture. Accelerometry, measured while subjects were in an upright posture, was used to categorize time spent in different levels of movement (standing, walking slowly, quickly, etc.). There were no differences in SPA between groups when examined across all study periods (P > 0.05). However, 3 days following overfeeding, OP subjects significantly decreased the amount of time they spent walking (?2.0% of time, P = 0.03), whereas OR subjects maintained their walking (+0.2%, P > 0.05). The principle findings of this study are that increased levels of SPA either during eucaloric feeding or following short term overfeeding likely do not significantly contribute to obesity resistance although a decrease in SPA following overfeeding may contribute to future weight gain in individuals prone to obesity.     

Brain orexin promotes obesity resistance

Resistance to obesity is becoming an exception rather than the norm, and understanding mechanisms that lead some to remain lean in spite of an obesigenic environment is critical if we are to find new ways to reverse this trend. Levels of energy intake and physical activity both contribute to body weight management, but it is challenging for most to adopt major long-term changes in either factor. Physical activity outside of formal exercise, also referred to as activity of daily living, and in stricter form, spontaneous physical activity (SPA), may be an attractive modifiable variable for obesity prevention. In this review, we discuss individual variability in SPA and NEAT (nonexercise thermogenesis, or the energy expended by SPA) and its relationship to obesity resistance. The hypothalamic neuropeptide orexin (hypocretin) may play a key role in regulating SPA and NEAT. We discuss how elevated orexin signaling capacity, in the context of a brain network modulating SPA, may play a major role in defining individual variability in SPA and NEAT. Greater activation of this SPA network leads to a lower propensity for fat mass gain and therefore may be an attractive target for obesity prevention and therapy.     

Default Mode Network Connectivity in Stroke Patients

The pathophysiology of episodic memory dysfunction after infarction is not completely understood. It has been suggested that infarctions located anywhere in the brain can induce widespread effects causing disruption of functional networks of the cortical regions. The default mode network, which includes the medial temporal lobe, is a functional network that is associated with episodic memory processing. We investigated whether the default mode network activity is reduced in stroke patients compared to healthy control subjects in the resting state condition. We assessed the whole brain network properties during resting state functional MRI in 21 control subjects and 20 ‘first-ever’ stroke patients. Patients were scanned 9–12 weeks after stroke onset. Stroke lesions were located in various parts of the brain. Independent component analyses were conducted to identify the default mode network and to compare the group differences of the default mode network. Furthermore, region-of-interest based analysis was performed to explore the functional connectivity between the regions of the default mode network. Stroke patients performed significantly worse than control subjects on the delayed recall score on California verbal learning test. We found decreased functional connectivity in the left medial temporal lobe, posterior cingulate and medial prefrontal cortical areas within the default mode network and reduced functional connectivity between these regions in stroke patients compared with controls. There were no significant volumetric differences between the groups. These results demonstrate that connectivity within the default mode network is reduced in ‘first-ever’ stroke patients compared to control subjects. This phenomenon might explain the occurrence of post-stroke cognitive dysfunction in stroke patients.     

Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers

Aquaporin 7 (AQP7) is an aquaglyceroprotein responsible for the secretion and uptake of glycerol from the adipocyte. The modulation of the expression of this membrane transport protein might play an important role in the susceptibility to the development of obesity. The aim of the present study was to compare the AQP7 gene expression in subcutaneous abdominal fat in lean vs. obese high fat intakers with a similar daily physical activity pattern. Twelve young men, 6 lean (BMI=23.2+/-0.4kg/m(2)) and 6 obese (35.0+/-1.1kg/m(2)) with a similar habitual dietary intake of fat (45.5+/-2.5 vs. 43.5+/-1.7% daily energy from fat for lean and obese, respectively) and physical activity (16.0+/-5.7 vs. 17.2+/-5.1 METsh/week for lean and obese, respectively), were recruited. Subcutaneous abdominal fat biopsies were obtained and total RNA was extracted and purified. Pools of RNA from lean and obese individuals were probed into Affymetrix GeneChip Human U133A. The microarray analysis revealed that AQP7 gene was down-regulated in obese compared to lean subjects. The results of the microarray analysis were confirmed by real-time PCR studies. In summary, our data show that the AQP7 gene is differentially expressed in adipose tissue of lean and obese individuals. The down-regulation of the AQP7 gene could be implicated in the susceptibility to obesity by reducing glycerol release and promoting the accumulation of lipids in the adipose tissue.     

