Delivery of alpha-tocopherol through soluble dietary fibre-based nanofibres for improving the life span of Caenorhabditis elegans.

The effect of alpha-tocopherol (α-TOC) delivered by soluble dietary fibre-based nanofibres (α-TOC-SDNF) on the life span of nematode Caenorhabditis elegans N2 (wild type) and TK22 (mev-1 mutants) with and without heat shock was investigated. Without heat shock, the wild-type and mev-1 mutants maintained in the 100 µg/mL of α-TOC-SDNF had longer life spans than their respective blank control groups. With heat shock, the wild-type N2 in the 200 µg/mL of α-TOC-SDNF had a survival rate of 5% at day 49, while no nematodes survived in the blank control group. An increased pharyngeal pumping rate was observed in the α-TOC-SDNF treated mev-1 mutants worms compared to the blank control group. Encapsulating α-TOC in SDNF yielded protective effects and the life span and pumping rate of C. elegans was increased with α-TOC delivered by SDNF.

Pomegranate juice and extract extended lifespan and reduced intestinal fat deposition in Caenorhabditis elegans.

Pomegranate juice with a high content of polyphenols, pomegranate extract, ellagic acid, and urolithin A, have anti-oxidant and anti-obesity effects in humans. Pomegranate juice extends lifespan of Drosophila melanogaster. Caenorhabditis elegans (C. elegans) (n = 6) compared to the control group in each treatment, lifespan was increased by pomegranate juice in wild type (N2, 56 %, P < 0.001) and daf-16 mutant (daf-16(mgDf50)I) (18 %, P = 0.00012), by pomegranate extract in N2 (28 %, P = 0.00004) and in daf-16(mgDf50)I (10 %, P < 0.05), or by ellagic acid (11 %, P < 0.05). Pomegranate juice reduced intestinal fat deposition (IFD) in C. elegans (n = 10) N2 (-68 %, P = 0.0003) or in the daf-16(mgDf50)I (-33 %, P = 0.0034). The intestinal fat deposition was increased by pomegranate extract in N2 (137 %, P < 0.0138) and in daf-16(mgDf50)I (26 %, P = 0.0225), by ellagic acid in N2 (66 %, P < 0.0001) and in daf-16(mgDf50)I (74 %, P < 0.0001), or by urolithin A in N2 (57 %, P = 0.0039) and in daf-16(mgDf50)I (43 %, P = 0.0001). These effects were partially mediated by the daf-16 pathway. The data may offer insights to human aging and obesity due to homology with C. elegans.

Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development.

The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine-olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 µg/mL) increased the IFD (12.1 ± 0.1%, P < 0.02), which was blocked by betahistine (763 µg/mL, 39.3 ± 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions.

Quantitative Comparison of 2 Dual-Energy X-ray Absorptiometry Systems in Assessing Body Composition and Bone Mineral Measurements.

Dual-energy X-ray absorptiometry (DXA) is widely used in body composition measurement and evaluation. Because of its numerous applications, the probability of instrument discrepancies has increased dramatically. This study quantitatively compares 2 different DXA systems. In this study, 96 subjects (60 female and 36 male, aged 19-82 years) were recruited and scanned using a General Electric Lunar iDXA and a Hologic Discovery scanner. Four measurements (percent fat, total mass, bone mineral density [BMD], and bone mineral content [BMC]) were quantitatively compared in the whole body and in specific anatomic regions (arms, legs, trunk, android, gynoid, head, ribs, and pelvis). A simple linear regression of each measurement was performed to examine the correlation between the 2 systems. Percent fat, total mass, BMC, and BMD were highly correlated between the 2 DXA systems, with correlation r values greater than 0.854 for both the whole body and the individual anatomic regions except for BMC and BMD in ribs. The high correlation between the 2 DXA systems with systematic differences enabled development of calibration equations for extending the multisystem measurements to advanced quantitative analyses.

Muscle Echogenicity and Changes Related to Age and Body Mass Index.

