Body Composition and Energy Metabolism Following Roux‐en‐Y Gastric Bypass Surgery

Roux‐en‐Y gastric bypass (RYGB) surgery has become an accepted treatment for excessive obesity. We conducted a longitudinal study to assess regional body composition, muscle proteolysis, and energy expenditure before RYGB, and 6 and 12 months after RYGB. Whole‐body and regional fat mass (FM) and lean mass (LM) were assessed via dual energy X‐ray absorptiometry (DXA), and myofibrillar protein degradation was estimated by urinary 3‐methylhistidine (3‐MeH) in 29 subjects. Energy expenditure and substrate oxidation were also determined using a whole‐room, indirect calorimeter in 12 of these subjects. LM loss constituted 27.8 ± 10.2% of total weight loss achieved 12 months postoperatively, with the majority of LM loss (18 ± 6% of initial LM) occurring in the first 6 months following RYGB. During this period, the trunk region contributed 66% of whole‐body LM loss. LM loss occurred in the first 6 months after RYGB despite decreased muscle protein breakdown, as indicated by a decrease in 3‐MeH concentrations and muscle fractional breakdown rates. Sleep energy expenditure (SEE) decreased from 2,092 ± 342 kcal/d at baseline to 1,495 ± 190 kcal/day at 6 months after RYGB (P < 0.0001). Changes in both LM and FM had an effect on the reduction in SEE (P < 0.001 and P = 0.005, respectively). These studies suggest that loss of LM after RYGB is significant and strategies to maintain LM after surgery should be explored.     

Randomized double‐blind placebo‐controlled study of leptin administration after gastric bypass

Objective:

Obese individuals have high levels of circulating leptin and are resistant to the weight‐reducing effect of leptin administration at physiological doses. Although Roux‐en‐Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post‐RYGB patients would promote further weight reduction.

Design and Methods:

This was a randomized, double‐blind, placebo‐controlled cross‐over study of 27 women who were at least 18 months post‐RYGB and lost on average 30.8% of their presurgical body weight. Subjects received either leptin or placebo via subcutaneous injection twice daily for 16 weeks, then crossed over to receive the alternate treatment for 16 weeks.

Results:

Weight change after 16 weeks of placebo was not significantly different from that after 16 weeks of leptin. No changes were observed in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels.

Conclusion:

Contrary to our hypothesis, we did not observe a significant effect of leptin treatment on body weight in women with relative hypoleptinemia after RYGB.     

Development and Verification of a Mouse Model for Roux-en-Y Gastric Bypass Surgery with a Small Gastric Pouch

Existing mouse models of Roux-en-Y gastric bypass (RYGB) surgery are not comparable to human RYGB in gastric pouch volume for a large or absent gastric volume. The aim of this study was to develop and characterize a mouse RYGB model that closely replicates gastric pouch size of human RYGB surgery of about 5% of total gastric volume. We established this model in diet-induced obese (DIO) mice of C57BL/6J. This surgery resulted in a sustained 30% weight loss, entirely accounted for by decreased fat mass but not lean mass, compared to sham-operated mice on the high fat diet. Compared to sham-operated mice, energy expenditure corrected for total body weight was significantly increased by about 25%, and substrate utilization was shifted toward higher carbohydrate utilization at 8 weeks after RYGB when body weight had stabilized at the lower level. The energy expenditure persisted and carbohydrate utilization was even more pronounced when the mice were fed chow diet. Although significantly increased during daytime, overall locomotor activity was not significantly different. In response to cold exposure, RYGB mice exhibited an improved capacity to maintain the body temperature. In insulin tolerance test, exogenous insulin-induced suppression of plasma glucose levels was significantly greater in RYGB mice at 4 weeks after surgery. Paradoxically, food intake measured at 5 weeks after surgery was significantly increased, possibly in compensation for increased fecal energy loss and energy expenditure. In conclusion, this new model is a viable alternative to existing murine RYGB models and the model matches human RYGB surgery in anatomy. This model will be useful for studying molecular mechanisms involved in the beneficial effects of RYGB on body weight and glucose homeostasis.     