The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects

Background

Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named “cerebral insulin resistance”, is responsible for overeating and the development of obesity.

Methodology/Principal Findings

To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category.Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects.

Conclusions/Significance

We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a “cerebral insulin resistance” in obese subjects and might be relevant in the pathogenesis of obesity.     

PEGylated neuromedin U-8 shows long-lasting anorectic activity and anti-obesity effect in mice by peripheral administration

Neuromedin U (NMU) is a neuropeptide found in the brain and gastrointestinal tract. The NMU system has been shown to regulate energy homeostasis by both a central and a peripheral mechanism. Peripheral administration of human NMU-25 was recently shown to inhibit food intake in mice. We examined the possibility that other NMU-related peptides exert an anorectic activity by intraperitoneal (i.p.) administration. We found that rat NMU-23 and its structurally-related peptide rat neuromedin S (NMS) significantly reduced food intake in lean mice, whereas NMU-8, an active fragment of the octapeptide sequence conserved in porcine, human and mouse NMU, had no effect. When rat NMU-23, NMU-8, and rat NMS were covalently conjugated to polyethylene glycol (PEG) (PEGylation) at the N-terminus of these peptides, PEGylated NMU-8 showed the most long-lasting and robust anorectic activity. The exploration of the linker between NMU-8 and PEG using hetero-bifunctional chemical cross-linkers led to an identification of PEGylated NMU-8 analogs with higher affinity for NMU receptors and with more potent anorectic activity in lean mice. The PEGylated NMU-8 showed potent and robust anorectic activity and anti-obesity effect in diet-induced obesity (DIO) mice by once-daily subcutaneous (s.c.) administration. These results suggest that PEGylated NMU-8 has the therapeutic potential for treatment of obesity.     

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 .     

Effect of the estrous cycle and surgical ovariectomy on energy balance, fuel utilization, and physical activity in lean and obese female rats

This study presents an in-depth analysis of the effects of obesity on energy balance (EB) and fuel utilization in adult female rats, over the estrous cycle and immediately after surgical ovariectomy (OVX), to model pre- and postmenopausal states, respectively. Female Wistar rats were fed a high-fat (46%) diet for 16 wk to produce mature lean and obese animals. Stage of estrous was identified by daily vaginal lavage, while energy intake (EI), total energy expenditure (TEE), and fuel utilization were monitored in a multichamber indirect calorimeter and activity was monitored by infrared beam breaks. Metabolic monitoring studies were repeated during the 3-wk period of rapid OVX-induced weight gain. Component analysis of TEE was performed to determine the nonresting and resting portions of energy expenditure. Obesity was associated with a greater fluctuation in EB across the estrous cycle. Cycling obese rats were less active, expended more energy per movement, and oxidized more carbohydrate than lean rats. The changes in EB over the cycle in lean and obese rats were driven by changes in EI. Finally, OVX induced a large positive energy imbalance in obese and lean rats. This resulted primarily from an increase in EI in both groups, with little change in TEE following OVX. These observations reveal a dominant effect of obesity on EB, fuel utilization, and activity levels in cycling rats, which has implications for studies focused on obesity and EB in female rodents.     