INTRODUCTION: Muscle fibers are lost and replaced by fat- and fibrous-tissue infiltration during aging. This process decreases muscle quality and influences tissue appearance on ultrasound images over time. Increased muscle "echogenicity" represents changes caused by fat- and fibrous-tissue infiltration and can be quantified with recently developed software. OBJECTIVE: To investigate skeletal muscle quality through echogenicity, estimates according to participant's body mass index (BMI) and age were taken. METHODS: This was a cross-sectional study performed at the Pennington Biomedical Research Center, Baton Rouge, Louisiana with 117 participants (57 men and 60 women), with mean age (±SD) 38.9 ± 17.0 years and BMI 28.6 ± 6.2 kg/m². All participants were examined by ultrasound (LOGIQ GE Healthcare), using a 5.0-MHz linear transducer. Participants had muscle thickness measured by ultrasound at 4 anatomic locations (biceps and triceps brachial, femoral quadriceps, and calf triceps). Echogenicity was analyzed with specific software (Pixel Health) that evaluated the image in gray scale. RESULTS: According to BMI, 41% of participants were obese. There was a positive correlation between age and thigh-muscle echogenicity (rp = 0.534, P < .0001) and a negative correlation between thigh-muscle echogenicity and thickness (rp = -0.395, P <.0001). There was high muscle echogenicity in participants with overweight and obesity aged 50 years or older (P < .05). CONCLUSION: Older age and higher BMI were associated with stronger echogenicity signals and smaller muscle thickness. People with overweight, obesity, and/or older than 50 years old have reduced muscle quality with smaller muscle thickness, as observed with ultrasound.

Caenorhabditis elegans: A Convenient In Vivo Model for Assessing the Impact of Food Bioactive Compounds on Obesity, Aging, and Alzheimer's Disease.

Caenorhabditis elegans is a small free-living nematode that lives in temperate soil environments. It has been widely employed as an animal model in research involving obesity, aging, and neurodegenerative diseases, including Alzheimer's disease, because of its various advantages, such as small size, large number of progeny, completely sequenced genome, and short life span, over traditional animal models of vertebrates. These benefits contribute to an ideal research model organism. In this review, we provide an introduction to C. elegans and its applications in obesity, aging, and Alzheimer's disease studies, with the aim of stimulating scientists to use C. elegans as an experimental model in various fields of research.

Lower Doses of Fructose Extend Lifespan in Caenorhabditis elegans.

Epidemiological studies indicate that the increased consumption of sugars including sucrose and fructose in beverages correlate with the prevalence of obesity, type-2 diabetes, insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension in humans. A few reports suggest that fructose extends lifespan in Saccharomyces cerevisiae. In Anopheles gambiae, fructose, glucose, or glucose plus fructose also extended lifespan. New results presented here suggest that fructose extends lifespan in Caenorhabditis elegans (C. elegans) wild type (N2). C. elegans were fed standard laboratory food source (E. coli OP50), maintained in liquid culture. Experimental groups received additional glucose (111 mM), fructose (55 mM, 111 mM, or 555 mM), sucrose (55 mM, 111 mM, or 555 mM), glucose (167 mM) plus fructose (167 mM) (G&F), or high fructose corn syrup (HFCS, 333 mM). In four replicate experiments, fructose dose-dependently increased mean lifespan at 55 mM or 111 m Min N2, but decreased lifespan at 555 mM (P < 0.001). Sucrose did not affect the lifespan. Glucose reduced lifespan (P < 0.001). Equal amount of G&F or HFCS reduced lifespan (P < 0.0001). Intestinal fat deposition (IFD) was increased at a higher dose of fructose (555 mM), glucose (111 mM), and sucrose (55 mM, 111 mM, and 555 mM). Here we report a biphasic effect of fructose increasing lifespan at lower doses and shortening lifespan at higher doses with an inverse effect on IFD. In view of reports that fructose increases lifespan in yeast, mosquitoes and now nematodes, while decreasing fat deposition (in nematodes) at lower concentrations, further research into the relationship of fructose to lifespan and fat accumulation in vertebrates and mammals is indicated.

