Obesity and the gut microbiota: does up-regulating colonic fermentation protect against obesity and metabolic disease?

Obesity is now considered a major public health concern globally as it predisposes to a number of chronic human diseases. Most developed countries have experienced a dramatic and significant rise in obesity since the 1980s, with obesity apparently accompanying, hand in hand, the adoption of "Western"-style diets and low-energy expenditure lifestyles around the world. Recent studies report an aberrant gut microbiota in obese subjects and that gut microbial metabolic activities, especially carbohydrate fermentation and bile acid metabolism, can impact on a number of mammalian physiological functions linked to obesity. The aim of this review is to present the evidence for a characteristic "obese-type" gut microbiota and to discuss studies linking microbial metabolic activities with mammalian regulation of lipid and glucose metabolism, thermogenesis, satiety, and chronic systemic inflammation. We focus in particular on short-chain fatty acids (SCFA) produced upon fiber fermentation in the colon. Although SCFA are reported to be elevated in the feces of obese individuals, they are also, in contradiction, identified as key metabolic regulators of the physiological checks and controls mammals rely upon to regulate energy metabolism. Most studies suggest that the gut microbiota differs in composition between lean and obese individuals and that diet, especially the high-fat low-fiber Western-style diet, dramatically impacts on the gut microbiota. There is currently no consensus as to whether the gut microbiota plays a causative role in obesity or is modulated in response to the obese state itself or the diet in obesity. Further studies, especially on the regulatory role of SCFA in human energy homeostasis, are needed to clarify the physiological consequences of an "obese-style" microbiota and any putative dietary modulation of associated disease risk.     

Obesity and post-prandial lipid metabolism. Feast or famine?

Both in Western countries and in third world countries there is an increasing incidence of obesity. Obesity per se or insulin resistance associated with obesity may increase cardiovascular risk factors including dyslipidemia, hypertension and Type 2 diabetes. Over the past decade the understanding has increased of specific mediators in the hypothalamus that are involved in regulating food intake and body weight. In obese humans fasting plasma lipids can be normal but postprandial lipid metabolism is abnormal with an accumulation of triglyceride-rich remnant lipoproteins. In viscerally obese men chylomicron remnant catabolism was markedly decreased when compared with lean individuals. The decreased clearance of chylomicron remnants in viscerally obese subjects may be explained by competition between chylomicron remnants and the increased hepatic production of VLDL for clearance by low density lipoprotein receptors. Increased food intake in rodent models of obesity was shown to be associated with a delay in the catabolism of remnant lipoprotein particles. Prevention of hyperphagia was found to correct the impairment in the metabolism of remnant lipoproteins. Under fasting and food restricted conditions the improvement of remnant metabolism was associated with an increased oxidation of remnant lipids as determined by a novel stable isotope breath test. Anti-obesity and lipid lowering drugs have been used for the treatment of obesity. Inhibitors of cholesterol synthesis inhibitors (statins) have been shown to be effective in treating dyslipidemia. Inhibition of cholesterol synthesis with Atorvastatin was shown to improve chylomicron metabolism by increasing chylomicron remnant catabolism in obese subjects as assessed by the newly developed stable isotope breath test.     

Effects of exercise on longevity of rats

It has been postulated that life span is inversely related to energy expenditure. If this is correct, regularly performed exercise could accelerate the aging process. In two early studies, exercise shortened the life span of rats; the results of these studies have been cited as evidence for the concept that an increase in energy expenditure accelerates aging. However, subsequent studies have not confirmed this finding. Instead, the weight of evidence now indicates that rats that exercise regularly have a longer average life span than sedentary, ad libitum-fed controls. Freely eating sedentary rats become obese, indicating that their food intake is in excess of their energy requirements. Available evidence seems compatible with the interpretation that exercise results in improved survival in rats by countering deleterious effects of a sedentary life combined with overeating.     

What Do We Most Need to Learn about Food Intake Regulation?

