Successful dieters have increased neural activity in cortical areas involved in the control of behavior.

OBJECTIVE: To investigate whether dietary restraint, a landmark of successful dieting, is associated with specific patterns of brain responses to the sensory experience of food and meal consumption. DESIGN AND SUBJECTS: Cross-sectional study of the brain's response to the sensory experience of food and meal consumption in nine successful dieters (age: 38+/-7 years, body fat (%): 28+/-3) and 20 non-dieters (age: 31+/-9 years, body fat (%): 33+/-9), all women. MEASUREMENTS: Changes in brain activity in response to the sensory experience of food and meal consumption were assessed by using positron emission tomography and (15)O water as a radiotracer. Body fatness was assessed by dual X-ray absorptiometry. Subjective ratings of hunger and fullness were measured by visual analogue scale. Dietary restraint, disinhibition and hunger were assessed by the Three Factor Eating Questionnaire. RESULTS: Successful dieters had a significantly higher level of dietary restraint compared to non-dieters. In response to meal consumption, successful dieters had a greater activation in the dorsal prefrontal cortex (DPFC), dorsal striatum and anterior cerebellar lobe as compared to non-dieters. In response to the same stimulation, the orbitofrontal cortex (OFC) was significantly more activated in non-dieters as compared to successful dieters. Dietary restraint was positively correlated with the response in the DPFC and negatively with the response in the OFC. The responses in the DPFC and OFC were negatively intercorrelated. CONCLUSION: Cortical areas involved in controlling inappropriate behavioral responses, such as the DPFC, are particularly activated in successful dieters in response to meal consumption. The association between the degree of dietary restraint and the coordinated neural changes in the DPFC and OFC raises the possibility that cognitive control of food intake is achieved by modulating neural circuits controlling food reward.

Comparison of plasma insulin levels after a mixed-meal challenge in children with and without intrauterine exposure to diabetes.

BACKGROUND: The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring. OBJECTIVE: We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest. DESIGN: After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point. RESULTS: After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01). CONCLUSION: A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.

Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes.

AIMS/HYPOTHESIS: Obesity increases the risk of developing major diseases such as diabetes and cardiovascular disease. Adipose tissue, particularly adipocytes, may play a major role in the development of obesity and its comorbidities. The aim of this study was to characterise, in adipocytes from obese people, the most differentially expressed genes that might be relevant to the development of obesity. METHODS: We carried out microarray gene profiling of isolated abdominal subcutaneous adipocytes from 20 non-obese (BMI 25+/-3 kg/m2) and 19 obese (BMI 55+/-8 kg/m2) non-diabetic Pima Indians using Affymetrix HG-U95 GeneChip arrays. After data analyses, we measured the transcript levels of selected genes based on their biological functions and chromosomal positions using quantitative real-time PCR. RESULTS: The most differentially expressed genes in adipocytes of obese individuals consisted of 433 upregulated and 244 downregulated genes. Of these, 410 genes could be classified into 20 functional Gene Ontology categories. The analyses indicated that the inflammation/immune response category was over-represented, and that most inflammation-related genes were upregulated in adipocytes of obese subjects. Quantitative real-time PCR confirmed the transcriptional upregulation of representative inflammation-related genes (CCL2 and CCL3) encoding the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein 1alpha. The differential expression levels of eight positional candidate genes, including inflammation-related THY1 and C1QTNF5, were also confirmed. These genes are located on chromosome 11q22-q24, a region with linkage to obesity in the Pima Indians. CONCLUSIONS/INTERPRETATION: This study provides evidence supporting the active role of mature adipocytes in obesity-related inflammation. It also provides potential candidate genes for susceptibility to obesity.

Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians.

AIMS/HYPOTHESIS: The specific contributions made by the various cell types in adipose tissue to obesity, particularly obesity-related inflammation, need to be clarified. The aim of this study was to elucidate the potential role of adipocyte precursor cells (preadipocytes/stromal vascular cells [SVC]). METHODS: We performed Affymetrix oligonucleotide microarray expression profiling of cultured abdominal subcutaneous preadipocytes/SVC isolated from the adipose tissue of 14 non-obese (BMI 25+/-4 kg/m2) and 14 obese (55+/-8 kg/m2) non-diabetic Pima Indian subjects. Quantitative real-time PCR (RT-PCR) was used to verify the differential expression of several genes in an independent group of subjects. RESULTS: We identified 218 differentially expressed genes with p values less than 0.01. Microarray expression profiling revealed that the expression of inflammation-related genes was significantly upregulated in preadipocytes/SVC of obese individuals. Quantitative RT-PCR confirmed the upregulation of IL8, CTSS, ITGB2, HLA-DRA, CD53, PLA2G7 and MMP9 in preadipocytes/SVC of obese subjects. CONCLUSIONS/INTERPRETATION: The upregulation of inflammation-related genes in preadipocytes/SVC of obese subjects may increase the recruitment of immune cells into adipose tissue and may also result in changes in the extracellular matrix (tissue remodelling) to accommodate adipose tissue expansion in obesity.