Physical activity and body functionality: implications for obesity prevention and treatment

Physical activity promotes metabolic adaptations that improve body functionality and contribute to the prevention of some diseases. With respect to energy and fat balance, physical activity facilitates the equilibrium between energy intake and expenditure as well as between fat intake and fat oxidation. When combined with a healthy diet that favors satiety with a reduced energy intake, exercise can induce a substantial mass loss in obese individuals. However, even the impact of an exemplary lifestyle does not seem to have the potential to decrease body mass in obese individuals down to the mass range of lean people. Up to now, we have not been able to induce mass changes exceeding 12%-15% initial body mass in obese male subjects under tolerable exercise and dietary habits, and this moderate success was accompanied by modifications in appetite and energy expenditure susceptible to compromise subsequent mass stability. As described in this paper, many environmental factors can influence energy balance and the ability to lose body fat in response to a healthy diet and (or) physical activity program. Particular attention is given to preliminary data obtained in our laboratory that suggest that knowledge-based work does not favor the same potential mass reducing effects as physical work. In fact, the acute effects of knowledge-based work suggest that this work modality may be rather susceptible to promote a more pronounced positive energy balance compared with what we may expect from a sedentary relaxing activity. This is problematic for obesity prevention in the future since knowledge-based work now represents the main working modality in a context of modernity.     

The Pig as a Model for the Study of Obesity and of Control of Food Intake: A Review

The use of the pig for studies of food intake and obesity is reviewed. Effects of ambient temperature and taste on food intake as well as satiety factors impicating both neural and hormonal mechanisms originating in the gastrointestinal tract are considered; the integration of information in the central nervous system for both internal and external sources is hypothesized. Special concerns of food intake controls in the neonate are discussed, including effects of neonate sweet preference on food intake, gastrointestinal satiety factors, and hypoglycemia as a stimulus for food ingestion.For obesity studies, pigs offer several advantages, including their general physiological similarity to humans, similar fat cell size, and body fat distribution. Lipogenesis, lipolysis, and lipid mobilization are under intensive study in swine and the information obtained may have important application in studies of human obesity. The voluminous literature on metabolic differences between genetically lean versus obese populations of pigs suggests possibilities for application in humans. Greater characterization of differences and similarities between pigs and humans in important metabolic parameters related to regulation of food intake and obesity should facilitate better understanding and control of human obesity.     

Factor structure of regional cerebral blood flow and glucose metabolism rate as a tool to study the default mode of the brain

The functional connectivity of anatomical and functional brain structures in the state of operational rest was assessed on the basis of positron emission tomography (PET) data to study the so-called default mode of the brain, i.e., the brain’s spontaneous activity at rest. It is concluded that the possibility of identifying neuroanatomical systems of the default mode (default mode network) in routine clinical PET studies of the cerebral blood flow and glucose metabolism is important for studying the functional organization of the brain in the normal state and its rearrangements in pathologies.     

Peripheral-specific y2 receptor knockdown protects mice from high-fat diet-induced obesity

Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone. These changes occur in association with significant increases in energy expenditure, respiratory exchange ratio, and physical activity and despite concurrent hyperphagia. On a chow diet, knockdown of peripheral Y2 receptors results in increased respiratory exchange ratio and physical activity with no effect on lean or bone mass, but decreases energy expenditure without effecting body weight or food intake. These results suggest that peripheral Y2 receptor signaling is critical in the regulation of oxidative fuel selection and physical activity and protects against the diet-induced obesity. The lack of effects on bone mass seen in this model further indicates that bone mass is primarily controlled by non-peripheral Y2 receptors. This study provides evidence that novel drugs that target peripheral rather than central Y2 receptors could provide benefits for the treatment of obesity and glucose intolerance without adverse effects on lean and bone mass, with the additional benefit of avoiding side effects often associated with pharmaceuticals that act on the central nervous system.     