Dietary Plant Lectins Appear to Be Transported from the Gut to Gain Access to and Alter Dopaminergic Neurons of Caenorhabditis elegans, a Potential Etiology of Parkinson's Disease.

Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N) in transgenic Caenorhabditis elegans (C. elegans) [egIs1(Pdat-1:GFP)] where the mutant has the green fluorescent protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic-N. The lectins were supplemented along with the food organism Escherichia coli (OP50). Among nine tested rhodamine/TRITC-tagged lectins, four, including Phaseolus vulgaris erythroagglutinin (PHA-E), Bandeiraea simplicifolia (BS-I), Dolichos biflorus agglutinin (DBA), and Arachis hypogaea agglutinin (PNA), appeared to be transported from gut to the GFP-DAergic-N. Griffonia Simplicifolia and PHA-E, reduced the number of GFP-DAergic-N, suggesting a toxic activity. PHA-E, BS-I, Pisum sativum (PSA), and Triticum vulgaris agglutinin (Succinylated) reduced fluorescent intensity of GFP-DAergic-N. PHA-E, PSA, Concanavalin A, and Triticum vulgaris agglutinin decreased the size of GFP-DAergic-N, while BS-I increased neuron size. These observations suggest that dietary plant lectins are transported to and affect DAergic-N in C. elegans, which support Braak and Hawkes' hypothesis, suggesting one alternate potential dietary etiology of Parkinson's disease (PD). A recent Danish study showed that vagotomy resulted in 40% lower incidence of PD over 20 years. Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model.

Mobile evaluation of human energy balance and weight control: Potential for future developments.

Quantification of energy storage is essential in understanding energy balance and can be determined by bioelectrical impedance analysis (BIA). Here, we have developed a smartphone form factor multi-frequency BIA device that incorporates an analog front end for body composition measurements. The device was compared against a reference gel-electrode based BIA system in a clinical trial of 311 subjects for predicting BIA equations by calibrating the impedance index to body composition data from dual energy X-ray absorptiometry (DXA). Strong correlations were observed between DXA-based lean soft tissue and the impedance index generated at 50 KHz (R(2)=0.87; p<;0.001). A similar trend was also evident at higher frequencies which matched results from the reference gel-electrode BIA device. The findings support the role of our consumer-oriented mobile Health initiative for multi-frequency BIA assessments to aid weight management.

Skeletal muscle mass and quality: evolution of modern measurement concepts in the context of sarcopenia.

The first reports of accurate skeletal muscle mass measurement in human subjects appeared at about the same time as introduction of the sarcopenia concept in the late 1980s. Since then these methods, computed tomography and MRI, have been used to gain insights into older (i.e. anthropometry and urinary markers) and more recently developed and refined methods (ultrasound, bioimpedance analysis and dual-energy X-ray absorptiometry) of quantifying regional and total body skeletal muscle mass. The objective of this review is to describe the evolution of these methods and their continued development in the context of sarcopenia evaluation and treatment. Advances in these technologies are described with a focus on additional quantifiable measures that relate to muscle composition and 'quality'. The integration of these collective evaluations with strength and physical performance indices is highlighted with linkages to evaluation of sarcopenia and the spectrum of related disorders such as sarcopenic obesity, cachexia and frailty. Our findings show that currently available methods and those in development are capable of non-invasively extending measures from solely 'mass' to quality evaluations that promise to close the gaps now recognised between skeletal muscle mass and muscle function, morbidity and mortality. As the largest tissue compartment in most adults, skeletal muscle mass and aspects of muscle composition can now be evaluated by a wide array of technologies that provide important new research and clinical opportunities aligned with the growing interest in the spectrum of conditions associated with sarcopenia.

A resistant-starch enriched yogurt: fermentability, sensory characteristics, and a pilot study in children.