Exaggerated insulin secretion in Pima Indians and African-Americans but higher insulin resistance in Pima Indians compared to African-Americans and Caucasians.

AIMS: African-Americans have a higher prevalence of Type 2 diabetes than Caucasians, but a lower prevalence than Pima Indians. Studies suggest that both African-Americans and Pima Indians are more insulin resistant and have higher acute insulin secretory responses to glucose than Caucasians; however, a direct comparison between these three populations is lacking. METHODS: We measured insulin secretory responses to intravenous glucose (acute insulin response, AIR, 25 g ivGTT); insulin action at physiological (M-low) and supra-physiological (M-high) levels of hyperinsulinaemia (2-step hyperinsulinaemic clamp); basal and insulin-suppressed endogenous glucose production in 30 African-Americans, 30 Pima Indians and 30 Caucasians with normal glucose tolerance who were carefully matched for age, sex, and body fat (hydrodensitometry or DEXA). A subgroup of 24 subjects from each group additionally underwent a standardized mixed meal test. RESULTS: M-low was lower in Pima Indians (0.50 +/- 0.03) compared to Caucasians (0.59 +/- 0.02, P = 0.02) and African-Americans [0.58 +/- 0.03 mg/kgEMBS/min, log10 (means +/- SE), P = 0.03] but was not different between African-Americans and Caucasians. Basal endogenous glucose production was lower in Pima Indians (2.43 +/- 0.06) compared to African-Americans (2.70 +/- 0.06, P = 0.02) and was not different between Pima Indians and Caucasians (2.59 +/- 0.09 mg/kgEMBS/min) or African-Americans and Caucasians (all P > 0.18). Insulin-suppressed endogenous glucose production during the clamp was not different among the groups (all P > 0.40). AIR was higher in both African-Americans (13.51 +/- 0.26) and Pima Indians (13.72 +/- 0.27) compared to Caucasians (12.33 +/- 0.25 pM, log10, both P < 0.01). The areas under the curve for glucose in response to the oral glucose tolerance test and mixed meal test were higher in Pima Indians compared to African-Americans (P = 0.03 and P = 0.03, respectively) and Caucasians (P = 0.01, mixed meal test), but not different between African-Americans and Caucasians. CONCLUSIONS: Exaggerated glucose-stimulated insulin secretion, manifested initially as an increased response to an intravenous glucose challenge, appears to be a characteristic in people with normal glucose tolerance at higher risk for diabetes. Lower whole-body insulin sensitivity in Pima Indians compared to African-Americans, however, may contribute to the higher risk for Type 2 diabetes in Pima Indians compared to African-Americans.

11beta-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle.

AIMS/HYPOTHESIS: The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) modulates tissue-specific glucocorticoid concentrations by generating active cortisol. We have shown that adipose tissue 11beta-HSD1 mRNA levels were associated with adiposity and insulinaemia. Here we conducted further expression and genetic association studies in Pima Indians. METHODS: The 11beta-HSD1 mRNA concentrations were measured in abdominal subcutaneous adipocytes (n=61) and skeletal muscle tissues (n=64). Single nucleotide polymorphisms in the HSD11B1 gene were genotyped in a larger group of full-blooded Pima Indians. RESULTS: Two representative SNPs (SNP1, n=706; SNP5, n=839) were associated with Type 2 diabetes mellitus (p=0.01), although neither SNP was associated with obesity. Among subjects with normal glucose tolerance, SNP1 (n=127) and SNP5 (n=159) were associated with insulin-mediated glucose uptake rates (p=0.03 and p=0.04), and SNP1 was further associated with fasting, 30-min, and 2-h plasma insulin concentrations (p=0.002, p=0.002 and p=0.03). Adipocyte 11beta-HSD1 mRNA concentrations were correlated positively with adiposity and insulinaemia, and were additionally negatively correlated with insulin-mediated glucose uptake rates; nevertheless, the adipocyte 11beta-HSD1 expression did not correlate with genotypes of the donors. The muscle 11beta-HSD1 mRNA concentrations did not correlate with any anthropometric or metabolic variables. CONCLUSIONS/INTERPRETATION: We confirmed that adipocyte 11beta-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity. The variable adipose expression might not be a primary consequence of these HSD11B1 SNPs. Therefore, it is possible that the HSD11B1 gene is under tissue-specific regulation, and has tissue-specific consequences.

Persistence of abnormal neural responses to a meal in postobese individuals.