Gastric Motor and Sensory Functions in Obesity

In the vast majority of affected individuals, obesity involves overconsumption of food relative to calorie requirements. The sensory function of the stomach may play a key role in the cessation of food ingestion. This sensation of the stomach is, in part, determined by its motor functions, such as tone and compliance and the rate of emptying. However, studies of gastric emptying in normal‐weight and obese persons have shown inconsistent results. Gastric capacity was larger in obese persons when tested with an intragastric latex balloon filled with water. In contrast, other studies using the barostat or imaging (single‐photon emission computed tomography) techniques reported no differences in gastric volume or compliance between obese and lean subjects. On the other hand, increased body mass and fasting gastric volume are independently associated with delayed satiation under standard laboratory conditions of food ingestion. These data suggest that changes in gastric motor and sensory functions in obesity may present useful targets to prevent and treat obesity. Further well‐controlled, validated studies are needed to clarify the potential role of altering the stomach's function as a means of controlling food intake in obesity.     

The Obesity Epidemic: Metabolic Imprinting on Genetically Susceptible Neural Circuits

The apparent obesity epidemic in the industrialized world is not explained completely by increased food intake or decreased energy expenditure. Once obesity develops in genetically predisposed individuals, their obese body weight is avidly defended against chronic caloric restriction. In animals genetically predisposed toward obesity, there are multiple abnormalities of neural function that prime them to become obese when dietary caloric density and quantity are raised. Once obesity is fully developed, these abnormalities largely disappear. This suggests that obesity might be the normal state for such individuals. Formation of new neural circuits involved in energy homeostasis might underlie the near permanence of the obese body weight. Such neural plasticity can occur during both nervous system development and in adult life. Maternal diabetes, obesity, and undernutrition have all been associated with obesity in the offspring of such mothers, especially in genetically predisposed individuals. Altered brain neural circuitry and function often accompanies such obesity. This enhanced obesity may then be passed on to subsequent generations in a feed‐forward, upward spiral of increasing body weight across generations. Such findings suggest a form of “metabolic imprinting” upon genetically predisposed neural circuits involved in energy homeostasis. Centrally acting drugs used for obesity treatment lower the defended body weight and alter the function of neural pathways involved in energy homeostasis. But they generally have no permanent effect on body weight or neural function. Thus, early identification of obesity‐prone mothers, infants, and adults and treatment of early obesity may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals.     

基于ICA的颞叶癫痫缺省模式网络的研究

很多fMRI研究表明部分癫痫患者缺省模式网络存在中断现象,但均采用广义线性模型的假设驱动方法。作者尝试运用独立成分分析（independent component analysis, ICA）分离出l5例单侧颞叶癫痫（temporal lobe epilepsy,TLE）患者和17例正常对照的缺省模式网络,并采用拟合度值（goodness-of-fit scores）分析对感兴趣成分进行挑选,将其结果进行组内分析和组间分析。结果表明颞叶癫痫患者的缺省模式网络犬部分区域功能连接度下降,以前额叶和同侧颞上回为著,这可能是由于颞叶癫痫患者的大脑功能内源性组织发生破坏所致。拟合度值下降表明缺省模式网络激活区域为单侧TLE患者提供了一个灵敏的生物信号特征。     

Intracellular and computational evidence for a dominant role of internal network activity in cortical computations

The mammalian cerebral cortex is characterized by intense spontaneous activity, depending on brain region, age, and behavioral state. Classically, the cortex is considered as being driven by the senses, a paradigm which corresponds well to experiments in quiescent or deeply anesthetized states. In awake animals, however, the spontaneous activity cannot be considered as 'background noise', but is of comparable-or even higher-amplitude than evoked sensory responses. Recent evidence suggests that this internal activity is not only dominant, but also it shares many properties with the responses to natural sensory inputs, suggesting that the spontaneous activity is not independent of the sensory input. Such evidence is reviewed here, with an emphasis on intracellular and computational aspects. Statistical measures, such as the spike-triggered average of synaptic conductances, show that the impact of internal network state on spiking activity is major in awake animals. Thus, cortical activity cannot be considered as being driven by the senses, but sensory inputs rather seem to modulate and modify the internal dynamics of cerebral cortex. This view offers an attractive interpretation not only of dreaming activity (absence of sensory input), but also of several mental disorders.