The rising prevalence of obesity and the vulnerability of the pediatric age group have highlighted the critical need for a careful consideration of effective, safe, remedial and preventive dietary interventions.  Amylose starch (RS2) from high-amylose maize (HAM) ferments in the gut and affects body weight.   One hundred and ten children, of 7-8 (n=91) or 13-14 (n=19) years of age scored the sensory qualities of a yogurt supplemented with either HAM-RS2 or an amylopectin starch.  The amylopectin starch yogurt was preferred to the HAM-RS2-enriched yogurt by 7-8 year old panelists ( P<0.0001).  Appearance, taste, and sandiness scores given by 13- to 14-year-old panelists were more favorable for the amylopectin starch yogurt than for HAM-RS2-enriched yogurt ( P<0.05).  HAM-RS2 supplementation resulted in acceptable (≥6 on a 1-9 scale) sensory and hedonic ratings of the yogurt in 74% of subjects.  Four children consumed a HAM-RS2-enriched yogurt for four weeks to test its fermentability in a clinical trial.  Three adolescents, but not the single pre-pubertal child, had reduced stool pH ( P=0.1) and increased stool short-chain fatty acids (SCFAs) ( P<0.05) including increased fecal acetate ( P=0.02), and butyrate ( P=0.089) from resistant starch (RS) fermentation and isobutyrate ( P=0.01) from protein fermentation post-treatment suggesting a favorable change to the gut microbiota.  HAM-RS2 was not modified by pasteurization of the yogurt, and may be a palatable way to increase fiber intake and stimulate colonic fermentation in adolescents.  Future studies are planned to determine the concentration of HAM-RS2 that offers the optimal safe and effective strategy to prevent excessive fat gain in children.

Oat consumption reduced intestinal fat deposition and improved health span in Caenorhabditis elegans model.

In addition to their fermentable dietary fiber and the soluble ß-glucan fiber, oats have unique avenanthramides that have anti-inflammatory and antioxidant properties that reduce coronary heart disease in human clinical trials. We hypothesized that oat consumption will increase insulin sensitivity, reduce body fat, and improve health span in Caenorhabditis elegans through a mechanism involving the daf-2 gene, which codes for the insulin/insulin-like growth factor-1-like receptor, and that hyperglycemia will attenuate these changes. Caenorhabditis elegans wild type (N2) and the null strains sir-2.1, daf-16, and daf-16/daf-2 were fed Escherichia coli (OP50) and oat flakes (0.5%, 1.0%, or 3%) with and without 2% glucose. Oat feeding decreased intestinal fat deposition in N2, daf-16, or daf-16/daf-2 strains (P < .05); and glucose did not affect intestinal fat deposition response. The N2, daf-16, or sir-2.1 mutant increased the pharyngeal pumping rate (P < .05), a surrogate marker of life span, following oat consumption. Oat consumption increased ckr-1, gcy-8, cpt-1, and cpt-2 mRNA expression in both the N2 and the sir-2.1 mutant, with significantly higher expression in sir-2.1 than in N2 (P < .01). Additional glucose further increased expression 1.5-fold of the 4 genes in N2 (P < .01), decreased the expression of all except cpt-1 in the daf-16 mutant, and reduced mRNA expression of the 4 genes in the daf-16/daf-2 mutant (P < .01). These data suggest that oat consumption reduced fat storage and increased ckr-1, gcy-8, cpt-1, or cpt-2 through the sir-2.1 genetic pathway. Oat consumption may be a beneficial dietary intervention for reducing fat accumulation, augmenting health span, and improving hyperglycemia-impaired lipid metabolism.

Prowashonupana barley dietary fibre reduces body fat and increases insulin sensitivity in Caenorhabditis elegans model.

Prowashonupana barley (PWB) is high in ß-glucan with moderate content of resistant starch. PWB reduced intestinal fat deposition (IFD) in wild type Caenorhabditis elegans (C. elegans, N2), and in sir-2.1 or daf-16 null mutants, and sustained a surrogate marker of lifespan, pharyngeal pumping rate (PPR), in N2, sir-2.1, daf-16, or daf-16/daf-2 mutants. Hyperglycaemia (2% glucose) reversed or reduced the PWB effect on IFD in N2 or daf-16/daf-2 mutants with a sustained PPR. mRNA expression of cpt-1, cpt-2, ckr-1, and gcy-8 were dose-dependently reduced in N2 or daf-16 mutants, elevated in daf-16/daf-2 mutants with reduction in cpt-1, and unchanged in sir-2.1 mutants. mRNA expressions were increased by hyperglycaemia in N2 or daf-16/daf-2 mutants, while reduced in sir-2.1 or daf-16 mutants. The effects of PWB in the C. elegans model appeared to be primarily mediated via sir-2.1, daf-16, and daf-16/daf-2. These data suggest that PWB and ß-glucans may benefit hyperglycaemia-impaired lipid metabolism.

