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1.  Differences in the pathways for metabolism of benzene in rats and mice simulated by a physiological model. 
Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice were more sensitive to the carcinogenic effects of benzene than were F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice. Our objective was to determine if differences in toxic effects could be explained by differences in pathways for benzene metabolism or by differences in total uptake of benzene. Compartments incorporated into the model included liver, fat, a poorly perfused tissue group, a richly perfused tissue group, an alveolar or lung compartment and blood. Metabolism of benzene was assumed to take place only in the liver and to proceed by four major competing pathways. These included formation of hydroquinone conjugates (HQC), formation of phenyl conjugates (PHC), ring-breakage and formation of muconic acid (MUC), and conjugation with glutathione with subsequent mercapturic acid (PMA) formation. Values for parameters such as alveolar ventilation, cardiac output, organ volumes, blood flow, partition coefficients, and metabolic rate constants were taken from the literature. Model simulations confirmed that during and after 6-hr inhalation exposures mice metabolized more benzene on a mumole per kilogram body weight basis than did rats. After oral exposure, rats metabolized more benzene than mice at doses above 50 mg/kg because of the more rapid absorption and exhalation of benzene by mice. Model simulations for PHC and PMA, generally considered to be detoxification metabolites, were similar in shape and dose-response to those for total metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1568104  PMID: 2792050
2.  Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice. 
Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1568117  PMID: 2676495
3.  Differential effects of natural palm oil, chemically- and enzymatically-modified palm oil on weight gain, blood lipid metabolites and fat deposition in a pediatric pig model 
Nutrition Journal  2011;10:53.
Increasing prevalence of obesity and overweight in the Western world, continue to be a major health threat and is responsible for increased health care costs. Dietary intervention studies show a strong positive association between saturated fat intake and the development of obesity and cardiovascular disease. This study investigated the effect of positional distribution of palmitic acid (Sn-1, 2 & 3) of palm oil on cardiovascular health and development of obesity, using weaner pigs as a model for young children.
Male and female weaner piglets were randomly allocated to 4 dietary treatment groups: 1) pork lard (LRD); 2) natural palm olein (NPO); 3) chemically inter-esterified PO (CPO) and 4) enzymatically inter-esterified PO (EnPO) as the fat source. Diets were formulated with 11% lard or with palm olein in order to provide 31% of digestible energy from fat in the diet and were balanced for cholesterol, protein and energy across treatments.
From 8 weeks onwards, pigs on EnPO diet gained (P < 0.05) more weight than all other groups. Feed conversion efficiency (feed to gain) over the 12 week experimental period did not vary between treatment groups. Plasma LDL-C content and LDL-C/HDL-C ratio in pigs fed natural PO tended to be lower compared to all other diets. The natural PO lowered (P < 0.02) the plasma triglyceride (TG) content relative to the lard or EnPO diets, but was not different from the CPO diet. The natural PO diet was associated with lower (P < 0.05) saturated fat levels in subcutaneous adipose tissue than the CPO and EnPO diets that had lower saturated fat levels than the lard diet. Female pigs had lower lean and higher fat and fat:lean ratio in the body compared with male pigs. No difference in weight gain or blood lipid parameters was observed between sexes.
The observations on plasma TG, muscle and adipose tissue saturated fatty acid contents and back fat (subcutaneous) thickness suggest that natural palm oil may reduce deposition of body fat. In addition, dietary supplementation with natural palm oil containing palmitic acid at different positions in meat producing animals may lead to the production of meat and meat products with lower saturated fats. An increase in fat content and a decrease in lean content in female pigs resulted in an increased body fat:lean ratio but gender had no effect on blood lipid parameters or insulin concentrations.
PMCID: PMC3115846  PMID: 21586170
4.  Consumption of diets high in prebiotic fiber or protein during growth influences the response to a high fat and sucrose diet in adulthood in rats 
Early dietary exposure can influence susceptibility to obesity and type 2 diabetes later in life. We examined the lasting effects of a high protein or high prebiotic fiber weaning diet when followed by a high energy diet in adulthood.
At birth, litters of Wistar rats were culled to 10 pups. At 21 d pups were weaned onto control (C), high prebiotic fiber (HF) or high protein (HP) diet. Rats consumed the experimental diets until 14 wk when they were switched to a high fat/sucrose (HFHS) diet for 6 wk. Body composition and energy intake were measured and an oral glucose tolerance test (OGTT) performed. Blood was analyzed for satiety hormones and tissues collected for real-time PCR.
Weight gain was attenuated in male rats fed HF from 12 wk until study completion. In females there were early reductions in body weight that moderated until the final two wk of HFHS diet wherein HF females weighed less than HP. Final body weight was significantly higher following the high fat challenge in male and female rats that consumed HP diet from weaning compared to HF. Lean mass was higher and fat mass lower with HF compared to HP and compared to C in males. Energy intake was highest in HP rats, particularly at the start of HFHS feeding. Plasma glucose was higher in HP rats compared to HF during an OGTT. Plasma amylin was higher in HF females compared to C and glucagon-like peptide-1 (GLP-1) was higher in HF rats during the OGTT. Leptin was higher in HP rats during the OGTT. HF upregulated GLUT 5 mRNA expression in the intestine and downregulated hepatic hydroxymethylglutaryl coenzyme A reductase. Male rats fed HP had higher hepatic triglyceride content than C or HF.
These data suggest that while a long-term diet high in protein predisposes to an obese phenotype when rats are given a high energy diet in adulthood, consumption of a high fiber diet during growth may provide some protection.
