Pubertal alterations in growth and body composition. V. Energy expenditure, adiposity, and fat distribution

We determined whether activity energy expenditure (AEE, from doubly labeled water and indirect calorimetry) or physical activity [7-day physical activity recall (PAR)] was more related to adiposity and the validity of PAR estimated total energy expenditure (TEE(PAR)) in prepubertal and pubertal boys (n = 14 and 15) and girls (n = 13 and 18). AEE, but not physical activity hours, was inversely related to fat mass (FM) after accounting for the fat-free mass, maturation, and age (partial r = -0.35, P < or = 0.01). From forward stepwise regression, pubertal maturation, AEE, and gender predicted FM (r(2) = 0.36). Abdominal visceral fat and subcutaneous fat were not related to AEE or activity hours after partial correlation with FM, maturation, and age. When assuming one metabolic equivalent (MET) equals 1 kcal. kg body wt(-1). h(-1), TEE(PAR) underestimated TEE from doubly labeled water (TEE bias) by 555 kcal/day +/- 2 SD limits of agreement of 913 kcal/day. The measured basal metabolic rate (BMR) was >1 kcal. kg body wt(-1). h(-1) and remained so until 16 yr of age. TEE bias was reduced when setting 1 MET equal to the measured (bias = 60 +/- 51 kcal/day) or predicted (bias = 53 +/- 50 kcal/day) BMR but was not consistent for an individual child (+/- 2 SD limits of agreement of 784 and 764 kcal/day, respectively) or across all maturation groups. After BMR was corrected, TEE bias remained greatest in the prepubertal girls. In conclusion, in children and adolescents, FM is more strongly related to AEE than activity time, and AEE, pubertal maturation, and gender explain 36% of the variance in FM. PAR should not be used to determine TEE of individual children and adolescents in a research setting but may have utility in large population-based pediatric studies, if an appropriate MET value is used to convert physical activity data to TEE data.     

Body fat, abdominal fat, and body fat distribution is related to left atrial diameter in young children

In adults, the size of the left atria (LA) has important prognostic information. In obese adults, adolescents and children enlargement of LA have been observed. This has not been investigated on a population-based level in young children. We therefore assessed if total body fat mass (TBF), abdominal fat, and body fat distribution were related to LA diameter. Cross-sectional study of 244 children (boys = 137 and girls n = 107) aged 8-11 years, recruited from an urban population-based cohort. Dual-energy X-ray absorptiometry (DXA) measured total lean body mass, TBF, and abdominal fat mass (AFM). Body fat was also calculated as a percentage of body mass (BF%). Body fat distribution (AFM/TBF) was calculated. Echocardiography was performed with two-dimensional guided M-mode. LA diameter was measured and left ventricular mass (LVM) was calculated. Systolic blood pressure and diastolic blood pressure were measured and maturity assessed according to Tanner. There were significant (P < 0.05) univariate correlations for all children between TBF (r = 0.40), BF% (r = 0.32), AFM (r = 0.41), and AFM/TBF (r = 0.41) vs. LA diameter. Multiple regression analyses with the inclusion of possible confounders such as lean body mass, blood pressure, gender, age, and Tanner stage revealed that TBF, AFM, and AFM/TBF were all independently related to LA diameter. Differences in the different body fat measurements explained 6-9% of the variance in LA size. These results demonstrated that both total body fat, AFM, and body fat distribution are already at a young age negatively and independently associated to LA diameter.     

Endogenous estrogens and breast cancer a possible relationship between body fat distribution and estrogen availability

The growth of hormone-dependent human breast cancer is related to the activity of endogenous estrogens. The evidence for an etiological role of endogenous estrogens is still circumstantial. Life style and in particular dietary factors are held responsible for large geographic differences and time-trends in breast cancer incidence. The measurement of urinary estrogen metabolites and plasma estrogens has given no satisfactory explanation for the latter. The newly developed interest in the bioavailability of plasma sex steroids may offer a better understanding of the biology and epidemiology of breast cancer. Based on our observations on the relationship between plasma free fatty acids and estrogen-protein-binding and recently gained insight in the metabolic consequences of different types of body fat distribution we postulate that Western life style may act on breast cancer incidence through an influence on body fat distribution and resulting changes in sex steroid availability.     

LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations

Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A-type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases.     

Lipoprotein lipase in lungs, spleen, and liver: synthesis and distribution.

Lipoprotein lipase (LPL, E C 3.1.1.34) is the enzyme responsible for hydrolysis of triacylglycerols in plasma lipoproteins, making the fatty acids available for use by subjacent tissues. LPL is functional at the surface of endothelial cells, but it is not clear which cells synthesize the enzyme and what its distribution within tissues and vessels is. In previous studies we reported that in the major LPL-producing tissues (muscles, adipose tissue, and mammary gland) the enzyme is made by the major cell types. In the present work we have studied in adult guinea pigs some tissues that present LPL activity but in lower amounts (lung, spleen, and liver). On cryosections of these tissues we have searched for specific cell expression of the LPL gene (by in situ hybridization using a RNA probe) and for the corresponding protein distribution (by immunocytochemistry). Based on morphological criteria we can suggest that, contrary to the main LPL-producing tissues, in these tissues the enzyme is made by scattered cells, such as macrophages in the lung and spleen and Kupffer cells in the liver; endothelial cells present but do not synthesize the enzyme, indicating that the endothelial LPL originates in other cells. In the liver strong immunoreaction was detected in the sinusoid in contrast to the low level of mRNA expression, suggesting that liver takes up circulating LPL from blood.     

Inactivity induces increases in abdominal fat.

Previously, inducing inactivity for 53 h after 21 days of voluntary running resulted in a 25 and 48% increase in epididymal and omental fat pad weights, respectively, while rats continued to eat more than a group that never had access to a running wheel (J Physiol 565: 911-925, 2005). We wanted to test the hypothesis that inactivity, independent of excessive caloric intake, could induce an increase in fat pad mass. Twenty-one-day-old rats were given access to voluntary running wheels for 42-43 days so that they were running approximately 9 km/day in the last week of running, after which wheels were locked for 5, 53, or 173 h (WL5, WL53, WL173) before the rats were killed. During the 53 and 173 h of inactivity, one group of animals was pair fed (PF) to match sedentary controls, whereas the other continued to eat ad libitum (AL). Epididymal and retroperitoneal fat masses were significantly increased in the WL173-PF vs. the WL5 group, whereas epididymal, perirenal, and retroperitoneal fat masses were all significantly increased in the WL173-AL group compared with the WL5 group. Additionally, hyperplasia, and not hypertrophy, of the epididymal fat mass was responsible for the increase at WL173-AL as demonstrated by a significant increase in cell number vs. WL5, with no change in cell diameter or volume. Thus two important findings have been elucidated: 1) increases in measured abdominal fat masses occur in both AL and PF groups at WL173, and 2) adipocyte expansion via hyperplasia occurred with an ad libitum diet following cessation of voluntary running.     

Sodium-lithium countertransport and body fat distribution.

The relationship between erythrocyte sodium-lithium countertransport (Na-Li CT) and body fat distribution is analyzed in a sample (n = 101) of normotensive and untreated hypertensive men participating in an epidemiological study of coronary heart disease risk factors. Na-Li CT is significantly and positively associated with both subscapular skinfold and waist to hip ratio, but not with triceps skinfold. The univariate correlation between Na-Li CT and blood pressure is diminished when adjusted for body mass index and waist to hip ratio. These findings support the existence of an association between Na-Li CT and central body fat distribution and suggest that the metabolic abnormalities associated with centrally distributed body fat could explain, at least in part, the association between Na-Li CT and blood pressure. The maximal velocity of the sodium-lithium countertransport (Na-Li CT) in erythrocytes has been reported to be directly associated with blood pressure and hypertension in numerous reports from both clinical and epidemiological studies. In most of these studies, indices of weight and/or adiposity (body mass index, in particular) have been shown to be among the most important correlates of Na-Li CT. Adiposity is an important determinant of blood pressure, and there is evidence suggesting that the patterning of the fat cells in the body is linked to a number of metabolic disturbances that could lead to hypertension and an increase in other CHD risk factors. The present report analyses the relationship between Na-Li CT and body fat distribution in a sample of normotensive and untreated hypertensive men participating in an epidemiological study.     

