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.     

AT1 Receptor Blockade Attenuates Insulin Resistance and Myocardial Remodeling in Rats with Diet-Induced Obesity

Background

Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity.

Material and Methods

Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit β (βIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot.

Results

Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group.

Conclusion

Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.     

Meal Pattern Analysis of Diet‐Induced Obesity in Susceptible and Resistant Rats

Objective: To characterize the meal patterns of free feeding Sprague‐Dawley rats that become obese or resist obesity when chronically fed a high‐fat diet. Research Methods and Procedures: Male Sprague‐Dawley rats (N = 120) were weaned onto a high‐fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet‐induced obese (DIO)] and lower [diet‐resistant (DR)] deciles for body‐weight gain were selected for study. A cohort of chow‐fed (CF) rats weight‐matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. Results: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. Discussion: The hyperphagia of a Sprague‐Dawley rat model of chronic diet‐induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.     

Polyunsaturated Fatty Acids Attenuate Diet Induced Obesity and Insulin Resistance,Modulating Mitochondrial Respiratory Uncoupling in Rat Skeletal Muscle

Objectives

Omega (ω)-3 polyunsaturated fatty acids (PUFA) are dietary compounds able to attenuate insulin resistance. Anyway, the precise actions of ω-3PUFAs in skeletal muscle are overlooked. We hypothesized that PUFAs, modulating mitochondrial function and efficiency, would ameliorate pro-inflammatory and pro-oxidant signs of nutritionally induced obesity.

Study Design

To this aim, rats were fed a control diet (CD) or isocaloric high fat diets containing either ω-3 PUFA (FD) or lard (LD) for 6 weeks.

Results

FD rats showed lower weight, lipid gain and energy efficiency compared to LD-fed animals, showing higher energy expenditure and O₂ consumption/CO₂ production. Serum lipid profile and pro-inflammatory parameters in FD-fed animals were reduced compared to LD. Accordingly, FD rats exhibited a higher glucose tolerance revealed by an improved glucose and insulin tolerance tests compared to LD, accompanied by a restoration of insulin signalling in skeletal muscle. PUFAs increased lipid oxidation and reduced energy efficiency in subsarcolemmal mitochondria, and increase AMPK activation, reducing both endoplasmic reticulum and oxidative stress. Increased mitochondrial respiration was related to an increased mitochondriogenesis in FD skeletal muscle, as shown by the increase in PGC1-α and -β.

Conclusions

our data strengthened the association of high dietary ω3-PUFA intake with reduced mitochondrial energy efficiency in the skeletal muscle.     

Characterization of β‐Cell Mass and Insulin Resistance in Diet‐induced Obese and Diet‐resistant Rats

The selectively bred diet‐induced obese (DIO) and diet‐resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high‐energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin‐producing β‐cells. At the time of weaning, DR rats were found to have a higher body weight and β‐cell mass compared to DIO rats, and elevated insulin and glucose responses to an oral glucose load. However, at 2.5 months of age, and for the remaining study period, the effect of genotype became evident: the chow‐fed DIO rats steadily increased their body weight and β‐cell mass, as well as insulin and glucose levels compared to the DR rats. HE feeding affected both DIO and DR rats leading to an increased body weight and an increased β‐cell mass. Interestingly, although the β‐cell mass in DR rats and chow‐fed DIO rats appeared to constantly increase with age, the β‐cell mass in the HE‐fed DIO rats did not continue to do so. This might constitute part of an explanation for their reduced glucose tolerance. Collectively, the data support the use of HE‐fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex.     

Impact of Diet‐Induced Weight Loss on the Cardiac Autonomic Nervous System in Severe Obesity

Objective: To determine the impact of diet‐induced weight loss on cardiac autonomic nervous system modulation and arrhythmias in subjects with severe obesity and the influence of a high‐fat or a high‐carbohydrate diet regimen on heart rate variability in reduced‐obese individuals. Research Methods and Procedures: Eight severely obese subjects (BMI ≥ 40.0 kg/m²) underwent a 3‐month weight loss program followed by a 3‐month reduced‐weight maintenance regimen. Thereafter, each subject was admitted for an inpatient period of 17 days on two separate occasions. A high‐carbohydrate (60%) or high‐fat (55%) diet of appropriate energy content for weight maintenance was prescribed during each inpatient phase. Heart rate variability was derived from a 24‐hour Holter monitoring system in all subjects during their inpatient stay. Cardiac Holter monitoring was performed at three occasions (baseline, diet phase I, and diet phase II), including the second night of a two overnight calorimetry chamber stay. Results: After the diet regimen, there was a 10% decrease in weight. There were no significant changes in systolic and diastolic blood pressure, arrhythmias, glucose, insulin, total cholesterol, low‐density lipoprotein‐cholesterol, high‐density lipoprotein‐cholesterol, respiratory exchange ratio, and resting energy expenditure between experiments. Mean heart rate was lower after weight loss compared with baseline (p < 0.001). After weight loss, there was an increase in the parasympathetic indices of heart rate variability showing an increase in cardiac vagal modulation (all p < 0.05). Discussion: Weight loss is associated with significant improvement in autonomic cardiac modulation through enhancement of parasympathetic modulation, which clinically translates into a decrease in heart rate.     

Relationships Among Obesity,Inflammation, and Insulin Resistance in African Americans and West Africans

Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist‐to‐hip ratio (WHR)), inflammatory markers (high‐sensitivity C‐reactive protein (hsCRP), haptoglobin, interleukin (IL)‐6, and tumor necrosis factor (TNF)‐α), and IR (homeostasis model assessment of insulin resistance (HOMA_IR)) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL‐6 (but not TNF‐α level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMA_IR, and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL‐6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity.     

Ski Overexpression in Skeletal Muscle Modulates Genetic Programs That Control Susceptibility to Diet‐Induced Obesity and Insulin Signaling

Transgenic mice overexpressing chicken Ski (c‐Ski) have marked decrease in adipose mass with skeletal muscle hypertrophy. Recent evidence indicates a role for c‐Ski in lipogenesis and energy expenditure. In the present study, wild type (WT) and c‐Ski mice were challenged on a high‐fat (HF) diet to determine whether c‐Ski mice were resistant to diet‐induced obesity. During the HF feeding WT mice gained significantly more weight than chow‐fed animals, while c‐Ski mice were partially resistant to the effects of the HF diet on weight. Body composition analysis confirmed the decreased adipose mass in c‐Ski mice compared to WT mice. c‐Ski mice possess a similar metabolic rate and level of food consumption to WT littermates, despite lower activity levels and on chow diet show mild glucose intolerance relative to WT littermates. On HF diet, glucose tolerance surprisingly remained unchanged in c‐Ski mice, while it became worse in WT mice. Skeletal muscle of c‐Ski mice exhibit impaired insulin‐stimulated Akt phosphorylation and glucose uptake. In concordance, gene expression profiling of skeletal muscle of chow and HF‐fed mice indicated that Ski suppresses gene expression associated with insulin signaling and glucose uptake and alters gene pathways involved in myogenesis and adipogenesis. In conclusion, c‐Ski mice are partially resistant to diet‐induced obesity and display aberrant insulin signaling and glucose homeostasis which is associated with alterations in gene expression that inhibit lipogenesis and insulin signaling. These results suggest Ski plays a major role in skeletal muscle metabolism and adipogenesis and hence influences risk of obesity and diabetes.     

Association of Pericardial Fat With Liver Fat and Insulin Sensitivity After Diet‐Induced Weight Loss in Overweight Women

Pericardial adipose tissue (PAT) is positively associated with fatty liver and obesity‐related insulin resistance. Because PAT is a well‐known marker of visceral adiposity, we investigated the impact of weight loss on PAT and its relationship with liver fat and insulin sensitivity independently of body fat distribution. Thirty overweight nondiabetic women (BMI 28.2–46.8 kg/m², 22–41 years) followed a 14.2 ± 4‐weeks low‐calorie diet. PAT, abdominal subcutaneous (SAT), and visceral fat volumes (VAT) were measured by magnetic resonance imaging (MRI), total fat mass, trunk, and leg fat by dual‐energy X‐ray absorptiometry and intrahepatocellular lipids (IHCL) by (¹)H‐magnetic resonance spectroscopy. Euglycemic hyperinsulinemic clamp (M) and homeostasis model assessment of insulin resistance (HOMA_IR) were used to assess insulin sensitivity or insulin resistance. At baseline, PAT correlated with VAT (r = 0.82; P < 0.001), IHCL (r = 0.46), HOMA_IR (r = 0.46), and M value (r = ?0.40; all P < 0.05). During intervention, body weight decreased by ?8.5%, accompanied by decreases of ?12% PAT, ?13% VAT, ?44% IHCL, ?10% HOMA2‐%B, and +24% as well as +15% increases in HOMA2‐%S and M, respectively. Decreases in PAT were only correlated with baseline PAT and the loss in VAT (r = ?0.56; P < 0.01; r = 0.42; P < 0.05) but no associations with liver fat or indexes of insulin sensitivity were observed. Improvements in HOMA_IR and HOMA2‐%B were only related to the decrease in IHCL (r = 0.62, P < 0.01; r = 0.65, P = 0.002) and decreases in IHCL only correlated with the decrease in VAT (r = 0.61, P = 0.004). In conclusion, cross‐sectionally PAT is correlated with VAT, liver fat, and insulin resistance. Longitudinally, the association between PAT and insulin resistance was lost suggesting no causal relationship between the two.     

Associations of Fibroblast Growth Factor-23 with Markers of Inflammation,Insulin Resistance and Obesity in Adults

Introduction

Elevated fibroblast growth factor-23 (FGF23) is an established marker of cardiovascular disease. The underlying reason(s) for the rise accompanying cardiovascular health decline are unclear. Prior studies have shown that FGF23 concentrations are associated with markers of inflammation and insulin resistance but they have been limited by a focus on persons with chronic kidney disease (CKD) and lack of race and sex diversity. The objective of this study was to examine the associations of FGF23 and markers of inflammation, insulin resistance, and anthropometrics in a large cohort of community-dwelling adults.

Methods

Associations of FGF23 with markers of inflammation [interleukin-6 (IL-6), IL-10, high sensitivity-CRP (hsCRP)], insulin utilization [resistin, adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR)] and anthropometrics [BMI and waist circumference (WC)] were examined cross-sectionally in a 1,040 participants randomly selected from the Reason for Geographic and Racial Differences in Stroke (REGARDS) Study, a national study of black and white adults ≥45 years. Effect modification by race and CKD status was tested, and stratified models were analyzed accordingly.

Results

Median FGF23 concentration was 69.6 RU/ml (IQR: 53.2, 102.7). Higher quartiles of FGF23 were associated with higher mean concentrations of IL-6, IL-10, hsCRP and resistin (P _trend<0.001 for all). There were no significant differences in HOMA-IR, adiponectin concentrations, BMI, or WC across FGF23 quartiles in the crude analyses. CKD significantly modified the relationships between FGF23 and inflammatory markers, HOMA-IR, BMI and WC (P ≤ 0.01 for all). In linear regression models adjusted for sociodemographic and clinical variables, FGF23 was positively associated with IL-6, hsCRP, IL-10, HOMA-IR, BMI and WC in individuals without CKD, but not among individuals with CKD. Additionally, FGF23 was positively associated with resistin irrespective of CKD status.

Conclusions

Elevated FGF23 concentrations may be considered a biomarker for decline in metabolic function among individuals with normal kidney function.     

FFA‐Induced Adipocyte Inflammation and Insulin Resistance: Involvement of ER Stress and IKKβ Pathways

Free‐fatty acids (FFAs) are well‐characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA‐induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X‐box protein 1 (XBP‐1s) only attenuates FFA‐induced inflammation. PKR‐like eukaryotic initiation factor 2α kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA‐induced inflammation and insulin resistance. The key downstream target of FFA‐induced ER stress is IκB kinase β (IKKβ), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA‐induced activation of IKKβ and deficiency of IKKβ alleviates FFA‐induced inflammation and insulin resistance. Consistently, overexpression of IKKβ in 3T3‐L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKβ overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKβ expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high‐fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA‐induced inflammation and insulin resistance in adipocytes with PERK and IKKβ as the critical signaling components.     

RBP4 Activates Antigen-Presenting Cells,Leading to Adipose Tissue Inflammation and Systemic Insulin Resistance

1. Download : Download high-res image (251KB)
2. Download : Download full-size image

     

Exercise‐Induced Reduction in Obesity and Insulin Resistance in Women: a Randomized Controlled Trial

Objectives : To determine the effects of equivalent diet‐ or exercise‐induced weight loss and exercise without weight loss on subcutaneous fat, visceral fat, and insulin sensitivity in obese women. Research Methods and Procedures : Fifty‐four premenopausal women with abdominal obesity [waist circumference 110.1 ± 5.8 cm (mean ± SD)] (BMI 31.3 ± 2.0 kg/m²) were randomly assigned to one of four groups: diet weight loss (n = 15), exercise weight loss (n = 17), exercise without weight loss (n = 12), and a weight‐stable control group (n = 10). All groups underwent a 14‐week intervention. Results : Body weight decreased by ～6.5% within both weight loss groups and was unchanged in the exercise without weight loss and control groups. In comparison with controls, cardiorespiratory fitness improved within the exercise groups only (p < 0.01). Reduction in total, abdominal, and abdominal subcutaneous fat within the exercise weight loss group was greater (p < 0.001) than within all other groups. The reduction in total and abdominal fat within the diet weight loss and exercise without weight loss groups was greater than within controls (p < 0.001) but not different from each other (p > 0.05). Visceral fat decreased within all treatment groups (p < 0.008), and these changes were not different from each other. In comparison with the control group, insulin sensitivity improved within the exercise weight loss group alone (p < 0.001). Discussion : Daily exercise without caloric restriction was associated with substantial reductions in total fat, abdominal fat, visceral fat, and insulin resistance in women. Exercise without weight loss was also associated with a substantial reduction in total and abdominal obesity.     

Intracerebroventricular Glucocorticoid Infusion in Normal Rats: Induction of Parasympathetic‐Mediated Obesity and Insulin Resistance

Objective: The aims of the present study were to determine whether increased body weight resulting from intracerebroventricular (ICV) glucocorticoid (dexamethasone) infusion in normal rats is associated, as in obesity, with changes in glucose metabolism and to investigate whether the parasympathetic nervous system is involved in the glucocorticoid‐induced effects. Research Methods and Procedures: Male Sprague–Dawley rats were infused with ICV dexamethasone (2.5 μg/d) or its vehicle for 2 days during which food intake, body weight, and basal insulinemia were measured. Euglycemic–hyperinsulinemic clamps associated with the labeled 2‐deoxyglucose technique were then performed to determine the total rate of glucose disappearance and the tissue glucose use indices. Similar experiments were carried out in vagotomized rats. Results: Two days of ICV glucocorticoid infusion in normal rats resulted in increases in food intake, body weight, basal insulinemia, and produced decreases in the insulin‐stimulated total rate of glucose disappearance, as well as in glucose use indices of all muscle types studied. None of these alterations was observed when glucocorticoid infusion was carried out in vagotomized rats. Discussion: These data show that central glucocorticoid infusion favors anabolic processes, such as feeding behavior, body weight gain, and insulin output, while promoting muscle insulin resistance. These effects seem to be mediated by an activation of the parasympathetic nervous system, because they all disappear when tested in vagotomized rats.     

Inflammation in Obesity is a Common Link Between Defects in Fatty Acid Metabolism and Insulin Resistance

Over the past two decades increases in obesity, due to high caloric intakes and immobilizing technologies, has led to a surge in type 2 diabetes. In obesity elevated circulating fatty acids set-off a pro-inflammatory cascade that increases the production of tumour necrosis factor-α (TNFα) from macrophages. Obesity is associated with blunted skeletal muscle fatty acid oxidation, accumulation of bioactive lipids and insulin resistance. The factors contributing to defects in fatty acid metabolism are not understood but new data demonstrates that increased TNFα in obesity increases protein phosphatase 2C (PP2C), which in turn suppresses the activity of AMP-activated protein kinase (AMPK), a critical regulator of energy metabolism 1. These data identify a novel mechanism by which inflammation in obesity is a precursor to defects in skeletal muscle fatty acid oxidation that generates a vicious cycle exacerbating the development of insulin resistance.     

Hormones and Obesity: Changes in Insulin and Growth Hormone Secretion Following Surgically Induced Weight Loss

Ten obese patients were subjected to insulin tolerance tests (0.2 unit per kg. regular insulin intravenously) and/or treadmill exercise tolerance testing (2.6 m.p.h. at 11° angulation) before and after surgically induced weight reduction. Immunoreactive growth hormone (IRGH) responses returned to normal with weight reduction in all but one—a grossly obese woman studied relatively early in the postoperative period when still far from the ideal body weight. Five of these patients and two additional subjects had intravenous glucose tolerance tests (0.5 g. per kg.) before and after weight reduction. In all, there was a significant diminution in immunoreactive insulin (IRI) values, accompained by little or no change in the glucose disappearance rate (K_G) and a significant improvement in insulin effectiveness as indicated by the calculated “insulinogenic index”. It was concluded that the abnormalities in IRGH and IRI secretion, as well as the insulin resistance in obesity, are probably secondary and not of primary importance in the etiology of this disorder.     

Defective Dietary Induction of Uncoupling Protein 3 in Skeletal Muscle of Obesity‐Prone Rats

Objective: The goal of this study was to determine whether differential induction of skeletal muscle uncoupling protein 3 (UCP3) contributes to the development of diet‐induced obesity (DIO) or resistance to the development of obesity (DR) when rats are placed on a moderate fat (31%) high energy (HE) diet. Research Methods and Procedures: Gastrocnemius muscle was obtained from Sprague‐Dawley rats that were identified as DIO‐prone (n = 5) or DR (n = 5) on the basis of urinary norepinephrine excretion while consuming a chow diet. Muscle was also obtained from animals in the top tertile of weight gain (DIO_HE, n = 5) and the bottom tertile of weight gain (DR_HE, n = 5) after 2 weeks on the HE diet. UCP3 and actin mRNA levels were measured in all muscle samples by Northern analysis. To distinguish the effect of dietary energy content from the effect of obesity itself, we studied additional DIO and DR animals that had been returned to a chow diet for 10 weeks after consuming a HE diet for 10 weeks. Results: The muscle UCP3/actin mRNA ratio in animals that resisted the development of obesity during 2 weeks on the HE diet was 3‐fold higher than in the other groups (DR_HE = 3.24 ± 0.83, DIO_HE = 0.91 ± 0.20, DIO‐prone = 0.72 ± 0.15, DR = 0.63 ± 0.15; p = 0.002). However, there was no difference in muscle UCP3/actin mRNA ratios between DIO animals and DR animals that had been fed the HE diet for 10 weeks and then returned to either an ad libitum chow diet for 10 weeks (DIO = 13.8 ± 3.53, DR = 11.1 ± 3.43, p = NS) or to a restricted chow diet for 10 weeks (DIO = 11.0 ± 2.85, DR = 10.6 ± 2.20, p = NS) despite significantly greater body weight of the DIO animals. Discussion: DR animals may initially resist weight gain when placed on a HE diet through a greater induction of muscle UCP3. This induction is transient and is related more closely to dietary fat content than to body fat stores. DIO animals show no initial induction of muscle UCP3, which may contribute to their increased metabolic efficiency soon after exposure to a HE diet.