PMCID: PMC2958159  PMID: 20920272
The present report on experimental hepatic injury is based on observations amassed during the last 9 years, comprising 1922 rats. It has been shown that there are several dietary factors which may intervene, singly or in combination, in the development of massive or zonal hepatic necrosis. Deficiency of sulfur-containing amino acids is only one of them. From the present studies, tocopherol emerges as an additional protective dietary factor. With regard to the development of massive hepatic necrosis tocopherol may compensate for the absence of sulfur-containing amino acids (cystine, methionine) and vice versa. As a further factor, the quality of dietary fat should be taken into consideration. Fats, like lard and cod liver oil, with a high content of unsaturated fatty acids enhance, whereas fats low in unsaturated fatty acids, such as crisco and butter, retard or prevent the development of massive hepatic necrosis. It is questionable whether with all these dietary factors the etiology of massive hepatic necrosis is completely defined. The interchangeability of sulfur-containing amino acids (cystine, methionine) and vitamin E as leading etiologic factors makes it difficult to accept pure deficiency as the basis of massive hepatic necrosis. The rôle of possible endogenous hepatotoxic substances and their neutralization by cystine (methionine) or tocopherol are discussed. Diffuse hepatic fibrosis is a regular occurrence in rats kept for 100 to 150 days on a diet low in lipotropic factors. Cystine, and, among the fats, lard and especially cod liver oil, have an enhancing effect on the production of hepatic cirrhosis. In rats fed rations free from cod liver oil, and with vegetable shortening such as crisco as source of fat, the incidence and severity of cirrhosis are reduced. Ceroid deposit accompanies cirrhosis only in rats which have been kept on a cirrhosis-producing diet containing fats with a high content of unsaturated fatty acids (cod liver oil, lard). Tocopherol, even when given in excessively large doses (30 mg. daily) will not prevent the formation of ceroid, and will reduce only slightly its total quantity. Under the same treatment the incidence and intensity of cirrhosis remain uninfluenced. Cellular injury in the form of degenerated or necrotic hepatic parenchymal cells, found singly or in small groups in and around the fibrous bands in the cirrhotic liver of rats, is a common occurrence. The fibrotic changes seem to begin, not in the portal spaces, but close to the central vein, although they are not as distinctly and exclusively pericentral as, for instance, in cardiac cirrhosis. Thus, experimental dietary cirrhosis is non-portal. The role of fat infiltration is discussed with special reference to the other microscopic changes found in hepatic cirrhosis. Acute necrotizing nephrosis or various stages of healing of this process are often found with great frequency in rats kept on a cirrhosis-producing diet.
PMCID: PMC2135860  PMID: 18107974
It will be seen from the above that we have studied the conditions associated with the deposit of calcareous salts: (I) in connection with normal and pathological ossification, and (2) in pathological calcification as exhibited in (a) atheroma of the vessels; (b) calcification of caseating tubercular lesions; (c) calcification of inflammatory new growth, and (d) degenerating tumors; and we have induced experimentally deposits of calcareous salts in the lower animals: (a) within celloidin capsules containing fats and soaps; (b) in the kidney, and (c) in connection with fat necrosis. I. We have found that bone formation and pathological calcareous infiltration are wholly distinct processes. In the former there is no evidence of associated fatty change, and the cells associated with the process of deposition of calcium are functionally active. In the latter there is an antecedent fatty change in the affected areas, and the cells involved present constant evidences of degeneration. The view that would seem to account best for the changes observed in the latter case is that with lowered vitality the cells are unable to utilize the products brought to them by the blood, or which they continue to absorb, so that the normal series of decompositions associated with their metabolism fails to take place and hence they interact among themselves in the cytoplasm with the result that insoluble compounds replace soluble ones. II. Besides the fact that calcification is always preceded by fatty change within the cells, another fact should be emphasized. namely: that combination of the fats present with calcium salts to form calcium soaps tends to occur. The stages immediately preceding these are difficult to follow with anything approaching certainty, perhaps because the earlier stages vary under different conditions. In fat necrosis, for instance, the cells affected are normally storehouses for neutral fats, and as long as they remain healthy neutral fats alone are present in them. When they are subjected to the action of the pancreatic juice with its fat-splitting ferment the cells are killed and coincidently the neutral fats are decomposed, fatty acids being deposited. The fatty acids now slowly combine with the calcium salts. In degenerating lipomata the process would seem to be similar. But in other cases the cells are not obviously fat-containing in the normal state; nevertheless prior to calcification they undergo so-called fatty degeneration, which is really a form of cell degeneration accompanied by fat infiltration. As regards the source of the cell fats in general we may safely accept: 1. That fats are transported in the blood as diffusible soaps. 2. That taken up by the cells these soaps may either— (a) Be reconverted into neutral fats and become stored in the cytoplasm as such, or (b) undergo assimilation proper, becoming part and parcel of the cell substance, in which case they are not recognizable by the ordinary microchemical tests. 3. If these two possibilities be accepted it follows that the appearance of fats and soaps in the degenerating cell may be due to either— (a) Absorption or infiltration of soaps from the surrounding medium, the degenerating cell retaining the power of splitting off the fat but being unable to utilize this in metabolism. (b) Cytoplasmic disintegration with dissociation of the soap-albumen combination or, more broadly, liberation of the fats from their combination with the cytoplasm. The appearances seen in the cells of atheromatous areas indicate that the first of these does occur. III. In areas undergoing calcareous infiltration we have demonstrated. the presence of soaps, and this often in such quantities that they can be isolated and estimated by gross chemical methods. By microchemical methods also we have been able to show that after removing all the neutral fats and fatty acids by petroleum ether there remains behind a substance giving with Sudan III the reaction we associate with the presence of soap. And experimentally we have produced these soaps within the organism, more particularly by placing capsules containing fats and fatty acids within the tissues and after several days finding that the capsules contain calcium soaps and possess a calcium content far in excess of that of the normal blood and lymph. IV. While these are the facts, certain of the details of this reaction demand elucidation. The existence of sodium and it may be potassium soaps in the degenerated cells is comprehensible if we accept that these are present in the circulating lymph and simply undergoing absorption. But even then, as these are diffusible substances how is it to be explained that they become stored up in these particular areas? We have found that, as a matter of fact, in regions which give the reaction for soaps, but which give no reaction for calcium (which therefore presumably contain at most amounts of the insoluble calcium soap too small to need consideration, the ordinary solvents for potassium and sodium soaps do not forthwith remove the stainable material; they are relatively insoluble. The reason for this insolubility is suggested by the observations made in the test tube, that soap solutions mixed with solutions of white of egg or blood serum form a precipitate of combined soap and albumen, which likewise is insoluble in water and alcohol. The indications are therefore that in cells undergoing degeneration, with degeneration of the cytoplasm, certain albuminous molecules unite with the soaps present to form relatively insoluble soap-albuminate. V. With regard to calcium soaps, these are also present and in certain stages appear to be the dominating form in the affected tissues. Two questions suggest themselves, viz.: what is the source of calcium, and what is the process by which they become formed? As to the source, the amount present in well-marked calcification is far in excess of the normal calcium contents of the affected tissue. If in the kidneys of experimental calcification three hundred times as much calcium may be present as in the normal kidney (von Kossa), the calcium must be conveyed to the part by the blood and lymph, and that this is so is demonstrated, as we have pointed out, by the distribution of the infiltration in solid organs, that like ovarian fibroids have undergone necrosis, in which the earliest deposits are superficial. As to the process, there are three possibilities: 1. That sodium and potassium soaps and soap albuminates are first formed and that interaction occurs between them and the diffused calcium salts from the lymph, the less soluble-calcium replacing the sodium and potassium. 