Tamoxifen induced membrane alterations in human breast cancer cells

It was previously shown that proliferation of CG-5 cells, an estrogen supersensitive variant of the MCF-7 cell line, is inhibited by tamoxifen starting three days after addition to culture medium. In this paper we report here on the effect of tamoxifen on CG-5 cell membrane morphology using scanning electron microscope. The addition of the antiestrogen to CG-5 cells causes marked alterations of cell surface, consisting of reduction in the length and the number of microvilli. Moreover, cells appear flattened and of reduced thickness. These modifications are more pronounced in cells plated at low density, but they are observed also in nearly confluent monolayers. In this case alterations are more evident in the center of cell islands, while at the periphery there is a certain mobility as reflected by the persistence of few microvilli and philopodia. These early effects of tamoxifen on cell membrane raise the possibility that parallel modifications in membrane function may occur which are responsible for alterations impairing transport mechanisms.     

Sugar,fat, and the risk of colorectal cancer.

The habitual diet of 50 patients with large bowel cancer, as assessed by a dietary history method, was compared with that of 50 closely matched controls. Patients were included only if their symptoms were unlikely to have changed previous eating habits. The mean daily intakes of all major nutrient classes and of dietary fibre were estimated. Patients with large bowel cancer consumed 16% more energy than controls (mean (SEM) daily intake 9.92 (0.41) v 8.56 (0.32) MJ (2370 (98) v 2046 (76) kcal), respectively; p less than 0.0001), mainly in the form of carbohydrate (21% more; 282.6 (13.7) v 233.4 (10.5) g; p less than 0.0001) and fat (14% more; 100.8 (4.3) v 88.4 (3.2) g; p less than 0.001). The extra carbohydrate was largely in the form of sugars depleted in fibre and the extra fat as combinations of fat and such sugars. As the selection criteria used make it unlikely that this eating pattern was caused by the disease the data suggest that a high intake of sugars depleted in fibre and fat predisposes to the development of large bowel cancer.     

Contribution of breast volume and weight to body fat distribution in females

Breast volume and body composition were measured in 45 adult females to determine the contribution of breast weight and breast volume to total body fat. Plaster casts were filled with sand of known density to obtain breast volume. Breast weight was computed as breast volume times its density. The correlation between total breast volume and percent body fat was r = .40. Breast weight (X = 484 grams) accounted for 3.5 percent of the total weight of body fat, and at most, 12 percent of the estimated quantities of sex-specific fat. A theoretical model is proposed for the distribution of body fat in the female which subdivides total body fat into three components: reserve storage fat, essential fat, and expendable storage fat.     

Genetic analysis of abdominal fat distribution in SM/J and A/J mice

Each abdominal fat depot, such as mesenteric or epididymal, differently contributes to the development of insulin resistance. The aim of this study was to identify the genetic regions that contribute to fat accumulation in epididymal/mesenteric fat and to examine whether or not the genetic regions that affect glucose metabolism and body fat distribution are coincident. We previously mapped a major quantitative trait locus (QTL) (T2dm2sa) for impaired glucose tolerance on chromosome 2 and revealed that SM.A-T2dm2sa congenic mice showed not only glucose tolerance but also fat accumulation. In the present study, to identify the loci/genes that control the accumulation of abdominal fat, we perfomed QTL analyses of epididymal/mesenteric fat weight by using (A/J×SM.A-T2dm2sa)F2 mice in which the effect of T2dm2sa was excluded. As a result, two highly significant QTLs for mesenteric fat, as well as three significant QTLs for epididymal/mesenteric fat, were mapped on the different chromosomal regions. This suggests that the fat accumulations in individual fat depots are controlled by distinct genomic regions. Our comparison of these QTLs for abdominal fat distribution with those for glucose metabolism revealed that the major genetic factors affecting body fat distribution do not coincide with genetic factors affecting glucose metabolism in (A/J×SM.A-T2dm2sa)F2.     

