Abnormalities of Energy Expenditure and the Development of Obesity

The role of energy expenditure in the development of obesity remains unclear. This issue is examined using data from prospective studies of energy expenditure and obesity, the effects of overfeeding and diet composition on energy expenditure, and studies of the relationship between energy expenditure for physical activity and body composition. The combined results from these investigations strongly support the view that low energy expenditure can facilitate rapid weight gain in susceptible individuals. It is speculated that, in susceptible individuals, low energy expenditure for resting energy expenditure as well as physical activity are part of a range of mechanisms available for providing surplus energy for rapid weight gain. In addition, both cross-sectional and intervention studies indicate that there is an equilibration between the level of energy expenditure for physical activity and body fat content. While genetic and other factors clearly play an important role in this relationship, it appears that a modest reduction in body fat content can be achieved by increasing energy expenditure for physical activity in physical exercise programs.     

The Obesity Epidemic: A Consequence of Reduced Energy Expenditure and the Uncoupling of Energy Intake?

Obesity prevalence has increased, and increased energy intake or decreased physical activity are the two most obvious contributing factors. The percentage of Americans engaging in exercise has been stable over the past few decades, but decreases in occupation‐related energy expenditure are sufficient to partially explain increased obesity prevalence. Further, the contribution of energy intake and energy expenditure to the obesity epidemic is complicated because they are not independent—they are influenced by each other. For example, Mayer found that low activity levels were marked by higher body weight and higher “unregulated” energy intake levels. Conversely, higher activity levels were marked by lower body weight and energy intake that matched energy expenditure. Consistent with Mayer, we propose that because most Americans have low levels of occupation‐related activity, they do not benefit from the regulation of energy intake achieved at higher activity levels, resulting in weight gain due to energy intake exceeding energy expenditure.     

Genetic variation in brown fat activity and body weight regulation in mice: Lessons for human studies

The recent characterization of brown fat in humans has generated much excitement on the possibility that increased energy expenditure by heat production by this tissue will be able to reduce obesity. This expectation has largely been stimulated by studies with mice that show strong associations between increased brown fat activity and reductions in obesity and insulin resistance. Research in the mouse has been largely based upon the induction or suppression of brown fat and mitochondrial uncoupling protein by genetic methods. The review of this research literature underscores the idea that reductions in obesity in mice are secondary to the primary role of brown adipose tissue in the regulation of body temperature. Given that the variation in brown fat in humans, as detected by PET imaging, is highly associated with administration of adrenergic agonists and reductions in ambient temperature, the effects on obesity in humans may also be secondary to the regulation of body temperature. Induction of thermogenesis by reduced ambient temperature now becomes like muscle and physical activity, another natural method of increased energy expenditure to combat obesity. Furthermore, there is no evidence to indicate that heat production by adrenergic stimulation via cold exposure or drug treatment or the enriched physical environment is restricted to the thermogenic activity of the brown adipocyte.This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Protein kinase C-beta: An emerging connection between nutrient excess and obesity

There is currently a global epidemic of obesity as a result of recent changes in lifestyle. Excess body fat deposition is caused by an imbalance between energy intake and energy expenditure due to interactions between genetic and environmental factors. The signals and biological mechanisms that trigger fat accumulation by disrupting energy homeostasis are not well understood. There is considerable evidence now supporting a possible role of protein kinase C beta (PKCβ) in energy homeostasis. This review highlights recent findings on the role of PKCβ activation in the genesis and progression of obesity, and of PKCβ repression in mediating the beneficial effects of physical exercise. Available data support a model in which adipose PKCβ activation is among the initiating events that disrupt mitochondrial function through interaction with p66^shc and amplify fat accumulation and adipose dysfunction, with systemic consequences. Manipulation of PKCβ levels, activity, or signaling could provide a therapeutic approach to combat obesity and associated metabolic disorders.     