2. That under certain conditions the calcium salts act directly on the neutral fats present in the degenerating cells. 3. That the neutral fats are first broken down into fatty acids and that these react with the calcium salts to form the soaps. We are assured that the first process occurs and that because in the boundary zone of areas of calcification we can detect soapy particles devoid of calcium, identical in position and arrangement with the particles more deeply placed which give the calcium reactions. But this is not the only reaction. In case of fat necrosis we see clearly that the third process is in evidence. And we are far from being convinced that the second does not also obtain. We have been impressed by the large accumulation of neutral fats in the cells in cases of early atheroma and the absence at any stage of the process of recognizable fatty acid. While soaps, it is true, are compounds of fatty acids with alkalies, it is recognized in ordinary domestic life that they can be formed by the direct action of strong lye upon ordinary fats, and this even in the cold. It is quite possible therefore that there occurs a similar direct process in the organism. The point is worth noting, however, that this does not occur in healthy cells the seat of fatty infiltration. We therefore leave this an open question, only laying down that, as indicated by the hyalin albuminous matrix left when calcium salts are dissolved out of an area of calcification, there must exist a calcium soap- or fat-albuminate similar to the potassium and sodium soap-albuminates already mentioned—such an albuminate as we can form with calcium soaps in the test tube. VI. In old areas of calcification soaps are largely if not entirely wanting, although these are to be detected at the periphery, when the process is still advancing. The reactions given by these older areas are almost entirely those of calcium phosphate, though some calcium carbonate is at times to be made out. This seems surely to indicate that the final stage in calcification is an interaction between the calcium soap-albuminates and substances containing phosphoric and carbonic acids. Such substances, it is needless to say, are present in considerable amounts in the lymph and blood. We must conclude that the acid sodium phosphates of the lymph act on the calcium soap, the highly insoluble calcium phosphates being formed (plus the albuminous moiety of the original compound) and diffusible sodium soap being liberated, while similarly alkaline carbonates form calcium carbonate and liberate sodium and potassium soaps. Calcium phosphate and calcium carbonate thus become the insoluble earthy salts of old crystalline areas of calcification. VII. As already stated very little soap is to be found in these old areas. It is possibly worth suggestion that the soaps liberated in this last reaction, as they diffuse out, again react with diffusible calcium salts and form calcium soaps which once more react with the alkaline salts to produce the phosphates and carbonates; that, in short, they have a katalytic action. Certain it is that old calcareous areas are extraordinarily dense, and have a coarse crystalline structure, wholly at variance with the finely granular appearance of the more recent areas, and these large crystalline masses, it would seem, can only be formed by successive deposition of new material and eventual fusion, as the interspaces become filled in between the original masses.
PMCID: PMC2124594  PMID: 19867016
7.  Isocaloric intake of a high-fat diet modifies adiposity and lipid handling in a sex dependent manner in rats 
High-fat (HF) diet feeding usually leads to hyperphagia and body weight gain, but macronutrient proportions in the diet can modulate energy intake and fat deposition. The mechanisms of fat accumulation and mobilization may differ significantly between depots, and gender can also influence these differences.
To investigate, in rats of both sexes, the effect of an isocaloric intake of a diet with an unbalanced proportion of macronutrients on fatty acid composition of visceral and subcutaneous adipose tissues and how this is influenced by both dietary fatty acids and levels of proteins involved in tissue lipid handling.
Eight-week-old Wistar rats of both sexes were fed a control diet (3% w/w fat) or high-fat diet (30% w/w fat) for 14 weeks. Fatty acid composition was analyzed by gas-chromatography and levels of LPL, HSL, α2-AR, β3-AR, PKA and CPT1 were determined by Western blot.
The HF diet did not induce hyperphagia or body weight gain, but promoted an increase of adiposity index only in male rats. HF diet produced an increase of the proportion of MUFA and a decrease in that of PUFA in both adipose depots and in both sexes. The levels of proteins involved in the adrenergic control of the lipolytic pathway increased in the gonadal fat of HF females, whereas LPL levels increased in the inguinal fat of HF males and decreased in that of females.
Sexual dimorphism in adiposity index reflects a differential sex response to dietary fatty acid content and could be related to the levels of the proteins involved in tissue lipid management.
PMCID: PMC3095551  PMID: 21486445
8.  Relationship between the percentage of body fat and surrogate indices of fatness in male and female Polish active and sedentary students 
Limited data have indicated that body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and waist to height ratio (WHtR) of athletes and young adults provide misleading results concerning body fat content. This study was aimed at the evaluation of the relationship between different surrogate indices of fatness (BMI, WC, WHR, WHtR and body adiposity index (BAI)) with the percentage of body fat in Polish students with respect to their sex and physical activity.
A total of 272 students volunteered to participate in the study. Of these students, 177 physical education students (90 males and 87 females) were accepted as active (physical activity of 7 to 9 hours/week); and 95 students of other specializations (49 males and 46 females) were accepted as sedentary (physical activity of 1.5 hours/week). Weight, height, waist and hip circumferences were measured, and BMI, WHR, WHtR and BAI were calculated. Body fat percentage was assessed using four skinfold measurements.
Classification of fatness according to the BMI and the percentage of body fat have indicated that BMI overestimates fatness in lean subjects (active men and women, sedentary men), but underestimates body fat in obese subjects (sedentary women). In all groups, BMI, WHR, WHtR and BAI were significantly correlated with the percentage of body fat (with the exception of WHR and hip circumference in active and sedentary women, respectively). However, coefficients of determination not exceeding 50% and Lin’s concordance correlation coefficients lower than 0.9 indicated no relationship between measured and calculated body fat.
The findings in the present study support the concept that irrespective of physical activity and sex none of the calculated indices of fatness are useful in the determination of body fat in young adults. Thus, it seems that easily calculated indices may contribute to distorted body image and unhealthy dietary habits observed in many young adults in Western countries, but also in female athletes.
PMCID: PMC4047548  PMID: 24887103
Young adults; Physical activity; Body fat percent; Surrogate indices of adiposity
9.  Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity  
PLoS Medicine  2008;5(3):e51.
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.
Methods and Findings
We used a special study design of “clonal controls,” rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/m2. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.
Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
Leena Peltonen and colleagues uncover the metabolic changes that result from obesity through an analysis of genetically identical twin pairs in which one was obese and the other was not.
Editors' Summary
Around the world, the proportion of people who are obese (people with an unhealthy amount of body fat) is increasing. In the US, for example, 1 adult in 7 was obese in the mid 1970s. That is, their body mass index (BMI)—their weight in kilograms divided by their height in meters squared—was more than 30. Nowadays, 1 US adult in 3 has a BMI this high and, by 2025, it is predicted that 1 in 2 will be obese. This obesity epidemic is being driven by lifestyle changes that encourage the over-consumption of energy-rich foods and discourage regular physical activity. The resultant energy imbalance leads to weight gain (the excess energy is stored as body fat or adipose tissue) and also triggers numerous metabolic changes, alterations in the chemical processes that convert food into the energy and various substances needed to support life. These obesity-related metabolic changes increase a person's risk of developing adverse health conditions such as diabetes, a condition in which dangerously high levels of sugar from food accumulate in the blood.