Many mechanisms are known to contribute to the regulation of food intake. This notwithstanding, variations in food intake from day to day and deviations from daily energy balance are substantial and very readily tolerated. Yet, despite this very loose short-term adjustment of food intake to energy expenditure, most adults maintain stable body compositions during long periods of their lives. This is particularly puzzling when it occurs in the face of an ubiquitous supply of appealing foods and under circumstances that, in many ways, promote food consumption. Thus, the question arises as to why people in affluent societies eat substantially less on most days, than the amounts that they can so readily consume on high-intake days? In addition to conscious decisions, physiological phenomena restraining food consumption must be presumed to play an important role in limiting weight. But what are the phenomena that cause spontaneous reduction in food intake after a few days of overeating? Our ignorance about the nature and impact of these effects stands in the way of a better understanding of body weight regulation and of the factors responsible for the induction and maintenance of obesity.     

The Association of Body Weight,Dietary Intake,and Energy Expenditure with Dietary Restraint and Disinhibition

LAWSON, OLGA J, DONALD A WILLIAMSON, CATHERINE M CHAMPAGNE, JAMES P DELANY, ELLEN R BROOKS, PAULA M HOWAT, PATRICIA J WOZNIAK, GEORGE A BRAY AND DONNA H RYAN. The association of body weight, dietary intake, and energy expenditure with dietary restraint and disinhibition. Obes Res. 1995;3:153–161. The hypotheses that dieting and/or overeating are associated with adiposity, eating disturbances, and lowered energy expenditure were tested in this study. A sample of 44 premenopausal women scoring high and low on measures of dietary restraint and disinhibition of dietary control, as measured by the Three Factor Eating Questionnaire, was studied. A 2 × 2 factorial design was employed (High/Low Restraint x High/Low Disinhibition). Dependent variables were: body composition, dietary intake, activity, resting metabolic rate, and thermic effect of food. Unrestrained overeaters (Low Restraint/High Disinhibition group) were very obese. High Dietary Restraint was associated with intent to diet and controlled eating. High scores on the Disinhibition Scale were associated with episodic overeating. Groups did not differ in resting metabolic rate (controlled for fat-free mass). Lower thermic effect of food was found to be associated with the obesity found in High Disinhibition subjects. Thus, Dietary Restraint was not associated with significant adverse effects upon physical or psychological health. High Disinhibition, however, was associated with adiposity and significant disturbances of eating.     

Food reward in the obese and after weight loss induced by calorie restriction and bariatric surgery

Increased availability of tasty, energy-dense foods has been blamed as a major factor in the alarmingly high prevalence of obesity, diabetes, and metabolic disease, even in young age. A heated debate has started as to whether some of these foods should be considered addictive, similar to drugs and alcohol. One of the main arguments for food addiction is the similarity of the neural mechanisms underlying reward generation by foods and drugs. Here, we will discuss how food intake can generate reward and how behavioral and neural reward functions are different in obese subjects. Because most studies simply compare lean and obese subjects, it is not clear whether predisposing differences in reward functions cause overeating and weight gain, or whether repeated exposure or secondary effects of the obese state alter reward functions. While studies in both rodents and humans demonstrate preexisting differences in reward functions in the obese, studies in rodent models using calorie restriction and gastric bypass surgery show that some differences are reversible by weight loss and are therefore secondary to the obese state.     

Measurement of ad libitum food intake, physical activity, and sedentary time in response to overfeeding

Given the wide availability of highly palatable foods, overeating is common. Energy intake and metabolic responses to overfeeding may provide insights into weight gain prevention. We hypothesized a down-regulation in subsequent food intake and sedentary time, and up-regulation in non-exercise activity and core temperature in response to overfeeding in order to maintain body weight constant. In a monitored inpatient clinical research unit using a cross over study design, we investigated ad libitum energy intake (EI, using automated vending machines), core body temperature, and physical activity (using accelerometry) following a short term (3-day) weight maintaining (WM) vs overfeeding (OF) diet in healthy volunteers (n?=?21, BMI, mean ± SD, 33.2±8.6 kg/m(2), 73.6% male). During the ad libitum periods following the WM vs. OF diets, there was no significant difference in mean 3-d EI (4061±1084 vs. 3926±1284 kcal/day, p?=?0.41), and there were also no differences either in core body temperature (37.0±0.2°C vs. 37.1±0.2°C, p?=?0.75) or sedentary time (70.9±12.9 vs. 72.0±7.4%, p?=?0.88). However, during OF (but not WM), sedentary time was positively associated with weight gain (r?=?0.49, p?=?0.05, adjusted for age, sex, and initial weight). In conclusion, short term overfeeding did not result in a decrease in subsequent ad libitum food intake or overall change in sedentary time although in secondary analysis sedentary time was associated with weight gain during OF. Beyond possible changes in sedentary time, there is minimal attempt to restore energy balance during or following short term overfeeding. Trial registration: ClinicalTrials.gov NCT00342732.     

WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling

Obesity is a metabolic disorder that results from an imbalance of energy intake and consumption. As low-grade chronic inflammation caused by obesity can lead to various complications, it is important to develop effective treatments against obesity. In this study, we investigate the effects of WKYMVm, a strong anti-inflammatory agent, against obesity. Administration of WKYMVm into high fat diet (HFD)-induced obese mice significantly attenuated body weight gain, food intake and increased insulin sensitivity. HFD-induced hepatic steatosis and adipose tissue hypertrophy were also markedly ameliorated by WKYMVm. During the maturation of adipocytes, WKYMVm improves lipid metabolism by increasing lipolysis, adipogenesis, mitochondrial biogenesis and fat browning. WKYMVm administration also elicited a decrease in leptin levels, but an increase in leptin sensitivity via regulation of hypothalamic endoplasmic reticulum stress and the leptin receptor cascade. Taken together, our results show that WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling, suggesting that WKYMVm can be a useful molecule for the development of anti-obesity agents.     

运动改善肥胖症瘦素抵抗及其机制研究进展

大部分肥胖患者体内出现瘦素抵抗,表现为血清瘦素水平异常升高,但机体对瘦素不敏感或无反应,使瘦素抑制食欲、增加能量消耗和降低血糖等功能不能有效发挥.减轻瘦素抵抗被认为是治疗肥胖及肥胖相关疾病的有效途径.运动减轻肥胖、改善糖脂代谢和增强胰岛素敏感性的作用与运动降低瘦素水平、改善瘦素抵抗密切相关.本文在概述瘦素实现生理功能的机制、肥胖症的中枢及外周瘦素抵抗的基础上,主要综述近年来运动减轻肥胖症瘦素抵抗机制的研究进展,包括减轻高瘦素血症、改善中枢和外周瘦素抵抗,以期为运动防治肥胖机制的研究提供新视角.     

Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.     

Cannabinoids in Eating Disorders and Obesity

Cannabinoid system is a crucial mechanism in regulating food intake and energy metabolism. It is involved in central and peripheral mechanisms regulating such behavior, interacting with many other signaling systems with a role in metabolic regulation. Cannabinoid agonists promote food intake, and soon a cannabinoid antagonist, rimonabant, will be marketed for the treatment of obesity. It not only causes weight loss, but also alleviates metabolic syndrome. We present a review of current knowledge on this subject, along with data from our own research: genetic studies on this system in eating disorders and obesity and studies locating cannabinoid receptors in areas related to food intake. Such studies suggest cannabinoid hyperactivity in obesity, and this excessive activity may have prognostic implications.     

Diabetes mellitus in the Pima Indians: genetic and evolutionary considerations

Non-insulin-dependent diabetes mellitus is a common disease in the Pima Indians. It is familial and strongly related to obesity. Neel (1962) suggested that the introduction of a steady food supply to people who have evolved a "thrifty genotype" leads to obesity, insulin resistance, and diabetes. Our findings in the Pimas of differences in insulin sensitivity in different metabolic pathways suggest that the thrifty genotype involves the ability of insulin to maintain fat stores despite resistance to glucose disposal. The recent increase in diabetes incidence following the availability of an abundant food supply suggests that the ability to store energy efficiently during cycles of feast and famine may now lead to obesity, insulin resistance, and diabetes.     

AMPK, an active player in the control of metabolism

Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.     