Effects of three intense sweeteners on fat storage in the C. elegans model.

Beverages sweetened with caloric sweeteners (CS), glucose, sucrose or high-fructose corn syrup, are associated with weight gain. Beverages sweetened with intense sweeteners (IS) are marketed as low-calorie substitutes to prevent beverages-associated weight gain. Using Caenorhabditis elegans, the effects on intestinal fat deposition (IFD) and pharyngeal pumping rate (PPR) of cola beverages sweetened with glucose, aspartame, or aspartame plus acesulfame-potassium (AceK) were compared. Control groups received Escherichia coli (OP50) only. Study I: the nematodes received additional glucose- or IS-sweetened beverages. Study II: the nematodes received additional glucose, aspartame, or aspartame plus AceK (AAK). Beverages containing CS or IS (aspartame or AAK) did not alter IFD in wild type (N2) or in daf-16 deficiency. The CS cola increased IFD in sir-2.1 deficiency (P<0.05). The AAK-cola increased IFD in daf-16/daf-2 deficiency and sir-2.1 deficiency (P<0.05). Glucose increased IFD in N2 and daf-16 deficiency (P<0.05). Aspartame showed a tendency towards reduced IFD in N2 and decreased IFD in daf-16/daf-2 deficiency (P<0.05). AAK increased IFD in daf-16 deficiency and sir-2.1 deficiency (P<0.05), and reversed the aspartame-induced reduction in IFD. The aspartame-sweetened cola increased the PPR in daf-16/daf-2 deficiency and daf-16 deficiency (P<0.05); similar results were obtained in N2 with both IS (P<0.05). AAK increased the PPR in daf-16/daf-2, daf-16, and sir-2.1 deficiencies (P<0.05). Thus, IS increased the PPR, a surrogate marker of lifespan. Aspartame may have an independent effect in reducing IFD to assist humans desiring weight loss. AceK may increase IFD in presence of insulin resistance.

Resistant starch, fermented resistant starch, and short-chain fatty acids reduce intestinal fat deposition in Caenorhabditis elegans.

Obesity is a growing global public health dilemma. The objective of this project is to develop and validate a screening mechanism for bioactive compounds that may reduce body fat and promote health. Resistant starch (RS) reduces body fat in rodents. Amylose starch that has a high content of RS, endogenous compounds obtained from the ceca of amylose starch fed mice (fermented RS), and individual short-chain fatty acids (SCFA) were tested. The Caenorhabditis elegans model and Nile red staining were selected to determine the intestinal fat deposition response to bioactive components. The fluorescence intensity of Nile red was reduced to 76.5% (amylose starch), 78.8% (fermented RS), 63.6% (butyrate), or 28-80% (SCFAs) of controls, respectively (P < 0.001). The reduced intestinal fat deposition suggests reduced food intake or increased energy expenditure. C. elegans is a practical animal model to screen for bioactive compounds that may prevent or treat obesity.

Stimulation of sympathetic innervation in the upper gastrointestinal tract as a treatment for obesity.