Why Was This Study Done?
The changes in human fat in obesity have not been completely understood, although the abnormal metabolism of adipose tissue is increasingly seen as playing a critical part in excessive weight gain. It has been very difficult to decipher which molecular and metabolic changes associated with obesity are the result of becoming obese, and which might contribute towards the acquisition of obesity in humans in the first place. To discover more about the influence of environment on obesity-induced metabolic changes, the researchers in this study have investigated these changes in pairs of genetically identical twins.
What Did the Researchers Do and Find?
The researchers recruited 14 pairs of genetically identical Finnish twins born between 1975 and 1979 who were “obesity discordant”—that is, one twin of each pair had a BMI of about 25 (not obese); the other had a BMI of about 30 (obese). The researchers took fat and blood samples from each twin, determined the insulin sensitivity of each, and measured the body composition and various fat stores of each. They found that the obese twins had more subcutaneous, intra-abdominal, and liver fat and were less insulin sensitive than the non-obese twins. Insulin sensitivity correlated with the amount of liver fat. Analysis of gene expression in the fat samples showed that 19 gene pathways (mainly inflammatory pathways) were expressed more strongly (up-regulated) in the obese twins than the non-obese twins, whereas seven pathways were down-regulated. The most highly down-regulated pathway was a mitochondrial pathway involved in amino acid breakdown, but mitochondrial energy metabolism pathways were also down-regulated. Finally, mitochondrial DNA copy number in fat was reduced in the obese twins by nearly half, a novel observation that could partly account for the obesity-induced metabolic defects of these individuals.
What Do These Findings Mean?
These and other findings identify several pathways that are involved in the development of obesity and insulin resistance. In particular, they suggest that changes in mitochondrial energy production pathways and in mitochondrial amino acid metabolism pathways could play important roles in the development of obesity and of insulin resistance and in the accumulation of liver fat even in young obese people. The study design involving identical twins has here produced some evidence for aberrations in molecules critical for acquired obesity. The results suggest that careful management of obesity by lifestyle changes has the potential to correct the obesity-related metabolic changes in fat that would otherwise lead to diabetes and other adverse health conditions in obese individuals. In addition, they suggest that the development of therapies designed to correct mitochondrial metabolism might help to reduce the illnesses associated with obesity.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has pages on obesity and diabetes (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of obesity (in English and Spanish)
The UK National Health Service's health Web site (NHS Direct) provides information about obesity
The International Obesity Taskforce provides information about preventing obesity and on diabetes and obesity
The UK Foods Standards Agency and the United States Department of Agriculture provide online tools and useful advice about healthy eating for adults and children
Information is available for patients and carers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance
PMCID: PMC2265758  PMID: 18336063
10.  Reference Values for Body Composition and Anthropometric Measurements in Athletes 
PLoS ONE  2014;9(5):e97846.
Despite the importance of body composition in athletes, reference sex- and sport-specific body composition data are lacking. We aim to develop reference values for body composition and anthropometric measurements in athletes.
Body weight and height were measured in 898 athletes (264 female, 634 male), anthropometric variables were assessed in 798 athletes (240 female and 558 male), and in 481 athletes (142 female and 339 male) with dual-energy X-ray absorptiometry (DXA). A total of 21 different sports were represented. Reference percentiles (5th, 25th, 50th, 75th, and 95th) were calculated for each measured value, stratified by sex and sport. Because sample sizes within a sport were often very low for some outcomes, the percentiles were estimated using a parametric, empirical Bayesian framework that allowed sharing information across sports.
We derived sex- and sport-specific reference percentiles for the following DXA outcomes: total (whole body scan) and regional (subtotal, trunk, and appendicular) bone mineral content, bone mineral density, absolute and percentage fat mass, fat-free mass, and lean soft tissue. Additionally, we derived reference percentiles for height-normalized indexes by dividing fat mass, fat-free mass, and appendicular lean soft tissue by height squared. We also derived sex- and sport-specific reference percentiles for the following anthropometry outcomes: weight, height, body mass index, sum of skinfold thicknesses (7 skinfolds, appendicular skinfolds, trunk skinfolds, arm skinfolds, and leg skinfolds), circumferences (hip, arm, midthigh, calf, and abdominal circumferences), and muscle circumferences (arm, thigh, and calf muscle circumferences).
These reference percentiles will be a helpful tool for sports professionals, in both clinical and field settings, for body composition assessment in athletes.
PMCID: PMC4022746  PMID: 24830292
11.  Treatment of Rats with a Self-Selected Hyperlipidic Diet, Increases the Lipid Content of the Main Adipose Tissue Sites in a Proportion Similar to That of the Lipids in the Rest of Organs and Tissues 
PLoS ONE  2014;9(3):e90995.
Adipose tissue (AT) is distributed as large differentiated masses, and smaller depots covering vessels, and organs, as well as interspersed within them. The differences between types and size of cells makes AT one of the most disperse and complex organs. Lipid storage is partly shared by other tissues such as muscle and liver. We intended to obtain an approximate estimation of the size of lipid reserves stored outside the main fat depots. Both male and female rats were made overweight by 4-weeks feeding of a cafeteria diet. Total lipid content was analyzed in brain, liver, gastrocnemius muscle, four white AT sites: subcutaneous, perigonadal, retroperitoneal and mesenteric, two brown AT sites (interscapular and perirenal) and in a pool of the rest of organs and tissues (after discarding gut contents). Organ lipid content was estimated and tabulated for each individual rat. Food intake was measured daily. There was a surprisingly high proportion of lipid not accounted for by the main macroscopic AT sites, even when brain, liver and BAT main sites were discounted. Muscle contained about 8% of body lipids, liver 1–1.4%, four white AT sites lipid 28–63% of body lipid, and the rest of the body (including muscle) 38–44%. There was a good correlation between AT lipid and body lipid, but lipid in “other organs” was highly correlated too with body lipid. Brain lipid was not. Irrespective of dietary intake, accumulation of body fat was uniform both for the main lipid storage and handling organs: large masses of AT (but also liver, muscle), as well as in the ”rest” of tissues. These storage sites, in specialized (adipose) or not-specialized (liver, muscle) tissues reacted in parallel against a hyperlipidic diet challenge. We postulate that body lipid stores are handled and regulated coordinately, with a more centralized and overall mechanisms than usually assumed.
