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Biomedical subjects

E Ravussin

Publications and source records attributed to E Ravussin.

At least 19 recordsLinked to original sources
PubMed2006

A rare mutation in AgRP, +79G>A, affects promoter activity.

The agouti-related protein is a powerful orexigenic peptide. A rare mutation, +79G>A, was identified in its minimal promoter in two white carriers. Comparison of the 45-year-old male proband, who was also a carrier of the common Ala67Thr polymorphism, with an age- and weight-matching wild-type population showed marginal differences for resting metabolic rate (RMR) and body mass index. The second carrier however was an obese 57-year-old female with reduced RMR. Functional analysis in hypothalamus- and periphery-derived cell lines showed reduced promoter activity for the +79A allele in the adrenocortical cells only, suggesting that it could affect the peripheral expression levels of AgRP. The +79G>A mutation could predispose to body weight gain (as suggested by the phenotype of the second carrier), but it could only affect the proband at an older age as he may be protected by the Ala67Thr polymorphism that is associated with resistance to late-onset fatness.

Agouti-Related Protein↗
PubMed2005

The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. METHODS: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. RESULTS: We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects. CONCLUSIONS/INTERPRETATION: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.

Amino Acid Sequence↗
PubMed2004

Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes.

AIMS/HYPOTHESIS: The recent discovery of two adiponectin receptors (AdipoR1 and AdipoR2) will improve our understanding of the molecular mechanisms underlying the insulin-sensitising effect of adiponectin. The aim of this study was to determine for the first time whether skeletal muscle AdipoR1 and/or AdipoR2 gene expression levels are associated with insulin resistance. METHODS: Using RT-PCR and northern analysis we measured AdipoR1 and AdipoR2 gene expression in skeletal muscle from healthy Mexican Americans with normal glucose tolerance who had (n=8) or did not have (n=10) a family history of Type 2 diabetes. RESULTS: Gene expression profiling indicated that the AdipoR1 and AdipoR2 isoforms are highly expressed in human skeletal muscle, unlike in mice where AdipoR2 expression was highest in the liver, and AdipoR1 was highest in skeletal muscle. In the study subjects, the expression levels of AdipoR1 (p=0.004) and AdipoR2 (p=0.04), as well as plasma adiponectin concentration (p=0.03) were lower in people with a family history of Type 2 diabetes than in those with no family history of the disease. Importantly, the expression levels of both receptors correlated positively with insulin sensitivity (r=0.64, p=0.004 and r=0.47, p=0.048 respectively). CONCLUSIONS/INTERPRETATION: Collectively, these data indicate that both isoforms of the adiponectin receptor play a role in the insulin-sensitising effect of adiponectin.

Adiponectin↗
PubMed2004

Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus.

BACKGROUND: It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues. OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. (A) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (B) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.

Adipocytes↗
PubMed2004

Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects.

Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 +/- 4 yr; body mass index (BMI), 25.4 +/- 4.3 kg/m(2)], 12 obese subjects (age, 54 +/- 8 yr; BMI, 33.0 +/- 2.5 kg/m(2)), and 22 obese subjects with type 2 diabetes (age, 59 +/- 7 yr; BMI, 34.0 +/- 2.4 kg/m(2)) were studied. Serum resistin concentrations were not different among nonobese (4.1 +/- 1.7 ng/ml), obese (4.2 +/- 1.6 ng/ml), and obese diabetic subjects (3.7 +/- 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = -0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P < 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.

Abdomen↗
PubMed2003

Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure.

BACKGROUND: Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited. OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world. DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35+/-12 y, 35+/-9% body fat; mean+/-s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.8+/-6.5 kg) over a follow-up period of 4+/-3 y were available in 74 (49M/25F) of the 92 subjects. RESULTS: The baseline calculated total energy intake (r=0.25, P=0.028) and RMR (r=-0.28, P=0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight. CONCLUSION: Using state-of-the-art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population.

Adult↗
PubMed2003

The insulin-sensitizing role of the fat derived hormone adiponectin.

Adiponectin is an insulin-sensitizing hormone whose blood concentration is reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin in rodents increases glucose uptake and increases fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole body insulin resistance. The exact receptor and signaling systems are unknown, however, recent studies suggest adiponectin activates AMPK, a putative master metabolic regulator. Thus, excitement surrounds the potential for adiponectin, or a homologue of adiponectin, as pharamacotherapy agents for patients suffering from the metabolic syndrome and more particularly for individuals with insulin resistance and type 2 diabetes.

Adiponectin↗
PubMed2002

Chronic central infusion of cocaine- and amphetamine-regulated transcript (CART 55-102): effects on body weight homeostasis in lean and high-fat-fed obese rats.

BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART) is expressed within hypothalamic nuclei implicated in the regulation of feeding behaviour. It is up-regulated by leptin, and CART-derived peptides acutely inhibit food intake. OBJECTIVE: The present study was designed to assess the long-term effects of central CART administration on food intake, body weight, plasma levels of glucose, insulin, leptin, free fatty acids and triglycerides, and on fuel utilisation in normal and high-fat-fed obese rats. DESIGN: Normal and high-fat-fed obese rats were cannulated intracerebroventricularly (i.c.v.) and infused for 6 days with CART (55-102) or its vehicle. At day 4, animals were placed in an indirect calorimeter for a 24 h period during which the respiratory quotient and the energy expenditure were determined hourly. RESULTS: In both normal and obese animals, the chronic i.c.v. infusion of CART (55-102) had marked, sustained inhibitory effects on food intake and body weight gain that were accompanied by decreases in plasma insulin and leptin levels. Using indirect calorimetry, it was observed that CART infusion promoted an increase in lipid oxidation in normal and in obese animals, although this increase reached statistical significance only in the obese group. The hypothalamic CART mRNA expression was found to be higher in obese rats (displaying hyperleptinaemia) than in normal animals. CONCLUSION: The data together show that chronic i.c.v. CART infusion is effective in inhibiting food intake, favouring lipid oxidation and limiting fat storage, both in normal and high-fat-diet-induced obese rats. The CART pathway thus seems to be an important determinant of body weight homeostasis in normal animals as well as in a model of nutritionally induced obesity.

Animals↗
PubMed2002

The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism.

Leptin regulates body weight by its receptor-mediated anorectic, thermogenic and antisteatotic effects. Recently, lower leptin binding to the soluble form of the leptin receptor (LEPR) was shown in carriers of the Arg223-encoding allele of the Gln223Arg polymorphism of the LEPR. To investigate whether this variant influences energy metabolism and adiposity in Pima Indians, we genotyped non-diabetic Pima Indians in whom we had measured body composition and 24 h energy expenditure (24 h EE), physical activity level (PAL) and 24 h respiratory quotient (24 h RQ) in a respiratory chamber (n=268) and who had undergone percutaneous fat biopsies from the periumbilical region (n=184). Genotype was not associated with percent body fat (P>0.39), but was associated with 24 h EE, PAL and mean subcutaneous abdominal adipocyte size (SAAS all P<0.05). Homozygotes for the Arg223-encoding allele had lower 24 h EE (P=0.04) and PAL (P=0.007), but larger SAAS (P=0.01) than Gln homozygotes. These findings are consistent with a role of the Gln223Arg polymorphism in reducing peripheral and central leptin binding to the LEPR in humans. However, these effects do not seem to have a major impact on adiposity in this population.

Adipocytes↗
PubMed2002

Differences in oral temperature and body shape in two populations with different propensities for obesity.

OBJECTIVE: Body temperature is a function of heat production and heat dissipation. Substantial interindividual variability has been reported in healthy humans. We hypothesized that Pima Indians, a population with a high prevalence of abdominal obesity, may have a lower surface area relative to volume, that is, lower radiating area, and therefore a higher body temperature compared to Caucasians. METHODS: Body composition, including volume (hydrodensitometry), and oral temperature were assessed in 69 nondiabetic Caucasian [age, 30 +/- 7 years; body fat, 21 +/- 8% (mean +/- SD)] and 115 Pima Indian males [age, 27 +/- 6 years; body fat, 28 +/- 6%]. Surface area was estimated from height, weight, and waist circumference (Bouchard's equation). In 47 Pima Indians, measures of insulin sensitivity (M, hyperinsulinemic euglycemic clamp) were available. RESULTS: Compared to Caucasians, Pima Indians had a higher oral temperature [36.4 +/- 0.3 degrees C vs. 36.3 +/- 0.3 degrees C (mean +/- SD), p < 0.04] and lower surface area relative to volume (2.19 +/- 0.05 vs. 2.23 +/- 0.26 m(2), p < 0.0001). Surface area relative to volume was negatively correlated with oral temperature (r = -0.14, p < 0.05), but in a multiple linear regression model it did not entirely explain the ethnic difference in oral temperature. Oral temperature was inversely correlated with M (r = -0.28, p < 0.05). Conclusions-Pima Indians have higher oral temperature and lower surface area relative to volume than Caucasians. The ethnic difference in temperature does not seem to be entirely explained by differences in body composition and body shape. Interestingly, higher oral temperature was associated with insulin resistance, a risk factor for type 2 diabetes.