Physical inactivity and obesity: a vicious circle

Objective: Physical activity (PA) begins to decline in adolescence with a concomitant increase in weight. We hypothesized that a vicious circle may arise between decreasing PA and weight gain from adolescence to early adulthood. Methods and Procedures: PA and self‐perceived physical fitness assessed in adolescents (16–18 years of age) were used to predict the development of obesity (BMI ≥30 kg/m²) and abdominal obesity (waist ≥88 cm in females and ≥102 cm in males) at age 25 in 4,240 twin individuals (90% of twins born in Finland, 1975–1979). Ten 25‐year‐old monozygotic (MZ) twin pairs who were discordant for obesity (with a 16 kg weight difference) were then carefully evaluated for current PA (using a triaxial accelerometer), total energy expenditure (TEE, assessed by means of the doubly labeled water (DLW) method), and basal metabolic rate (BMR, assessed by indirect calorimetry). Results: Physical inactivity in adolescence strongly predicted the risk for obesity (odds ratio (OR) 3.9, 95% confidence interval (CI) 1.4–10.9) and abdominal obesity (4.8, 1.9–12.0) at age 25, even after adjusting for baseline and current BMI. Poor physical fitness in adolescence also increased the risk for overall obesity (5.1, 2.0–12.7) and abdominal obesity (3.2, 1.5–6.7) in adulthood. Physical inactivity was both causative and secondary to the development of obesity discordance in the MZ pairs. TEE did not differ between the MZ co‐twins. PA was lower whereas BMR was higher in the obese co‐twins. Discussion: Physical inactivity in adolescence strongly and independently predicts total (and especially) abdominal obesity in young adulthood, favoring the development of a self‐perpetuating vicious circle of obesity and physical inactivity. Physical activity should therefore be seriously recommended for obesity prevention in the young.     

Role of physical activity in preventing and treating obesity.

There is an inverse relationship between physical activity and weight gain. However, additional research is needed to quantify the amount of physical activity required to prevent weight gain in different populations, improve the way we convey physical activity recommendations to the public, and help the individuals increase their physical activity. Although physical activity does not appear to contribute significantly to weight loss, it is critical for maintenance of weight loss. Available data are consistent in that 60-90 min/day of moderate-intensity physical activity is required to maintain a significant weight loss. Although there is agreement about the need for high levels of physical activity to maintain weight loss, there is a need for more research to understand why physical activity is critical for weight loss maintenance. Finally, additional research is needed to determine whether there is an optimal level of physical activity below which it is difficult for most people to achieve a balance between energy intake and expenditure at a healthy body weight. The increasing prevalence of obesity may reflect the fact that the majority of the population has fallen below such a level of physical activity.     

Energy balance in exercise-trained rats acclimated at two environmental temperatures

The present study was carried out to investigate the effects of exercise training on energy balance in male rats acclimated at two different environmental temperatures. Sedimentary and exercised rats were housed and trained at either 24 or 4 degrees C, with the training program consisting of running on a motor-driven treadmill within their respective environments. After 45 days, energy, protein, and fat contents of rats were determined together with the energy content of food and feces. The results show that metabolizable energy intake was reduced by 10% in exercise-trained groups. Substantial differences in energy gains were observed between sedentary and trained rats; sedentary rats showed almost three times more energy gain than trained rats. Carcass analysis revealed the energy gain differences to be mainly due to varied amounts of fat deposition. Energy expenditure (kJ) excluding the cost of exercise training was corrected for metabolic body size (BW 0.75), which in turn showed no significant differences between trained rats and their respective sedentary controls. The present results suggested that exercise training in rats leads to neither increase nor decrease in energy expenditure through components additional to physical activity. The present results also indicated that brown adipose tissue thermogenesis, as assessed through mitochondrial guanosine 5'-diphosphate binding, was not significantly modified by exercise training, regardless of the temperature at which the rats were housed and trained.     

Low Resting and Sleeping Energy Expenditure and Fat Use Do Not Contribute to Obesity in Women

Objective: Determine whether sleeping and resting energy expenditure and sleeping, resting, and 24‐hour fuel use distinguish obesity‐prone from obesity‐resistant women and whether these metabolic factors explain long‐term weight gain. Research Methods and Procedures: Forty‐nine previously overweight but currently normal‐weight women were compared with 49 never‐overweight controls. To date, 87% of the 98 women have been re‐evaluated after 1 year of follow‐up, without intervention, and 38% after 2 years. Subjects were studied at a General Clinical Research Center after 4 weeks of tightly controlled conditions of energy balance and macronutrient intake. Forty‐nine obesity‐prone weight‐reduced women were group‐matched with 49 never‐overweight obesity‐resistant controls. All were premenopausal, sedentary, and normoglycemic. Energy expenditure and fuel use were assessed using chamber calorimetry. Body composition was assessed using DXA. Results: At baseline, percent body fat was not different between the obesity‐prone and control women (33 ± 4% vs. 32 ± 5%, respectively; p = 0.22). Analysis of covariance results show that after adjusting for lean and fat mass, sleeping and resting energy expenditure of obesity‐prone women was within 2% of controls. Neither sleeping nor resting energy expenditure nor sleeping, resting, or 24‐hour fuel use was significantly different between the groups (p > 0.25). None of the metabolic variables contributed significantly to patterns of weight gain at 1 or 2 years of follow‐up. Discussion: The results suggest that when resting and sleeping energy expenditure and fuel use are assessed under tightly controlled conditions, these metabolic factors do not distinguish obesity‐prone from obesity‐resistant women or explain long‐term weight changes.     