PMCID: PMC3946303  PMID: 24603584
12.  The relationship between regional abdominal fat distribution and both insulin resistance and subclinical chronic inflammation in non-diabetic adults 
Obesity is associated with a high risk of insulin resistance (IR) and its metabolic complications. It is still debated that distributions of adipose tissue relate to an excess risk of IR and chronic inflammation in different race. This study was designed to examine the relation between insulin sensitivity, chronic inflammation and central fat distribution in non-diabetic volunteers in Taiwanese.
There were 328 volunteers without family history of diabetes mellitus and with normal oral glucose tolerance test enrolled. Total body fat and abdominal fat were measured. Abdominal fat was categorized into intraperitoneal (IP), retroperitoneal (RP) and subcutaneous (SC) fat. The IR index was estimated by homeostatic model assessment. Five inflammatory markers: adiponectin, leptin, tumor necrosing factor-α (TNF-α), resistin and high sensitive CRP (hs-CRP) were measured.
IR was related to IP fat (r = 0.23, p < 0.001), but not RP fat, SC fat or total body fat. After correcting for age and sex, IP fat was the only significant predictor of IR (r2 = 58%, p = 0.001). Leptin showed the strongest relationship with all fat compartments (IP fat: r = 0.44, p = 0.001; RP fat: r = 0.36, p = 0.005, SC fat: r = 0.54, p < 0.001; total body fat: r = 0.61, p < 0.001). The hs-CRP and adiponectin were closely related both to IP (r = 0.29, p = 0.004; r = -0.20, p = 0.046, respectively) and total body fat (r = 0.29, p = 0.004; r = -0.29, p = 0.005, respectively), but not RP, or SC fat. TNF-α and resistin were not correlated to any fat compartment. After correcting for age and sex, leptin variance was mostly explained by SC fat (41.3%), followed by IP fat (33.6%) and RP fat (25.3%). The hs-CRP and adiponectin variance were mostly explained by IP fat (40% and 49% respectively).
IP fat is better predictors of IR and subclinical chronic inflammation in Taiwanese adults. A disproportionate accumulation of abdominal fat is associated with increased risk of cardiovascular diseases.
PMCID: PMC3978053  PMID: 24684833
Subcutaneous fat; Intra-peritoneal fat; Retroperitoneal fat; Insulin resistance; High sensitive C-reactive protein; Adiponectin
13.  Differential susceptibility to obesity between male, female and ovariectomized female mice 
Nutrition Journal  2009;8:11.
The prevalence of obesity has increased dramatically. A direct comparison in the predisposition to obesity between males, premenopausal females, and postmenopausal females with various caloric intakes has not been made. To determine the effects of sex and ovarian hormones on the susceptibility to obesity, we conducted laboratory studies with mice. To eliminate confounders that can alter body weight gain, such as age and food consumption; we used mice with the same age and controlled the amount of calories they consumed.
We determined sex-specific susceptibility to obesity between male, non-ovariectomized female, and ovariectomized female mice. To compare susceptibility to gaining body weight between males and females, animals from each sex were exposed to either a 30% calorie-restricted, low-fat (5% fat), or high-fat (35% fat) diet regimen. To establish the role of ovarian hormones in weight gain, the ovaries were surgically removed from additional female mice, and then were exposed to the diets described above. Percent body fat and percent lean mass in the mice were determined by dual energy x-ray absorptiometry (DEXA).
In all three diet categories, male mice had a greater propensity of gaining body weight than female mice. However, ovariectomy eliminated the protection of female mice to gaining weight; in fact, ovariectomized female mice mimicked male mice in their susceptibility to weight gain. In summary, results show that male mice are more likely to become obese than female mice and that the protection against obesity in female mice is eliminated by ovariectomy.
Understanding metabolic differences between males and females may allow the discovery of better preventive and treatment strategies for diseases associated with body weight such as cancer and cardiovascular disease.
PMCID: PMC2650703  PMID: 19220919
14.  Benzene induces a dose-responsive increase in the frequency of micronucleated cells in rat Zymbal glands. 
Environmental Health Perspectives  1996;104(Suppl 6):1331-1336.
The Zymbal gland, a sebaceous tissue associated with the ear duct of certain rodent species, is a principal target for carcinogenesis by benzene. To investigate the mechanism of induction of tumors in the rat Zymbal gland, we have developed a procedure for primary culture of epithelial cells from Zymbal gland explants so that cytogenetic analysis can be performed on this target tissue following an in vivo exposure to benzene. Cytogenetic analysis performed 45 hr after in vivo oral dosing with benzene revealed chromosome damage that occurred as a result of acute, subchronic, and chronic dosing. This damage, expressed as a dose-related increase in the frequency of micronucleated cells, was observed in Sprague-Dawley female rats over a range of benzene doses from 12.5 to 250 mg/kg/day, and in male Fischer 344 rats at doses ranging from 1 to 200 mg/kg/day. These results are consistent with the known clastogenicity of benzene in mouse bone marrow, which is also a target tissue. This study is the first report of a genotoxic effect of benzene in the rat Zymbal gland and shows that micronucleus formation may be used as a correlate for carcinogenesis induced by benzene in this target tissue.
PMCID: PMC1469769  PMID: 9118915
15.  Trafficking of Dietary Fat and Resistance to Obesity 
Physiology & behavior  2008;94(5):681-688.
The task of maintaining energy balance involves not only making sure that the number of calories ingested equals the number of calories burned but also involves ensuring nutrient balance. This means that over time, the quantity of carbohydrate, fat and protein consumed equals the amount of each oxidized. While the body has the ability to convert protein to carbohydrate and carbohydrate to fat, over long periods of time the body establishes nutrient balance with a high degree of accuracy storing excess nutrients as fat. To make decisions about food intake, the brain must assimilate information about the quantity of nutrients ingested and their disposition through the body over time. This is a very complex time ordered process as different tissues may be in different states of energy balance at different intervals following food ingestion. The fundamental task for the brain is to assess the influx of nutrients relative to stored pools of those nutrients and the rate at which they are being oxidized. It has been suggested that this task is particularly difficult for dietary fat because the stored pool of lipid is quite large compared to either the stored pools of carbohydrate and protein or the quantity of fat ingested per day. It is clear that some organisms resist weight gain even in the face of highly palatable diets. In fact most individuals eat less on any given day than they could given their maximal capacity for consumption. A central question then is: what restrains food intake in the setting of widely available highly palatable food? In this paper we will discuss the evidence that the movement of dietary fat between tissues may play an important role in the fidelity of nutrient sensing and as a result, resistance or susceptibility to obesity. In particular, the relative metabolism of dietary fat favoring oxidation over storage may be associated with more robust signaling of positive energy balance and resistance to dietary induced obesity in both humans and rats.