Body Composition↗
PubMed2002

[Determinants and control of energy expenditure].

Obesity is a risk factor for many diseases including cardio-vascular disease, type 2 diabetes, and certain forms of cancer, among others. Obesity results from a chronic imbalance between calorie intake and energy expenditure. Genetic factors obviously play an important role in weight gain, but only in certain environments. The principal cause of the obesity epidemic is not clear: is obesity due to excessive food intake, a dynamic reduction in energy expenditure, or an association of these two factors? However, most obese subjects gain weight because of an inaptitude to adjust energy expenditure in response to excessive food intake. In this article, we review briefly the respective role of genes and environment in the development of obesity, then describe metabolic risk factors involved. Longitudinal studies conducted in Pima Indians have demonstrated that a relative decrease in basal metabolism, weak lipid oxidation in the fasting state, reduced spontaneous physical activity, and lower sympathetic nervous system activity are risk factors for obesity. Unlike our growing knowledge of food intake regulation, little is known about the control of energy expenditure. New discoveries should provide information on obesity susceptibility genes and increase the chances of developing new anti-obesity treatments.

Animals↗
PubMed2001

Effect of satiation on brain activity in obese and lean women.

OBJECTIVE: To investigate the response of the brains of women to the ingestion of a meal. RESEARCH METHODS AND PROCEDURES: We used measures of regional cerebral blood flow (rCBF), a marker of neuronal activity, by positron emission tomography to describe the functional anatomy of satiation, i.e., the response to a liquid meal in the context of extreme hunger (36-hour fast) in 10 lean (BMI < or = 25 kg/m(2); 32 +/- 10 years old, 61 +/- 7 kg; mean +/- SD) and 12 obese (BMI > or = 35 kg/m(2); 30 +/- 7 years old, 110 +/- 14 kg) women. RESULTS: In lean and obese women, satiation produced significant increases in rCBF in the vicinity of the prefrontal cortex (p < 0.005). Satiation also produced significant decreases in rCBF in several regions including the thalamus, insular cortex, parahippocampal gyrus, temporal cortex, and cerebellum (in lean and obese women), and hypothalamus, cingulate, nucleus accumbens, and amygdala (in obese women only; all p < 0.005). Compared with lean women, obese women had significantly greater increases in rCBF in the ventral prefrontal cortex and had significantly greater decreases in the paralimbic areas and in areas of the frontal and temporal cortex. DISCUSSION: This study indicates that satiation elicits differential brain responses in obese and lean women. It also lends additional support to the hypothesis that the paralimbic areas participate in a central orexigenic network modulated by the prefrontal cortex through feedback loops.

Adult↗
PubMed2001

Changes in energy metabolism in response to 48 h of overfeeding and fasting in Caucasians and Pima Indians.

OBJECTIVE: Differences in the metabolic response to overfeeding and starvation may confer susceptibility or resistance to obesity in humans. To further examine this hypothesis, we assessed the changes in 24 h energy metabolism in response to short-term overfeeding and fasting in Caucasians (C) and Pima Indians (I), a population with a very high propensity for obesity. METHODS: We measured the changes in 24 h energy expenditure (24 -EE) and 24 h respiratory quotient (24-RQ) in response to 48 h of mixed diet overfeeding (100% above energy requirements) and fasting in a whole body respiratory chamber in 14 male subjects (7 C/7 I, age 30+/-6 y, mean+/-s.d.). Results were compared to a 24 h measurement under eucaloric conditions. RESULTS: Mean 24-EE increased in response to overfeeding and decreased in response to fasting (all changes P<0.01), with no differences between C (+9.1% and -9.1%) and I (+8.6% and -9.6%). Similarly, mean 24-RQ increased/decreased in response to overfeeding/fasting, respectively (all changes P<0.01), again with no differences between C (+0.06 and -0.05) and I (+0.05 and -0.05). The changes in 24-EE in response to overfeeding and fasting were positively correlated (r=0.70, P<0.01), whereas those in 24-RQ were not (r=0.40, NS). CONCLUSIONS: Pima Indians do not appear to have an impaired metabolic response to short-term overfeeding and fasting that could explain their propensity for obesity. Individuals with a large increase in energy expenditure in response to overfeeding appear to have a small decrease in energy expenditure in response to starvation (spendthrift phenotype) and vice versa (thrifty phenotype).

Adult↗
PubMed2001

Spontaneous physical activity in a respiratory chamber is correlated to habitual physical activity.