Interleukin‐15 Contributes to the Regulation of Murine Adipose Tissue and Human Adipocytes

An alarming global rise in the prevalence of obesity and its contribution to the development of chronic diseases is a serious health concern. Recently, obesity has been described as a chronic low‐grade inflammatory condition, influenced by both adipose tissue and immune cells suggesting proinflammatory cytokines may play a role in its etiology. Here we examined the effects of interleukin‐15 (IL‐15) on adipose tissue and its association with obesity. Over expression of IL‐15 (IL‐15tg) was associated with lean body condition whereas lack of IL‐15 (IL‐15^?/?) results in significant increase in weight gain without altering appetite. Interestingly, there were no differences in proinflammatory cytokines such as IL‐6 and tumor necrosis factor‐α (TNF‐α) in serum between the three strains of mice. In addition, there were significant numbers of natural killer (NK) cells in fat tissues from IL‐15tg and B6 compared to IL‐15^?/? mice. IL‐15 treatment results in significant weight loss in IL‐15^?/? knockout and diet‐induced obese mice independent of food intake. Fat pad cross‐sections show decreased pad size with over expression of IL‐15 is due to adipocyte shrinkage. IL‐15 induces weight loss without altering food consumption by affecting lipid deposition in adipocytes. Treatment of differentiated human adipocytes with recombinant human IL‐15 protein resulted in decreased lipid deposition. In addition, obese patients had significantly lower serum IL‐15 levels when compared to normal weight individuals. These results clearly suggest that IL‐15 may be involved in adipose tissue regulation and linked to obesity.     

An Endoluminal Sleeve Induces Substantial Weight Loss and Normalizes Glucose Homeostasis in Rats with Diet‐Induced Obesity

To investigate the contributions of two surgical gut manipulations—exclusion of the proximal intestine from alimentary flow and exposure of the jejunum to partially digested nutrients—to body weight regulation and metabolism, we have developed a rat model of an investigational device, the endoluminal sleeve (ELS). The ELS is a 10 cm, nutrient‐impermeable, flexible tube designed for endoluminal implantation. ELS devices were surgically implanted in the duodenal bulb of rats with diet‐induced obesity. Body weight, food intake, stool caloric content, and glucose homeostasis were subsequently evaluated. ELS‐implanted rats demonstrated a 20% reduction of body weight compared to sham‐operated (SO) controls. ELS‐treated animals consumed an average of 27% fewer kcal/day than SO, and there was no evidence of malabsorption. ELS treatment improved fasting glycemia and glucose tolerance after oral and intraperitoneal (IP) administration. ELS treatment enhanced insulin sensitivity, as demonstrated by decreased fasting and glucose‐stimulated insulin levels and confirmed by calculation of homeostasis model assessment of insulin resistance (IR). These data suggest that selective bypass of the proximal intestine by ELS, with enhanced delivery of partially digested nutrients to the jejunum, mimics many of the effects of Roux‐en‐Y gastric bypass (RYGB) on body weight and glucose metabolism. Thus, ELS implantation may be an effective treatment for obesity and diabetes. Since the ELS device is amenable to endoscopic placement, it may offer a valuable alternative to more invasive surgical approaches in selected patients with obesity and its metabolic complications.     

Using brown adipose tissue to treat obesity - the central issue

Current therapeutic strategies are proving inadequate to deal with growing obesity rates because of the inherent resistance of the human body to weight loss. The activation of human brown adipose tissue (BAT) represents an opportunity to increase energy expenditure and weight loss alongside improved lipid and glucose homeostasis. Research into the regulation of BAT has made increasing the thermogenic capacity of an individual to treat metabolic disease a plausible strategy, despite thermogenesis being under tight central nervous system control. Previous therapies targeted at the sympathetic nervous system have had deleterious effects because of a lack of organ specificity, but advances in our understanding of central BAT regulatory systems might open up better strategies to specifically stimulate BAT in obese individuals to aid weight reduction.     