PMCID: PMC2494849  PMID: 18514237
Dietary fat; appetite; obesity; thinness; humans; rat models
16.  Physiological models of body composition and human obesity 
The body mass index (BMI) is the standard parameter for predicting body fat fraction and for classifying degrees of obesity. Currently available regression equations between BMI and fat are based on 2 or 3 parameter empirical fits and have not been validated for highly obese subjects. We attempt to develop regression relations that are based on realistic models of body composition changes in obesity. These models, if valid, can then be extrapolated to the high fat fraction of the morbidly obese.
The analysis was applied to 3 compartment (density and total body water) measurements of body fat. The data was collected at the New York Obesity Research Center, Body Composition Unit, as part of ongoing studies. A total of 1356 subjects were included, with a BMI range of 17 to 50 for males and 17 to 65 for females. The body composition model assumes that obese subjects can be represented by the sum of a standard lean reference subject plus an extra weight that has a constant adipose, bone and muscle fraction.
There is marked age and sex dependence in the relationship between BMI and fat fraction. There was no significant difference among Caucasians, Blacks and Hispanics while Asians had significantly greater fat fraction for the same BMI. A linear relationship between BMI and fat fraction provides a good description for men but overestimates the fat fraction in morbidly obese women for whom a non-linear regression should be used. New regression relations for predicting body fat just from experimental measurements of body density are described that are more accurate then those currently used. From the fits to the experimental BMI and density data, a quantitative description of the bone, adipose and muscle body composition of lean and obese subjects is derived.
Physiologically realistic models of body composition provide both accurate regression relations and new insights about changes in body composition in obesity.
PMCID: PMC2082278  PMID: 17883858
17.  Effect of high-fat diet feeding on leptin receptor expression in white adipose tissue in rats: depot- and sex-related differential response 
Genes & Nutrition  2009;4(2):151-156.
Previous studies have illustrated the importance of leptin receptor (OB-Rb) mediated action on adipocytes in the regulation of body weight. The aim of the present study was to investigate in male and female rats the effects of high-fat (HF) diet feeding on the expression levels of OB-Rb in different depots of white adipose tissue (WAT), and its relation to fatty acid oxidation capacity. Male and female Wistar rats were fed until the age of 6 months with a normal-fat (NF) or non-isocaloric HF-diet (10 and 45% calories from fat, respectively). At this age, the weight of three different fat depots (retroperitoneal, mesenteric and inguinal) and the expression levels of OB-Rb, PPARα and CPT1 in these depots were measured. HF-diet feeding resulted in an increase in the weight of the different fat depots, the retroperitoneal depot being the one with the greatest increase in both sexes. In this depot, HF-diet feeding resulted in a significant decrease in OB-Rb mRNA levels, more marked in male than in female rats. In the mesenteric depot, the effects of HF-diet feeding on OB-Rb mRNA levels were sex-dependent: they decreased in males rats (associated with a decrease in PPARα and CPT1 mRNA levels), but increased in female rats. In the inguinal depot, OB-Rb expression was not affected by HF-diet feeding. These results show that a chronic intake of an HF-diet altered the expression of OB-Rb in WAT in a depot and sex-dependent manner. The decreased expression of OB-Rb in the internal depots of male rats under HF-diet feeding, with the resulting decrease in leptin sensitivity, can help to explain the higher tendency of males to suffer from obesity-linked disorders under HF-diet conditions.
PMCID: PMC2690722  PMID: 19277751
High-fat diet; Leptin; OB-Rb; Sex-dimorphism; White adipose tissue depots
18.  Body mass, fat percentage, and fat free mass as reference variables for lung function: effects on terms for age and sex 
Thorax  2001;56(11):839-844.
BACKGROUND—Sex specific cross sectional reference values for lung function indices usually employ a linear model with terms for age and stature. The effects of also matching for body mass index (BMI= mass/stature2) or its components, fat percentage of body mass (fat%) and fat free mass index (FFMI = fat free mass/stature2) were studied.
METHODS—The subjects were 458 asymptomatic male and female non-smokers (383 men) and 22 female ex-smokers. Measurements were made of ventilatory capacity, lung volumes, transfer factor (diffusing capacity, single breath CO method), and body composition (skinfold method). Linear and proportional regression models were used.
RESULTS—Terms for fat% and FFMI significantly improved the accuracy of reference values for all the primary lung function indices. The improvements in subjects with atypical physiques (fat% and FFMI at the ends of the distributions for the subjects) were in the range 0.3-2.3 SD compared with conventional regression equations. The new partial regression coefficients on age were independent of age related changes in body fat. The coefficient for total lung capacity (TLC) on age in men was now positive. Most differences between the sexes were eliminated. A term for BMI improved the descriptions of subdivisions of TLC but lacked the other advantages.
CONCLUSION—Allowance for fat% and FFMI increases the accuracy of reference equations for lung function, particularly for subjects with a lot of fat and little muscle or vice versa. Allowance for BMI is less informative.