Sympathetic activity and obesity have a reciprocal relationship. Firstly, hypothalamic obesity is associated with decreased sympathetic activity. Caffeine and ephedrine increase sympathetic activity and induce weight loss, of which 25% is due to increased metabolic rate and 75% is due to a reciprocally decreased food intake. Secondly, hormones and drugs that affect body weight have an inverse relationship between food intake and metabolic rate. Neuropeptide Y decreases sympathetic activity and increases food intake and body weight. Thirdly, a gastric pacemaker Transcend and vagotomy increase the ratio of sympathetic to parasympathetic activation, decrease food intake, and block gut satiety hormones. Weight loss with the pacemaker or vagotomy is variable. Significant weight reduction is seen only in a small group of those treated. This suggests that activation of the sympathetic arm of the autonomic nervous system may be most important for weight loss. Systemic sympathetic activation causes weight loss in obese patients, but side effects limited its use. We hypothesize that selective local electrical sympathetic stimulation of the upper gastrointestinal tract may induce weight loss and offer a safer, yet effective, obesity treatment. Celiac ganglia delivers sympathetic innervation to the upper gastrointestinal tract. Voltage regulated electrical simulation of the rat celiac ganglia increased metabolic rate in a dose-dependent manner. Stimulation of 6, 3, or 1.5 V increased metabolic rate 15.6%, 6.2%, and 5%, respectively in a single rat. These responses support our hypothesis that selective sympathetic stimulation of the upper GI tract may treat obesity while avoiding side effects of systemic sympathetic activation.

A pilot study to evaluate the effect of splanchnic nerve stimulation on body composition and food intake in rats.

BACKGROUND: Systemic sympathetic stimulation with caffeine and ephedrine increased metabolic rate, reduced food intake, and improved body composition but had systemic adverse events. We hypothesize that selective sympathetic stimulation of the upper gastrointestinal tract will preserve the advantages of systemic sympathetic stimulation without its adverse events. This study evaluated the effect of splanchnic nerve stimulation on metabolic rate, food intake, and body composition. METHODS: Sixteen Sprague Dawley rats had monopolar electrodes placed on the superior common splanchnic nerve innervating the celiac ganglia. An indifferent electrode was placed subcutaneously on the back. The animals were placed on a 60% fat diet, and eight rats were stimulated for 6 weeks. The stimulation was advanced over 3 days from 0.6 mA to 3 mA. Metabolic rate and food intake were measured daily; weight change was monitored weekly, and body composition was determined by nuclear magnetic resonance (NMR) at the end of the study. Four of the eight animals had metabolic rate measured three times over 2-day periods at 0 mA, 1 mA, and 3 mA of stimulation in a metabolic chamber. RESULTS: Except for the first week of stimulation, there was no difference in body weight between the stimulated and control groups. Cumulative food intake was less in the stimulated group (p<0. 001). The lean-to-fat ratio was greater in the stimulated group (p<0. 01), and the animals that received incremental stimulation showed significantly augmented metabolic rate (p<0. 02). CONCLUSIONS: Splanchnic nerve stimulation decreased food intake, increased metabolic rate, and improved body composition.

Electrical stimulation as treatment for obesity and diabetes.

The prevalence of obesity is growing, is driving an increase in the prevalence of diabetes, and is creating a major public health crisis in the United States. Lifestyle and behavior therapy rarely give durable weight loss. There are few medications approved for the treatment of obesity. Those that exist are limited in efficacy and using them in combination does not result in greater weight loss. Surgical treatments for obesity are effective and give durable weight loss, but are accompanied by measurable morbidity and mortality. Several pacing approaches are being tried and are an outgrowth of pacing for gastroparesis. The Transcend(R) pacemaker blocks vagal efferents and delays gastric emptying, giving a 40% loss of excess body weight, if certain screening procedures are employed. The Tantulus pacemaker is still in development but increases antral muscular contractions and delays gastric emptying by stimulation during the absolute refractory period. Weight loss has been 30% of excess body weight, and glycohemoglobin decreased 1.6% in a trial of obese type 2 diabetes. Stimulation to the subdiaphragmatic sympathetics, vagal nerve stimulation with or without unilateral vagotomy, and intestinal pacing are other approaches that are still being evaluated preclinically. Clearly a safe, effective, and durable treatment for obesity is desperately needed. Electrical pacing of the gastrointestinal tract is promising therapeutically, and because pacemakers work through different mechanisms, combining pacemaker treatments may be possible. Rapid progress is being made in the field of electrical stimulation as a treatment for obesity and even greater progress can be expected in the foreseeable future.