The leptin sensitizer celastrol reduces age‐associated obesity and modulates behavioral rhythms

The prevalence of obesity increases with age in humans and in rodents. Age‐related obesity is characterized by leptin resistance and associated with heightened risk of metabolic disorders. However, the effect of leptin resistance per se has been difficult to disentangle from other effects of aging. Here we demonstrate that celastrol, a natural phytochemical that was previously shown to act as a leptin sensitizer, induces weight loss in aged animals, but not in young controls. Celastrol reduces food intake and lowers fasting glucose without affecting energy expenditure. Unexpectedly, administration of celastrol just before the dark period disrupted circadian rhythms of sleep and activity. This regimen was also associated with loss of lean mass an outcome that would not be desirable in elderly patients. Adjusting the timing of celastrol administration by 12 hr, to the beginning of the light period, avoided interference with circadian rhythms while retaining the reductions in body weight and adiposity. Thus, targeting leptin signaling is an effective strategy to ameliorate age‐associated weight gain, and can profoundly impact circadian rhythms.     

Self‐Selected Macronutrient Diet Affects Energy and Glucose Metabolism in Brown Fat‐Ablated Mice

Objective: Obese transgenic UCP‐DTA mice have largely ablated brown adipose tissue and develop obesity and diabetes, which are highly susceptible to a high‐fat diet. We investigated macronutrient self‐selection and its effect on development of obesity, diabetes, and energy homeostasis in UCP‐DTA mice. Research Methods and Procedures: UCP‐DTA and wild‐type littermates were fed a semisynthetic macronutrient choice diet (CD) ad libitum from weaning until 17 weeks. Energy homeostasis was assessed by measurement of food intake, food digestibility, body composition, and energy expenditure. Diabetes was assessed by blood glucose measurements and insulin tolerance test. Results: Wild‐type and UCP‐DTA mice showed a high fat preference and increased energy digestion on CD compared with a low‐fat standard diet. On CD, wild‐type mice accumulated less body fat (16.9%) than UCP‐DTA (32.6%) mice, although they had a higher overall energy intake. Compared with wild‐type mice, resting metabolic rate was reduced in UCP‐DTA mice irrespective of diet. UCP‐DTA mice progressively decreased their carbohydrate intake, resulting in an almost complete avoidance of carbohydrate. UCP‐DTA mice developed severe insulin resistance but showed decreased fed and fasted blood glucose on CD. Discussion: In contrast to wild‐type mice, UCP‐DTA mice were not able to reduce their weight gain efficiency on CD. This suggests that, because of the high fat preference of the background strain and the increased metabolic efficiency, brown adipose tissue‐deficient mice still develop obesity and insulin resistance on a macronutrient CD even when decreasing overall energy intake. Through the avoidance of carbohydrates, however, they are able to maintain normoglycemia.     

Diet‐Induced Changes in Stearoyl‐CoA Desaturase 1 Expression in Obesity‐Prone and ‐Resistant Mice

Objective: To investigate stearoyl‐coenzyme A desaturase (SCD) 1 expression in obesity‐prone C57BL/6 mice and in obesity‐resistant FVB mice to explore the relationship of SCD1 expression and susceptibility to diet‐induced obesity. Research Methods and Procedures: Nine‐week‐old C57BL/6 and FVB mice were fed either a high‐ or low‐fat diet for 8 weeks. Body weight and body composition were measured before and at weeks 4 and 8 of the study. Energy expenditure was measured at weeks 1 and 5 of the study. Hepatic SCD1 mRNA was measured at 72 hours and at the end of study. Plasma leptin and insulin concentrations were measured at the end of study. Results: When C57BL/6 mice were switched to a calorie‐dense high‐fat diet, animals gained significantly more body weight than those maintained on a low‐calorie density diet primarily due to increased fat mass accretion. Fat mass continued to accrue throughout 8 weeks of study. Increased calorie intake did not account for all weight gain. On the high‐fat diet, C57BL/6 mice decreased their energy expenditure when compared with mice fed a low‐fat diet. In response to 8 weeks of a high‐fat diet, SCD1 gene expression in liver increased >2‐fold. In contrast, feeding a high‐fat diet did not change body weight, energy expenditure, or SCD1 expression in FVB mice. Discussion: Our study showed that a high‐fat hypercaloric diet increased body adiposity first by producing hyperphagia and then by decreasing energy expenditure of mice susceptible to diet‐induced obesity. Consumption of a high‐fat diet in species predisposed to obesity selectively increased SCD1 gene expression in liver.     