PMCID: PMC1745971  PMID: 11641507
588.780 grm. of frogs, all of the same sex, of the same comparative approximate weights, taken from the ground about the same time, kept awake and without food for nearly the same time, were divided into equal groups; the one group was poisoned with phosphorus, the other group held as a control. The frogs in the poisoned group lost in dried residue 8.821 grm. or 16.5 per cent of the dried residue of the control group; 1.182 grm. of nitrogen, corresponding to 7.388 of proteid, or 18.45 per cent of the nitrogen and protein in the control frogs; 1.026 grm. of fat, or 22.64 per cent of the fat in the control animals; and 0.261 grm. glycogen, or 13.3 + per cent of the glycogen in the control frogs. I believe that it is obvious that in these experiments no fats were produced from protein. Mathematically, it is possible to conceive that fats could have been formed but entirely burned up. As previously stated, the carbon in the proteid lost during the poisoning was equivalent to 4.600 grm. of fat, and it is conceivable that these 4.600 grm. of fat were formed, but that they, together with the 1.026 grm. of fat actually lost during the experiments, were burned. In brief, the fat combustion might have been tremendously increased, and masked an actual fat formation. This however is unsupported by evidence, and is highly improbable. It is hard to conceive that in an organism whose katabolic functions were greatly augmented as the result of phosphorus poisoning, in which protein, fat, and glycogen were being burned in excess, the carbon of the protein would first have been converted into fat and then the fat burned as such. I believe the only conclusion which can be drawn from these experiments is that no fat was formed as the result of phosphorus poisoning. Thus the fatty degenerations so-called which occurred in these frogs did not comprehend any formation of fat at all, but simply the deposition of fat. These results are directly opposite to those of Polimanti. Polimanti apparently did not weigh his animals before the beginning of the experiment, and based his calculations upon the relation of the fat to the dried residue. Obviously his calculation was based upon the assumption that the dried residue of a frog was unaffected by phosphorus poisoning. Polimanti, in declining to base his calculations upon the weight of the animals when dead, states that as water is often increased, such a calculation would be misleading. But since the dried residue may and does vary, calculations based upon it are also misleading, and thus the only proper basis of calculation is the original weight of the frogs before the experimentation. Calculated upon the basis of the dried residue, in my material the percentage of fat in the control animals was 8.48 per cent, in the poisoned animals 7.86 per cent, so that, even upon the basis of Polimanti's incorrect calculation, in my experiments fat was lost in notable quantity. Just before this study was completed, the publication of Athanasiu, (8) from Pflueger's laboratory, appeared. Operating with a large number of frogs, and under varying conditions, with careful methods and rigid controls, Athanasiu reached the conclusions: that phosphorus poisoning has no effect upon the total quantity of fat in frogs; that it has little effect upon the nitrogen; that it produces a diminution in the quantity of glycogen; and that the fatty degenerations are really fatty infiltrations. While my results agree with those of Athanasiu in the essential point, that no fat was produced by phosphorus poisoning, they differ in that the poisoned frogs, in my experiments, lost fat and protein as well as glycogen, while his frogs lost only glycogen. Since our methods were almost the same, the differences must have resided either in the conditions surrounding the experiments, or in the animals. I do not believe that such differences exist between the Rana fusca and esculenta of Europe and the Rana palustris of America as to explain the differences in our results. These differences I believe may be explained by varying conditions. My animals were kept in a warm cellar, at a temperature of from 18 to 20° C. The period of poisoning with Athanasiu's frogs varied from one to six days; all of my frogs lived over six days, most of them ten or twelve days. Since we know that the katabolic actions of most poisons are greater in prolonged intoxications, it is fair to assume that the time element was the factor in the production of my results. While it would be unscientific and illogical to state that fat cannot be formed from protein, the fact stands that it has never been shown, either in physiology or pathology, that fats are formed from protein. On the contrary, nearly all of the careful work upon the question has yielded negative results. Not. only has it never been shown that, in fatty degeneration so-called, fat is formed from the cellular protein, but it has never been demonstrated that fat is then formed at all, even from glucosides, etc., substances from which fats may be readily formed.
PMCID: PMC2124491  PMID: 19866916
20.  Central overweight and obesity in British youth aged 11-16 years: cross sectional surveys of waist circumference 
BMJ : British Medical Journal  2003;326(7390):624.
To compare changes over time in waist circumference (a measure of central fatness) and body mass index (a measure of overall obesity) in British youth.
Representative cross sectional surveys in 1977, 1987, and 1997.
Great Britain.
Young people aged 11-16 years surveyed in 1977 (boys) and 1987 (girls) for the British Standards Institute (n=3784) and in 1997 (both sexes) for the national diet and nutrition survey (n=776).
Main outcome measures
Waist circumference, expressed as a standard deviation score using the first survey as reference, and body mass index (weight(kg)/height(m)2), expressed as a standard deviation score against the British 1990 revised reference. Overweight and obesity were defined as the measurement exceeding the 91st and 98th centile, respectively.
Waist circumference increased sharply over the period between surveys (mean increases for boys and girls, 6.9 and 6.2 cm, or 0.84 and 1.02 SD score units, P<0.0001). In centile terms, waist circumference increased more in girls than in boys. Increases in body mass index were smaller and similar by sex (means 1.5 and 1.6, or 0.47 and 0.53 SD score units, P<0.0001). Waist circumference in 1997 exceeded the 91st centile in 28% (n=110) of boys and 38% (n=147) of girls (against 9% for both sexes in 1977-87, P<0.0001), whereas 14% (n=54) and 17% (n=68), respectively, exceeded the 98th centile (3% in 1977-87, P<0.0001). The corresponding rates for body mass index in 1997 were 21% (n=80) of boys and 17% (n=67) of girls exceeding the 91st centile (8% and 6% in 1977-87) and 10% (n=39) and 8% (n=32) exceeding the 98th centile (3% and 2% in 1977-87).
Trends in waist circumference during the past 10-20 years have greatly exceeded those in body mass index, particularly in girls, showing that body mass index is a poor proxy for central fatness. Body mass index has therefore systematically underestimated the prevalence of obesity in young people.
What is already known on this topicThe prevalence of overweight and obesity in youth based on body mass index has increased over the past 10-20 yearsBody mass index gives no indication of body fat distributionWaist circumference is a marker for central body fat accumulation; a large waist circumference is linked to an increased risk of metabolic complicationsWhat this study addsWaist circumference in British youth has increased over the past 10-20 years at a greater rate than body mass index, the increase being greatest in femalesThe accumulation of central body fat has risen more steeply than whole body fatness based on height and weightCurrent and future morbidity in British youth may be seriously affected due to accumulation of excess central fat
PMCID: PMC151972  PMID: 12649234
21.  Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women 
PLoS Genetics  2012;8(5):e1002695.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Author Summary
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
PMCID: PMC3349734  PMID: 22589738
22.  Analysis of time-dependent adaptations in whole-body energy balance in obesity induced by high-fat diet in rats 
High-fat (HF) diet has been extensively used as a model to study metabolic disorders of human obesity in rodents. However, the adaptive whole-body metabolic responses that drive the development of obesity with chronically feeding a HF diet are not fully understood. Therefore, this study investigated the physiological mechanisms by which whole-body energy balance and substrate partitioning are adjusted in the course of HF diet-induced obesity.
Male Wistar rats were fed ad libitum either a standard or a HF diet for 8 weeks. Food intake (FI) and body weight were monitored daily, while oxygen consumption, respiratory exchange ratio, physical activity, and energy expenditure (EE) were assessed weekly. At week 8, fat mass and lean body mass (LBM), fatty acid oxidation and uncoupling protein-1 (UCP-1) content in brown adipose tissue (BAT), as well as acetyl-CoA carboxylase (ACC) content in liver and epidydimal fat were measured.
Within 1 week of ad libitum HF diet, rats were able to spontaneously reduce FI to precisely match energy intake of control rats, indicating that alterations in dietary energy density were rapidly detected and FI was self-regulated accordingly. Oxygen consumption was higher in HF than controls throughout the study as whole-body fat oxidation also progressively increased. In HF rats, EE initially increased, but then reduced as dark cycle ambulatory activity reached values ~38% lower than controls. No differences in LBM were detected; however, epidydimal, inguinal, and retroperitoneal fat pads were 1.85-, 1.89-, and 2.54-fold larger in HF-fed than control rats, respectively. Plasma leptin was higher in HF rats than controls throughout the study, indicating the induction of leptin resistance by HF diet. At week 8, UCP-1 content and palmitate oxidation in BAT were 3.1- and 1.5-fold higher in HF rats than controls, respectively, while ACC content in liver and epididymal fat was markedly reduced.