Relationships of resting energy expenditure with body fat distribution and abdominal fatness in Japanese population

Body fat distribution and abdominal fatness are indicators of risks for coronary heart disease. However, the relationships between resting energy expenditure (REE) and the body fat distribution or the abdominal fatness are unclear. We examined the relationships of REE with whole-body fat distribution (waist, hip and waist-to-hip ratio: WHR) and abdominal fatness (intra-abdominal fat: IF and subcutaneous fat: SF) after adjustment for body composition. 451 men and 471 women were subdivided into two groups, 40-59 years: middle-aged group and 60-79 years: elderly group. REE was measured by an indirect calorimetry system. Percentage of fat mass (%FM), fat mass (FM) and fat-free mass (FFM) were assessed by a dual-energy x-ray absorptiometry method. The IF area (IFA) and SF area (SFA) at the level of the umbilicus were measured using computed tomography. Circumference of waist and hip were measured in a standing position. The WHR, waist circumference and SFA did not significantly (p>0.05) associate with the REE after adjusting for FM, FFM and age in any of the groups. The adjusted REE was significantly and inversely correlated with hip (r=-0.159, p<0.05) and IFA (r=-0.131, p<0.05) in the elderly men. These results suggest that lower REE may contribute to greater hip and IFA rather than WHR and waist in elderly men.     

Cytoskeleton alterations induced by Geodia corticostylifera depsipeptides in breast cancer cells

Crude extracts of the marine sponge Geodia corticostylifera from Brazilian Coast have previously shown antibacterial, antifungal, cytotoxic, haemolytic and neurotoxic activities. The present work describes the isolation of the cyclic peptides geodiamolides A, B, H and I (1-4) from G. corticostylifera and their anti-proliferative effects against sea urchin eggs and human breast cancer cell lineages. Its structure-activity relationship is discussed as well. In an initial series of experiments these peptides inhibited the first cleavage of sea urchin eggs (Lytechinus variegatus). Duplication of nuclei without complete egg cell division indicated the mechanism of action might be related to microfilament disruption. Further studies showed that the geodiamolides have anti-proliferative activity against human breast cancer cell lines (T47D and MCF7). Using fluorescence techniques and confocal microscopy, we found evidence that the geodiamolides A, B, H and I act by disorganizing actin filaments of T47D and MCF7 cancer cells, in a way similar to other depsipeptides (such as jaspamide 5 and dolastatins), keeping the normal microtubule organization. Normal cells lines (primary culture human fibroblasts and BRL3A rat liver epithelial cells) were not affected by the treatment as tumor cells were, thus indicating the biomedical potential of these compounds.     

Identification of specific nuclear structural protein alterations in human breast cancer

Breast cancer is the most commonly diagnosed type of cancer and a major cause of death in women. Reliable biomarkers are urgently needed to improve early detection or to provide evidence of the prognosis for each individual patient through expression levels in tumor tissue or body fluids. This proteomic analysis focused on the nuclear structure of human breast cancer tissue, which has been shown to be a promising tool for cancer biomarker development. The nuclear matrix composition of human breast cancer (n = 14), benign controls (n = 2), and healthy controls (n = 2) was analyzed by high‐resolution two‐dimensional gel electrophoresis and mass spectrometry. Validation studies were performed in an individual sample set consisting of additional breast cancer tissues (n = 3) and additional healthy control tissues (n = 2) by one‐dimensional immunoblot. In this setting, we identified five proteins that were upregulated in human breast cancer tissue, but absent in the healthy and benign controls (P < 0.001). These spots were also present in the investigated human breast cancer cell lines, but absent in the MCF10a cell line, which represents normal human epithelial breast cells. Two of the breast cancer‐specific proteins have been confirmed to be calponin h2 and calmodulin‐like protein 5 by one‐dimensional immunoblot. This is the first study demonstrating the expression of both proteins in human breast cancer tissue. Further studies are required to investigate the potential role of these proteins as biomarkers for early diagnosis or prognosis in human breast cancer. J. Cell. Biochem. 112: 3176–3184, 2011. © 2011 Wiley Periodicals, Inc.     

Monogenic disorders of obesity and body fat distribution.

Recently, great progress has been made towards understanding the molecular basis of body fat regulation. Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) gamma2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future.