Food and emotion

The relationship between eating and emotion has always interested researchers of human behavior. This relationship varies according to the particular characteristics of the individual and according to the specific emotional state. We consider findings on the reciprocal interactions between, on the one hand, emotions and food intake, and, on the other, the psychological and emotional consequences of losing weight and dieting. Theories on the relationship between emotions and eating behaviors have their origin in the literature on obesity. The psychosomatic theory of obesity proposes that eating may reduce anxiety, and that the obese overeat in order to reduce discomfort. The internal/external theory of obesity hypothesizes that overweight people do not recognize physiological cues of hunger or satiety because of faulty learning. It thus predicts that normal weight people will alter (either increase or decrease) their eating when stressed, while obese people will eat regardless of their physiological state. The restraint hypothesis postulates that people who chronically restrict their food intake overeat in the presence of disinhibitors such as the perception of having overeaten, alcohol or stress. These theories are examined in the light of present research and their implications on eating disorders are presented.     

The Effects of Leptin Administration in Non‐obese Human Subjects

Objective: Body fatness is partly under hypothalamic control with effector limbs that include the endocrine system and the autonomic nervous system (ANS). In previous studies of both obese and never‐obese subjects, we have shown that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the effect of leptin, independent of weight change, on the ANS. Research Methods and Procedures: Normal weight males (ages 20–40 years) were fed a solid food diet, measured carefully to maintain body weight, for 3 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single‐blind, 22‐day, placebo/drug/placebo design, six subjects received leptin 0.3 mg/kilogram subcutaneously for 6 days. ANS measures of amount of parasympathetic control and sympathetic control of heart period (interbeat interval) were made by sequential pharmacological blockade with intravenous atropine and esmolol. Norepinephrine, dopamine, and epinephrine levels in 24‐hour urine collections were also measured as well as resting metabolic rate. Results: Sufficient food intake maintained constant body weight in all subjects. There was no evidence that leptin administration led to changes in energy metabolism sufficient to require additional food intake or to alter resting metabolic rate. Likewise, leptin administration did not alter autonomic activity. Parasympathetic control and sympathetic control, as well as the urinary catecholamines, were not significantly affected by leptin administration. Glucose and insulin levels were increased by food intake as expected, but leptin had no affect on these levels before or after food intake. Discussion: ANS responses to changes in energy metabolism found when food intake and body weight are altered were not found in these never‐obese subjects given leptin for 6 days. Although exogenous leptin administration has profound effects on food intake and energy metabolism in animals genetically deprived of leptin, we found it to have no demonstrable effect on energy metabolism in never‐obese humans. The effects of longer periods of administration to obese individuals and to those who have lost weight demand additional investigation.     

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.     

BMI Modulates Calorie-Dependent Dopamine Changes in Accumbens from Glucose Intake

Objective

Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight.

Method

We used positron emission tomography with [¹¹C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21–35).

Results

Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [¹¹C]raclopride) triggered by calorie intake (contrast glucose – sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine.

Conclusion

These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.     

Maintenance of weight loss in obese patients after jaw wiring.

In treatment of obesity restriction of food intake is necessary to achieve good results. Various operations have been devised to prevent patients overeating, but in this study jaw wiring was used to limit food intake. This procedure produces weight loss in obese patients but when the wires are removed the weight is usually regained. This report studied a group of patients whose weight loss was maintained after the wires were removed. A nylon cord fastened round the waist of the patient after weight reduction was found to act as a psychological barrier to weight gain. Seven patients were followed for 4-14 months after removal of jaw wires and regained a mean of only 5.6 kg of the 31.8 kg lost while their jaws were wired. This procedure compares favourably with other treatments for severe obesity.     

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.     

Role of food intake in estradiol-induced body weight changes in female rats

In two experiments, we examined the relationship between estradiol-induced undereating and body weight loss in ovariectomized (OVX) rats. In the first experiment, both estradiol benzoate (EB) and the nonsteroidal anti-estrogen, MER-25, produced body weight losses that could not be duplicated simply by pair-feeding. In the second experiment, we compared the effects of EB treatments in obese OVX rats and in OVX rats in which the post-OVX obesity was prevented by food restriction. When fed ad libitum, both groups of oil-treated OVX rats exhibited substantial body weight gains that were not accompanied by overeating. In lean OVX rats, EB treatments caused a transient hypophagia but did not reduce body weight. These results suggest three conclusions. (1) Changes in food intake are neither necessary nor sufficient to cause some of the body weight changes induced by ovarian hormones. (2) Estradiol can depress food intake in female rats without altering the regulated body weight. (3) More attention should be paid to metabolic factors when studying gonadal influences on body weight.