The thermogenic response induced by the HF diet was offset by increased energy efficiency and time-dependent reduction in physical activity, favoring fat accumulation. These adaptations were mainly driven by the nutrient composition of the diet, since control and HF animals spontaneously elicited isoenergetic intake.
PMCID: PMC3129582  PMID: 21679418
Energy efficiency; brown adipose tissue; UCP-1; energy expenditure; leptin; ACC; skeletal muscle; fat oxidation; food intake; adiposity
23.  Muscle Histidine-Containing Dipeptides Are Elevated by Glucose Intolerance in Both Rodents and Men 
PLoS ONE  2015;10(3):e0121062.
Muscle carnosine and its methylated form anserine are histidine-containing dipeptides. Both dipeptides have the ability to quench reactive carbonyl species and previous studies have shown that endogenous tissue levels are decreased in chronic diseases, such as diabetes.
Design and Methods
Rodent study: Skeletal muscles of rats and mice were collected from 4 different diet-intervention studies, aiming to induce various degrees of glucose intolerance: 45% high-fat feeding (male rats), 60% high-fat feeding (male rats), cafeteria feeding (male rats), 70% high-fat feeding (female mice). Body weight, glucose-tolerance and muscle histidine-containing dipeptides were assessed. Human study: Muscle biopsies were taken from m. vastus lateralis in 35 males (9 lean, 8 obese, 9 prediabetic and 9 newly diagnosed type 2 diabetic patients) and muscle carnosine and gene expression of muscle fiber type markers were measured.
Diet interventions in rodents (cafeteria and 70% high-fat feeding) induced increases in body weight, glucose intolerance and levels of histidine-containing dipeptides in muscle. In humans, obese, prediabetic and diabetic men had increased muscle carnosine content compared to the lean (+21% (p>0.1), +30% (p<0.05) and +39% (p<0.05), respectively). The gene expression of fast-oxidative type 2A myosin heavy chain was increased in the prediabetic (1.8-fold, p<0.05) and tended to increase in the diabetic men (1.6-fold, p = 0.07), compared to healthy lean subjects.
Muscle histidine-containing dipeptides increases with progressive glucose intolerance, in male individuals (cross-sectional). In addition, high-fat diet-induced glucose intolerance was associated with increased muscle histidine-containing dipeptides in female mice (interventional). Increased muscle carnosine content might reflect fiber type composition and/or act as a compensatory mechanism aimed at preventing cell damage in states of impaired glucose tolerance.
PMCID: PMC4372406  PMID: 25803044
24.  Non-Invasive Quantification of White and Brown Adipose Tissues and Liver Fat Content by Computed Tomography in Mice 
PLoS ONE  2012;7(5):e37026.
Obesity and its distribution pattern are important factors for the prediction of the onset of diabetes in humans. Since several mouse models are suitable to study the pathophysiology of type 2 diabetes the aim was to validate a novel computed tomograph model (Aloka-Hitachi LCT-200) for the quantification of visceral, subcutaneous, brown and intrahepatic fat depots in mice.
Different lean and obese mouse models (C57BL/6, B6.V-Lepob, NZO) were used to determine the most adequate scanning parameters for the detection of the different fat depots. The data were compared with those obtained after preparation and weighing the fat depots. Liver fat content was determined by biochemical analysis.
The correlations between weights of fat tissues on scale and weights determined by CT were significant for subcutaneous (r2 = 0.995), visceral (r2 = 0.990) and total white adipose tissue (r2 = 0.992). Moreover, scans in the abdominal region, between lumbar vertebrae L4 to L5 correlated with whole-body fat distribution allowing experimenters to reduce scanning time and animal exposure to radiation and anesthesia. Test-retest reliability and measurements conducted by different experimenters showed a high reproducibility in the obtained results. Intrahepatic fat content estimated by CT was linearly related to biochemical analysis (r2 = 0.915). Furthermore, brown fat mass correlated well with weighted brown fat depots (r2 = 0.952). In addition, short-term cold-expose (4°C, 4 hours) led to alterations in brown adipose tissue attributed to a reduction in triglyceride content that can be visualized as an increase in Hounsfield units by CT imaging.
The 3D imaging of fat by CT provides reliable results in the quantification of total, visceral, subcutaneous, brown and intrahepatic fat in mice. This non-invasive method allows the conduction of longitudinal studies of obesity in mice and therefore enables experimenters to investigate the onset of complex diseases such as diabetes and obesity.
PMCID: PMC3353985  PMID: 22615880
25.  Critical Role of the Mesenteric Depot Versus Other Intra-abdominal Adipose Depots in the Development of Insulin Resistance in Young Rats 
Diabetes  2010;59(6):1416-1423.
Age-associated insulin resistance may be caused by increased visceral adiposity and older animals appear to be more susceptible to obesity-related resistance than young animals. However, it is unclear to what extent the portally drained mesenteric fat depot influences this susceptibility.
Young high-fat–fed and old obese rats were subjected to 0, 2, 4, or 6 weeks of caloric restriction. Insulin sensitivity (SI) was assessed by hyperinsulinemic clamp and lean body mass (LBM) and total body fat were assessed by 18O-water administration.
Six weeks of caloric restriction caused a similar reduction in body weight in young and old animals (P = 0.748) that was not due to reduced subcutaneous fat or LBM, but rather preferential loss of abdominal fat (P < 0.05). Most notably, mesenteric fat was reduced equivalently in young and old rats after 6 weeks of caloric restriction (∼↓53%; P = 0.537). Despite similar visceral fat loss, SI improved less in old (↑32.76 ± 9.80%) than in young (↑82.91 ± 12.66%) rats versus week 0. In addition, there was significantly more reversal of fat accumulation in the liver in young (% reduction: 89 ± 2) versus old (64 ± 5) rats (P < 0.0001). Furthermore, in young rats, SI changed much more rapidly for a given change in mesenteric fat versus other abdominal depots (slope = 0.53 vs. ≤0.27 kg/min/mg per % fat).
Improved SI during caloric restriction correlated with a preferential abdominal fat loss. This improvement was refractory in older animals, likely because of slower liberation of hepatic lipid. Furthermore, mesenteric fat was a better predictor of SI than other abdominal depots in young but not old rats. These results suggest a singular role for mesenteric fat to determine insulin resistance. This role may be related to delivery of lipid to liver, and associated accumulation of liver fat.
PMCID: PMC2874702  PMID: 20299478

Results 1-25 (955661)