OBJECTIVE: To determine whether abnormal obese-like neural responses to a meal persist in postobese individuals, who achieved and maintained a normal body weight despite a past history of severe obesity. DESIGN AND SUBJECTS: Cross-sectional study of the brain's response to tasting and consuming a satiating meal in 11 postobese (age: 40+/-6 y, body mass index (BMI): 23.6+/-1.9 kg/m(2)), 23 obese (age: 29+/-6 y, BMI: 39.6+/-3.8 kg/m(2)) and 21 lean (age: 33+/-9 y, BMI: 22.8+/-2.1 kg/m(2)) subjects. MEASUREMENTS: Regional cerebral blood flow (rCBF, a marker of neural activity) at baseline (after a 36-h fast), after tasting and after consuming a satiating liquid meal was assessed using positron emission tomography and state-dependent changes (taste-baseline; satiation-baseline), and compared across groups. Subjective ratings of hunger and fullness were measured by a visual analogue scale and body fatness by dual-energy X-ray absorptiometry. RESULTS: In response to tasting the liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (P<0.05, corrected for multiple comparisons) in the middle insula (peak voxel, x=-41, y=1, z=8; Montreal Neurological Institute coordinates) and posterior cingulate cortex (peak voxel, x=17, y=-47, z=40). The middle insular cortex exhibited a similar increase of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity did not change. In the posterior cingulate cortex, the changes in rCBF in the postobese subjects were not different from those in the other groups. In response to a satiating amount of the same liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (P<0.05, corrected for multiple comparisons) in the posterior hippocampus (peak voxel, x=21, y=-45, x=4), posterior cingulate cortex (peak voxel, x=17, y=-47, z=40), and amygdala (peak voxel, x=27, y=1, z=-24). The posterior hippocampus exhibited a similar decrease of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity increased. In the posterior cingulate cortex and amygdala, the changes in rCBF were not different between the postobese and lean individuals. None of the changes in neural activity were correlated with the age of the individuals, the subjective ratings of hunger and fullness, or the meal induced-changes in plasma glucose, insulin, or serum free fatty acids. CONCLUSION: Persistence of abnormal neural responses to a meal in the postobese individuals, a group at high risk for relapse, indicates that a predisposition to obesity may involve areas of the brain that control complex aspects of eating behavior including anticipation and reward, chemosensory perception, and autonomic control of digestion (insular cortex), as well as enteroception and learning/memory (hippocampus).

Functional neuroimaging: a new generation of human brain studies in obesity research.

Obesity is predominantly caused by overeating, an abnormal behaviour for which there is no unequivocal neurophysiological explanation. Functional neuroimaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have recently emerged as new tools to search for regions of the brain that are involved in the regulation of eating behaviours and those that are involved in the pathophysiology of obesity. Using these techniques, a limited number of studies have provided the first in vivo images of the human hypothalamic response to nutritional stimuli and revealed the complexity of the human brain response to hunger, taste, and satiation. Selective differences have been reported in the functional architecture of the brain of obese and lean individuals. We discuss current use and possible future developments of functional neuroimaging applied to obesity research. We conclude that functional neuroimaging provides an increasingly important tool for investigating how different regions of the brain work in concert to orchestrate normal eating behaviours and how they conspire to produce obesity and other eating disorders.

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.

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.

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.

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.

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).

Body mass index as a measure of adiposity in children and adolescents: relationship to adiposity by dual energy x-ray absorptiometry and to cardiovascular risk factors.

Body mass index is widely used as a measure of adiposity in adults, but its use in children and adolescents is controversial. We assessed body mass index as a measure of adiposity in children and adolescents between the ages of 5 and 20 yr examined as part of the NIH survey of health in the Pima Indian population. Body mass index (measured in 985 subjects and analyzed in 3 age groups: 5-9, 10-14, and 15-19 yr, in both sexes) was compared cross-sectionally to percent fat and fat mass derived from dual energy x-ray absorptiometry and to fasting and 2-h plasma glucose, systolic and diastolic blood pressures, cholesterol, high density lipoprotein cholesterol, fasting insulin, and triglycerides. Body mass index was strongly correlated in all age groups to both percent fat (r = 0.83-0.94; for each group, P < 0.0001) and fat mass (r = 0.96-0.98; P < 0.0001). The relationship of body mass index to percent fat was different in males and females; differences were more marked in older age groups. Body mass index, percent fat, and fat mass showed similar degrees of correlation to metabolic measures in childhood. Body mass index is strongly associated with measures of adiposity derived from dual energy x-ray absorptiometry. Both measures show similar associations with cardiovascular risk factors in Pima Indian children.

Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion.

OBJECTIVE: Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Fasting plasma IL-6 concentrations (enzyme-linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). RESULTS: Fasting plasma IL-6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = -0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL-6 was not related to M (partial r = -0.23, p = 0.089). DISCUSSION: Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL-6 and insulin action seems to be mediated through adiposity.