Energy Expenditure and Oxygen Consumption as Novel Biomarkers of Obesity‐induced Cardiac Disease in Rats

The purpose of the present study was to determine calorimetric parameters to predict obesity adverse effects on oxidative stress and cardiac energy metabolism. Male Wistar 24 rats were divided into three groups (n = 8): given standard chow and water (C), receiving standard chow and 30% sucrose in its drinking water (S), and given sucrose‐rich diet and water (SRD). After 45 days, both S and SRD rats had obesity, serum oxidative stress, and dyslipidemic profile, but the body weight gain and feed efficiency (FE) were higher in SRD than in S, whereas the obesity‐related oxidative stress, myocardial triacylglycerol accumulation, and enhanced cardiac lactate dehydrogenase (LDH) activity were higher in S than in SRD rats. Myocardial β‐hydroxyacyl coenzyme‐A‐dehydrogenase was lower in SRD and in S than in C, whereas glycogen was only depleted in S rats. Myocardial pyruvate dehydrogenase (PDH) was lowest in S rats indicating depressed glucose oxidation. There was higher myocardial LDH/citrate synthase (CS) ratio and lower adenosine triphosphate (ATP)‐synthetase indicating delayed aerobic metabolism in S rats than in the others. Cardiac ATP‐synthetase was positively correlated with energy expenditure, namely resting metabolic rate (RMR), and with oxygen consumption per body weight (VO₂/body weight). Myocardial lipid hydroperoxide (LH)/ total antioxidant substances (TAS) ratio and triacylglycerol accumulation were negatively correlated with RMR and with VO₂/body weight. In conclusion, the present study brought new insights into obesity because the study demonstrated for the first time that reduced energy expenditure and oxygen consumption may provide novel risk factors of obesity‐induced reduced energy generation for myocardial contractile function. The results serve to highlight the role of calorimetric changes as novel biomarkers of risk to obesity‐induced cardiac effects.     

Profiling of Energy Metabolism in Olanzapine‐Induced Weight Gain in Rats and Its Prevention by the CB1‐Antagonist AVE1625

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1‐antagonist AVE1625 might attenuate OLZ‐induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ‐treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ‐treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ‐treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ‐induced weight gain. Combination of OLZ treatment with the CB1‐antagonist AVE1625 attenuated body weight gain in rats.     

A low‐glycemic diet lifestyle intervention improves fat utilization during exercise in older obese humans

Objective: To determine the influence of dietary glycemic index on exercise training‐induced adaptations in substrate oxidation in obesity. Design and Methods: Twenty older, obese individuals undertook 3 months of fully supervised aerobic exercise and were randomized to low‐ (LoGIX) or high‐glycemic (HiGIX) diets. Changes in indirect calorimetry (VO₂; VCO₂) were assessed at rest, during a hyperinsulinemic‐euglycemic clamp, and during submaximal exercise (walking: 65% VO₂max, 200 kcal energy expenditure). Intramyocellular lipid (IMCL) was measured by ¹H‐magnetic resonance spectroscopy. Results: Weight loss (?8.6 ± 1.1%) and improvements (P < 0.05) in VO₂max, glycemic control, fasting lipemia, and metabolic flexibility were similar for both LoGIX and HiGIX groups. During submaximal exercise, energy expenditure was higher following the intervention (P < 0.01) in both groups. Respiratory exchange ratio during exercise was unchanged in the LoGIX group but increased in the HiGIX group (P < 0.05). However, fat oxidation during exercise expressed in relation to changes in body weight was increased in the LoGIX group (+10.6 ± 3.6%; P < 0.05). Fasting IMCL was unchanged, however, extramyocellular lipid was reduced (P < 0.05) after LoGIX. Conclusions: A LoGIX/exercise weight‐loss intervention increased fat utilization during exercise independent of changes in energy expenditure. This highlights the potential therapeutic value of low‐glycemic foods for reversing metabolic defects in obesity.     