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.     

Impact of leucine on energy balance

Body weight is determined by the balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the surplus energy is stored as fat in the adipose tissue, which causes its expansion and may even lead to the development of obesity. Thus, there is a growing interest to develop dietary interventions that could reduce the current obesity epidemic. In this regard, data from a number of in vivo and in vitro studies suggest that the branched-chain amino acid leucine influences energy balance. However, this has not been consistently reported. Here, we review the literature related to the effects of leucine on energy intake, energy expenditure and lipid metabolism as well as its effects on the cellular activity in the brain (hypothalamus) and in peripheral tissues (gastro-intestinal tract, adipose tissue, liver and muscle) regulating the above physiological processes. Moreover, we discuss how obesity may influence the actions of this amino acid.     

Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis

Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptin-regulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences.     

Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.     

Impaired fat-induced thermogenesis in obese subjects: the NUGENOB study

Objectives: To study energy expenditure before and 3 hours after a high‐fat load in a large cohort of obese subjects (n = 701) and a lean reference group (n = 113). Research Methods and Procedures: Subjects from seven European countries underwent a 1‐day clinical study with a liquid test meal challenge containing 95% fat (energy content was 50% of estimated resting energy expenditure). Fasting and 3‐hour postprandial energy expenditures, as well as metabolites and hormones, were determined. Results: Obese subjects had a reduced postprandial energy expenditure after the high‐fat load, independent of body composition, age, sex, research center, and resting energy expenditure, whereas within the obese group, thermogenesis increased again with increasing BMI category. Additionally, insulin resistance, habitual physical activity, postprandial plasma triacylglycerols, and insulin were all independently positively related to the postprandial energy expenditure. Resting energy expenditure, adjusted for fat‐free mass, increased with degree of obesity, a difference that disappeared after adjustment for fat mass. Furthermore, insulin resistance, fasting plasma free fatty acids, and cortisol were positively associated, whereas fasting plasma leptin and insulin‐like growth factor‐1 were negatively associated, with resting energy expenditure. Discussion: The 3‐hour fat‐induced thermogenic response is reduced in obesity. It remains to be determined whether this blunted thermogenic response is a contributory factor or an adaptive response to the obese state.     

High and low activity rats: Elevated intrinsic physical activity drives resistance to diet‐induced obesity in non‐bred rats

Objective: Humans and rodents show large variability in their individual sensitivity to diet‐induced obesity (DIO), which has been associated with differences in intrinsic spontaneous physical activity (SPA). Evidence from genetic and out‐bred rat obesity models shows that higher activity of the orexin peptides results in higher intrinsic SPA and protection against DIO. Based on this, we hypothesized that naturally occurring variation in SPA and orexin signaling is sufficient to drive differences in sensitivity to DIO. Design and Methods: Orexin expression, behavioral responses to orexin‐A, basal energy expenditure and sensitivity to DIO were measured in in non‐manipulated male Sprague‐Dawley rats selected for high and low intrinsic SPA. Results: Male Sprague‐Dawley rats were classified as high‐activity or low‐activity based on differences in intrinsic SPA. High‐activity rats showed higher expression of prepro‐orexin mRNA, higher sensitivity to behavioral effects of orexin injection, higher basal energy expenditure and were more resistant to obesity caused by high‐fat diet consumption than low‐activity rats. Conclusion: Our results define a new model of differential DIO sensitivity, the high‐activity and low‐activity rats, and suggest that naturally occurring variations in intrinsic SPA cause differences in energy expenditure that are mediated by orexin signaling and alter DIO sensitivity.     

Size at birth, postnatal growth and risk of obesity

Epidemiological studies over the last 15 years have shown that size at birth, early postnatal catch-up growth and excess childhood weight gain are associated with an increased risk of adult cardiovascular disease and type 2 diabetes. At the same time, rising rates of obesity and overweight in children, even at pre-school ages, have shifted efforts towards the identification of very early factors that predict risk of subsequent obesity, which may allow early targeted interventions. Overall, higher birth weight is positively associated with subsequent greater body mass index in childhood and later life; however, the relationship is complex. Higher birth weight is associated with greater subsequent lean mass, rather than fat mass. In contrast, lower birth weight is associated with a subsequent higher ratio of fat mass to lean mass, and greater central fat and insulin resistance. This paradoxical effect of lower birth weight is at least partly explained by the observation that infants who have been growth restrained in utero tend to gain weight more rapidly, or 'catch up', during the early postnatal period, which leads to increased central fat deposition. There is still debate as to whether there are critical early periods for obesity: does excess weight gain during infancy, childhood or even very early neonatal life have a greater impact on long-term fat deposition and insulin resistance? Early identification of childhood obesity risk will be aided by identification of maternal and fetal genes that regulate fetal nutrition and growth, and postnatal genes that regulate appetite, energy expenditure and the partitioning of energy intake into fat or lean tissue growth.     