OBJECTIVE: During a stay in a respiratory chamber without an exercise protocol, physical activity is limited to activities of daily living, change of posture and 'fidgeting,' collectively referred to as spontaneous physical activity (SPA). SPA is quite variable among individuals and is a heritable trait. A low SPA during a chamber stay is a predictor of weight gain in men. However, it remains to be established whether physical activity in a respiratory chamber relates to physical activity under habitual, free-living conditions. The purpose of the present study was to determine whether physical activity in a chamber is correlated to habitual, free-living physical activity. DESIGN: Fifty healthy, non-diabetic Pima Indians (30 M/20 F, 30+/-6 y; 37+/-10% body fat; means+/-s.d.) completed a 24 h stay in the respiratory chamber followed by a 7 day measurement of habitual, free-living energy expenditure by doubly labeled water. Free-living physical activity was expressed as activity energy expenditure (AEE(FL); daily energy expenditure-(sleeping metabolic rate+thermic effect of food)), physical activity level (PAL(FL); daily energy expenditure/sleeping metabolic rate) and body-size independent activity units. Activity during the chamber stay was expressed as PAL(Ch), AEE(Ch), and based on radar sensor measurements, as percentage of time with activity (SPA(Radar)). RESULTS: AEE(FL) (averaging 930+/-310 kcal/day (3.89+/-1.30 MJ/day)) was correlated to AEE(CH) (averaging 440+/-160 kcal/day (1.84+/-0.67 MJ/day)) and higher in men than in women (r=0.53, P=0.003) and r=0.53, P=0.02, respectively). Likewise, PAL(FL) (averaging 1.75+/-0.21) was correlated to PAL(Ch) (averaging 1.42+/-0.10) and higher in men than in women (r=0.49, P=0.006 and r=0.42, P=0.02, respectively). Free-living activity expressed in body-size independent activity units (averaging 17.8+/-7.0) was correlated to SPA(Radar) (averaging 6.4+/-1.7) with no effect of sex (r=0.30, P=0.03). CONCLUSION: Physical activity in a respiratory chamber was correlated to habitual physical activity, whether expressed as AEE, PAL or body-size independent activity units, providing a plausible explanation for the demonstrated association between a low SPA in the chamber and weight gain. The study encourages further studies of the genetic and non-genetic determinants of SPA and non-exercise activity thermogenesis (NEAT).

Activities of Daily Living↗
PubMed2001

Substrate utilization during exercise in formerly morbidly obese women.

The purpose of this study was to compare substrate utilization during fasting and submaximal exercise in morbidly obese women after weight loss (WL) with that in weight-matched controls (C). WL were studied in the weight-stable condition approximately 24 mo after gastric bypass surgery. Energy intake (self-reported) and expenditure ((2)H(2)(18)O) were also compared. The respiratory exchange ratio during exercise at the same absolute (15 W) workload was significantly (P < or = 0.05) elevated in WL vs. C (0.90 +/- 0.02 vs. 0.83 +/- 0.03); this was reflected as lower fat utilization in WL (29.7 +/- 4.8 vs. 53.2 +/- 9.7% of energy from fat). Respiratory exchange ratio during exercise at the same relative (65% of maximal O(2) uptake) intensity was also significantly (P < 0.05) elevated in WL (0.96 +/- 0.01 vs. 0.89 +/- 0.02), and fat use was concomitantly depressed (12.4 +/- 3.0 vs. 34.3 +/- 9.9% of energy from fat). Resting substrate utilization, daily energy expenditure, and self-reported relative macronutrient intake did not differ between groups. These data suggest that lipid oxidation is depressed during physical activity in WL. This defect may, at least in part, contribute to a propensity for the development of morbid obesity.

Adult↗
PubMed2001

Mutations in the preproghrelin/ghrelin gene associated with obesity in humans.

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/- 3.4 kg/m(2)) and in 96 non-obese female controls (mean BMI 23.0 +/- 1.4 (kg/m2) of the Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg51Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p < 0.05). The self-reported weight at 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respectively, among obese Gln allele carriers versus obese non-carriers. In addition, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detected in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozygotes) subjects. This mutation outside the coding region of the mature ghrelin product tended to be associated with lower age of self-reported onset of obesity (15.6 +/- 7.9 vs. 20.5 +/- 10.5 years; p = 0.09). In addition to these two mutations in coding regions, a G274A base change in a non-coding region between exons one and two was found only in two obese individuals. The Arg51Gln amino acid substitution may alter the cleavage site of endoproteases and the length of the mature ghrelin product. The functional significance of the Leu72Met mutation and a G274A base change remains to be determined. In conclusion, the data provide evidence that a low frequency sequence variation in the ghrelin gene could play a role in the etiology of obesity.

Adult↗