Peripheral Serotonin: a New Player in Systemic Energy Homeostasis

Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.     

Metabolic Determinants of Weight Gain in Humans

One of the fundamental challenges in obesity research is to identify subjects prone to weight gain so that obesity and its comorbidities can be promptly prevented or treated. The principles of thermodynamics as applied to human body energetics demonstrate that susceptibility to weight gain varies among individuals as a result of interindividual differences in energy expenditure and energy intake, two factors that counterbalance one another and determine daily energy balance and, ultimately, body weight change. This review focuses on the variability among individuals in human metabolism that determines weight change. Conflicting results have been reported about the role of interindividual differences in energy metabolism during energy balance in relation to future weight change. However, recent studies have shown that metabolic responses to acute, short‐term dietary interventions that create energy imbalance, such as low‐protein overfeeding or fasting for 24 hours, may reveal the underlying metabolic phenotype that determines the degree of resistance to diet‐induced weight loss or the propensity to spontaneous weight gain over time. Metabolically “thrifty” individuals, characterized by a predilection for saving energy in settings of undernutrition and dietary protein restriction, display a minimal increase in plasma fibroblast growth factor 21 concentrations in response to a low‐protein overfeeding diet and tend to gain more weight over time compared with metabolically “spendthrift” individuals. Similarly, interindividual variability in the causal relationship between energy expenditure and energy intake (“energy sensing”) and in the metabolic response to cold exposure (e.g., brown adipose tissue activation) seems, to some extent, to be indicative of individual propensity to weight gain. Thus, an increased understanding and the clinical characterization of phenotypic differences in energy metabolism among individuals (metabolic profile) may lead to new strategies to prevent weight gain or improve weight‐loss interventions by targeted therapies on the basis of metabolic phenotype and susceptibility to obesity in individual persons.     

The Short‐Term Effect of Diacylglycerol Oil Consumption on Total and Dietary Fat Utilization in Overweight Women

Diacylglycerol (DAG) is a natural component of edible oils with metabolic characteristics distinct from those of triacylglycerol (TAG). Consumption of DAG oil (containing >80% DAG) induces greater fat oxidation than consumption of TAG oil. We compared the effects of 4 days of DAG oil consumption with those of TAG oil consumption on total and dietary fat oxidation over 24 h in overweight women using a whole‐room respiratory chamber. Overweight (BMI (kg/m²) ≥25) females participated in this double‐blind, crossover‐controlled trial. The subjects consumed test diets containing either TAG or DAG oil as 15% of their total caloric intake (mean test oil intake was 33.0 ± 3.1 g/day) during each 4‐day treatment. Fat oxidation and energy expenditure were measured in a respiratory chamber on the 4th day of each treatment. Compared with TAG oil, DAG oil consumption significantly increased total fat oxidation and dietary fat oxidation in overweight subjects. Total energy expenditure (TEE) and carbohydrate (CHO) oxidation did not significantly differ between DAG oil and TAG oil consumption in overweight subjects. Compared with TAG oil, DAG oil consumption enhanced total fat oxidation and dietary fat oxidation in overweight subjects. The enhanced fat metabolism in overweight subjects that consumed DAG oil partly explains the greater loss of body weight and body fat related to DAG oil consumption in weight‐loss studies.     

An Obligate Role of Oxytocin Neurons in Diet Induced Energy Expenditure

Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways.     

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.