Dietary conjugated nonadecadienoic acid prevents adult-onset obesity in nescient basic helix–loop–helix 2 knockout mice

Conjugated linoleic acid (CLA) has been extensively studied during the last two decades with regard to its effects on controlling body composition. As a cognate to CLA, conjugated nonadecadienoic acid (CNA) has been previously reported to reduce body fat more effectively than CLA. However, it is not known whether CNA supplementation can influence adult-onset obesity. Thus, the purpose of this study was to evaluate the effects of dietary CNA on the prevention of adult-onset inactivity-induced obesity using nescient basic helix–loop–helix 2 knockout (N2KO) mice. CNA supplementation at 0.1 w/w% level starting in the preobese state significantly prevented the reduction of voluntary movement and the increase in weight gain in N2KO mice during the experimental period compared to wild-type animals. In both wild-type and N2KO mice, respiratory exchange ratio was significantly reduced by CNA treatment during light and dark cycles, and dietary CNA significantly increased energy expenditure in N2KO mice. Selected gene expression profiles in white adipose tissue, muscle or liver showed a beneficial action of CNA on lipid metabolism and energy expenditure. These findings suggest that CNA could prevent adult-onset obesity by enhancing voluntary activity and energy expenditure in N2KO mice.     

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.     

N-butylidenephthalide ameliorates high-fat diet-induced obesity in mice and promotes browning through adrenergic response/AMPK activation in mouse beige adipocytes

Thermogenesis (non-exercise activity) in brown adipose tissue (BAT) promotes energy expenditure because of its higher number of mitochondria than white adipose tissue (WAT). The main function of thermogenesis in BAT can counteract obesity through the dissipation of calories as heat. N-butylidenephthalide (BP) is a natural derivative from Angelica sinensis, a Chinese herb that has been used for thousands of years. In this report, we demonstrated that BP improved the metabolic profiles of mice with high fat diet-induced obesity (DIO) by preventing weight gain, improving serum blood parameters, enhancing energy expenditure, stimulating white fat browning, and reversing hepatic steatosis. Further investigations demonstrated that BP administration upregulated the mRNA expression of beige (CD137, TMEM26) and brown fat selected genes (UCP1, PRDM16, PGC-1α, PPARγ) in white adipose tissues. In vitro studies, BP treatment increased multilocular lipid droplet levels, induced β-adrenergic receptor (cAMP/PKA) and AMP-activated protein kinase (AMPK) signaling (AMPK/acetyl-CoA carboxylase/SIRT1), and increased oxygen consumption in murine differentiated beige adipocytes, and the effects of BP were blocked by an AMPK inhibitor. BP promoted the interaction of AMPK with PGC-1α in beige adipocytes. Our findings provide novel insights into the application of BP in regulating energy metabolism and suggest its utility for clinical use in the treatment of obesity and related diseases.     

Quantitative analysis of the energy requirements for development of obesity

OBJECTIVE: Obesity is typically developed over long time and reflected in an energy imbalance, which is too small to be measured and controlled. Our objective is to formulate a mathematical model for the relation between the change in body mass and the values of the energy intake and the energy expenditure, controlled by the physical activity factor PAF. DATA AND THEORY: The uncontrolled components of energy expenditure increases as result of body mass increase: expenditure of a larger mass and expenditure to convert matter in intake into tissue. Both contributions depend on the fraction of fat in the added tissue. Based on data from the literature, the fraction of fat in added tissue and the energy required to convert energy into tissue are estimated and included in the model. RESULTS: Application of the theory shows that an increase in body mass of 1 kg/year corresponds to an energy imbalance of 71 kJ/d for men. Of this imbalance, 82% are stored as new tissue, while 18% are used for energy conversion. If a man in steady state changes energy intake by 0.1 MJ/d, keeping the physical activity factor constant, then the corresponding increase in steady-state body mass is 1.77 kg/PAF, and it will take 320/PAF days before half the change of body mass has taken place. A typical value for PAF is 1.8. CONCLUSION: Energy-based theoretical relations between the various factors involved in energy balance help identifying and quantifying the components of the energy balance and understanding their relations during development of obesity. The inclusion of increased energy expenditure to convert food energy to tissue changes previous estimates of the energy imbalance by about 20 percent.     

Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity

Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity.