Genetic variation in two proteins of the endocannabinoid system and their influence on body mass index and metabolism under low fat diet.

The endocannabinoid system (ECS) plays an important and not yet fully understood role in hypothalamic and peripheral regulation of food intake, obesity, and metabolism. Two frequent single nucleotide polymorphisms (snp) have been identified in members of the ECS: the 1359 G/A variant in the cannabinoid receptor 1 ( CB1) and the P129T polymorphism in fatty acid amide hydrolase ( FAAH), a key degradation enzyme of endocannabinoids. -While for the 1359 G/A variant an association has been shown only with psychiatric diseases such as drug-abusing schizophrenia, the P129T polymorphism has recently been proved to be correlated to a higher body mass index (BMI) in a group of black and white Americans. However, no knowledge exists as to whether these variants affect the outcome of a low fat diet in obese subjects. Therefore, we genotyped a group of 451 obese and dyslipidaemic participants and observed the biometric and metabolic outcome of a 6 week low fat diet. While no significance was seen for the 1359 G/A variant, carriers of the P129T mutation in FAAH had a significantly greater decrease in triglycerides and total cholesterol as compared to wild type. The reason for our findings remains to be elucidated, however, a hepatic downregulation of endocannabinoid tone may contribute to the observed outcome in studied subjects.     

Androgens and body fat distribution

An important sex difference in body fat distribution is generally observed. Men are usually characterized by the android type of obesity, with accumulation of fat in the abdominal region, whereas women often display the gynoid type of obesity, with a greater proportion of their body fat in the gluteal-femoral region. Accordingly, the amount of fat located inside the abdominal cavity (intra-abdominal or visceral adipose tissue) is twice as high in men compared to women. This sex difference has been shown to explain a major portion of the differing metabolic profiles and cardiovascular disease risk in men and women. Association studies have shown that circulating androgens are negatively associated with intra-abdominal fat accumulation in men, which explains an important portion of the link between low androgens and features of the metabolic syndrome. In women, the low circulating sex hormone-binding globulin (SHBG) levels found in abdominal obesity may indirectly indicate that elevated free androgens are related to increased visceral fat accumulation. However, data on non SHBG-bound and total androgens are not unanimous and difficult to interpret for total androgens. These studies focusing on plasma levels of sex hormones indirectly suggest that androgens may alter adipose tissue mass in a depot-specific manner. This could occur through site-specific modulation of preadipocyte proliferation and/or differentiation as well as lipid synthesis and/or lipolysis in mature adipocytes. Recent results on the effects of androgens in cultured adipocytes and adipose tissue have been inconsistent, but may indicate decreased adipogenesis and increased lipolysis upon androgen treatment. Finally, adipose tissue has been shown to express several steroidogenic and steroid-inactivating enzymes. Their mere presence in fat indirectly supports the notion of a highly complex enzymatic system modulating steroid action on a local basis. Recent data obtained in both men and women suggest that enzymes from the aldoketoreductase 1C family are very active and may be important modulators of androgen action in adipose tissue.     

Effect of body fat and gender on body temperature distribution

It is well known that body composition can influence peripheral heat loss and skin temperature. That the distribution of body fat is affected by gender is well known; however, there is little information on how body composition and gender influences the measure of skin temperature. This study evaluated skin temperature distribution according to body fat percentage (BF%) and gender. A sample of 94 apparently healthy volunteers (47 women and 47 men) was assessed with Dual-Energy X-Ray Absorptiometry (DXA) and infrared thermography (mean, maximum and minimum temperatures – T_Mean, T_Max and T_Min). The sample was divided into groups, according to health risk classification, based on BF%, as proposed by the American College of Sports Medicine: Average (n = 58), Elevated (n = 16) or High (n = 20). Women had lower T_Mean in most regions of interest (ROI). In both genders, group High had lower temperature values than Average and Elevated in the trunk, upper and lower limbs. In men, palms and posterior hands had a tendency (p < 0.05) for increased temperature along with increased BF%. T_Mean, T_Max and T_Min of trunk, upper and lower limbs were negatively correlated with BF% and the fat percentage of each segment (upper limbs, lower limbs and trunk). The highest correlations found in women were between posterior trunk and BF% (rho = −0.564, p < 0.001) and, in men, between anterior trunk and BF% (rho = −0.760, p < 0.001). Overall, this study found that women have lower skin temperature than men, which was related with higher BF%. Facial temperature seems not to be influenced by body fat. With the future collection of data on the relationship between BF% and skin temperature while taking into account factors such as body morphology, gender, and ethnicity, we conclude that measurement of BF may be reliably estimated with the use of thermal imaging technology.     

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.     

The effect of body fat percentage and body fat distribution on skin surface temperature with infrared thermography

This study aimed to search for relations between body fat percentage and skin temperature and to describe possible effects on skin temperature as a result of fat percentage in each anatomical site. Women (26.11±4.41 years old) (n =123) were tested for: body circumferences; skin temperatures (thermal camera); fat percentage and lean mass from trunk, upper and lower limbs; and body fat percentage (Dual-Energy X-Ray Absorptiometry). Values of minimum (T_Mi), maximum (T_Ma), and mean temperatures (T_Me) were acquired in 30 regions of interest. Pearson's correlation was estimated for body circumferences and skin temperature variables with body fat percentage. Participants were divided into groups of high and low fat percentage of each body segment, of which T_Me values were compared with Student's t-test. Linear regression models for predicting body fat percentage were tested. Body fat percentage was positively correlated with body circumferences and palm temperatures, while it was negatively correlated with most temperatures, such as T_Ma and T_Me of posterior thighs (r =−0.495 and −0.432), T_Me of posterior lower limbs (r =−0.488), T_Ma of anterior thighs (r =−0.406) and T_Mi and T_Me of posterior arms (r =−0.447 and −0.430). Higher fat percentages in the specific anatomical sites tended to decrease T_Me, especially in posterior thighs, shanks and arms. Skin temperatures and body circumferences predicted body fat percentage with 58.3% accuracy (R =0.764 and R² =0.583). This study clarifies that skin temperature distribution is influenced by the fat percentage of each body segment.     

Effects of tea catechins on lipid metabolism and body fat accumulation

Long-term feeding of tea catechins suppressed body fat accumulation in high-fat diet-induced obesity in mice, and that their effects might be attributed, at least in part, to the activation of hepatic lipid metabolism. Consecutive intake of tea catechins (588 mg/day) reduced body fat, especially abdominal fat in humans. These results demonstrate that intake of tea catechins is beneficial for body fat accumulation.     

The influence of forskolin on the metabolism of ecdysone and 20-hydroxyecdysone in isolated fat body of the blowfly, Calliphora vicina

Rates of ecdysone and 20-hydroxyecdysone metabolism were measured by radio-assay in an in vitro system containing fat body isolated from blowfly larvae. The addition of forskolin which is known to stimulate artificially the intracellular adenylate cyclase system led to decreased rates of conversion of ecdysone into 20-hydroxyecdysone (= hormone activation) and of 20-hydroxyecdysone further to other metabolites (= hormone inactivation). The effect of forskolin was dose-dependent and reversible. Extracts prepared from larval brains were also tested. Some of them had the same effect as forskolin. It is concluded that the reactions leading from ecdysone to 20-hydroxyecdysone and further to hormonally inactive ecdysteroids are modulated by the intracellular level of cyclic nucleotides. We propose that a neurohormone is involved in the control of the reactions of the ecdysone metabolism. The observed new principle may contribute to the control of the titer of moulting hormone.     

Genetic code,attributive mappings and stochastic matrices

In this paper we construct three primitive mappings based on three kinds of genetic attribute equivalences. We then apply the mappings and basic addition operation to the universal genetic code to generate three square matrices. We show that these square matrices are stochastic in nature. They demonstrate some fractal similarity properties and resemble the similar properties to the original stochastic matrices.     

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.     

Capsaicin-sensitive intestinal mucosal afferent mechanism and body fat distribution

This report summarizes clinical and experimental data in support of the hypothesis that capsaicin-sensitive intestinal mucosal afferent mechanism plays a role in regulating body fat distribution. Epidemiological data have revealed that the consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Rural Thai people consume diets containing 0.014% capsaicin. Rodents fed a diet containing 0.014% capsaicin showed no change in caloric intake but a significant 24% and 29% reduction in the visceral (peri-renal) fat weight. Increase in intestinal blood flow facilitates nutrient energy absorption and decrease in adipose tissue blood flow facilitates storage of nutrient energy in adipose tissue. Stimulation of intestinal mucosal afferent nerves increases intestinal blood flow, but decreases visceral (mesenteric) adipost tissue blood flow. In in vitro cell studies capsaicin has a direct effect on adipocytes. Intravenous capsaicin produces measurable plasma level and subcutaneous capsaicin retards accumulation of adipose tissue. The data on a direct effect of oral capsaicin on adipose tissue at remote sites, however, are conflicting. Capsaicin absorbed from the gut lumen is almost completely metabolized before reaching the general circulation. Oral capsaicin significantly increases transient receptor potential vanilloid type-1 (TRPV1) channel expression as well as TRPV1 messenger ribonucleic acid (mRNA) in visceral adipose tissue. In TRPV1 knockout mice on a high fat diet the body weight was not significantly different in the absence or presence of oral capsaicin. In rodent experiments, daily intragastric administration of capsaicin for two weeks led to defunctionalization of intestinal mucosal afferent nerves, manifested by loss of acute mucosal capsaicin-induced effects; but not the corneal afferent nerves, with preservation of the paw wiping reflex of the eye exposed briefly to dilute capsaicin. The latter indicated the absence of an oral capsaicin effect at one remote site. There was an accompanying decrease and an increase in the proportion of body fat in visceral and subcutaenous compartments, respectively. Taken together, if oral capsaicin could regulate adipose tissue distribution, the process might involve the effect of intestinal mucosal afferent nerves in modulating intestinal and visceral adipose tissue blood flow. The hypothesis that the intestinal mucosal afferent mechanism is a plausible therapeutic target for abating visceral obesity deserves to be further evaluated.     

Genetic association study of common mitochondrial variants on body fat mass

Mitochondria play a central role in ATP production and energy metabolism. Previous studies suggest that common variants in mtDNA are associated with several common complex diseases, including obesity. To test the hypothesis that common mtDNA variants influence obesity-related phenotypes, including BMI and body fat mass, we genotyped a total of 445 mtSNPs across the whole mitochondrial genome in a large sample of 2,286 unrelated Caucasian subjects. 72 of these 445 mtSNPs passed quality control criteria, and were used for subsequent analyses. We also classified all subjects into nine common European haplogroups. Association analyses were conducted for both BMI and body fat mass with single mtSNPs and mtDNA haplogroups. Two mtSNPs, mt4823 and mt8873 were detected to be significantly associated with body fat mass, with adjusted P values of 4.94×10^-3 and 4.58×10^-2, respectively. The minor alleles mt4823 C and mt8873 A were associated with reduced fat mass values and the effect size (β) was estimated to be 3.52 and 3.18, respectively. These two mtSNPs also achieved nominally significant levels for association with BMI. For haplogroup analyses, we found that haplogroup X was strongly associated with both BMI (adjusted P = 8.31×10^-3) and body fat mass (adjusted P = 5.67×10^-4) Subjects classified as haplogroup X had lower BMI and fat mass values, with the β estimated to be 2.86 and 6.03, respectively. Our findings suggest that common variants in mitochondria might play a role in variations of body fat mass. Further molecular and functional studies will be needed to clarify the potential mechanism.     

The relationship between aromatase activity and body fat distribution

The metabolism of androstenedione (A) to estrone (E1) and 5 alpha-reduced androgens was studied in stromal cells derived from human adipose tissue from different body sites. The tissue was obtained from non-obese patients undergoing cosmetic liposuction or at the time of surgery for reduction mammoplasty. The conversion of A to E1 per 1x 10(6) cells was between 6- and 30-fold greater in the upper thigh, buttock, and flank than in the abdomen. These differences were present in primary culture and persisted to at least the third subculture. Estrogen formation in breast adipose tissue was similar to that found in cells from abdominal fat. The formation of 5 alpha-reduced metabolites (5 alpha-androstenedione, androsterone, and dihydrotestosterone) varied from patient to patient but was similar in cells from different body sites. These studies show that the regional distribution of fat may influence the metabolism of androgens in adipose tissue, with upper body fat tending to form a lower ratio of estrogens to 5 alpha-reduced androgens than lower body fat.     

Evidence of genetic influence on central body fat in middle-aged twins

The heritability of centrally and peripherally deposited subcutaneous body fat, as measured by thickness of subscapular and triceps skinfolds respectively, was examined in 173 monozygotic and 178 dizygotic pairs of white male twins, ages 54 to 65 years, who participated in the second examination of the National Heart, Lung, and Blood Institute's Twin Study. The heritability of two indices of body fat distribution (subscapular/triceps ratio and subscapular-triceps difference) and two indices of overall obesity (body mass index and sum of skinfolds) were also assessed. Evidence for a genetic influence on central deposition of body fat was suggested in that the classical estimate of heritability for subscapular skinfold thickness was 0.77 (p less than 0.0001). After adjusting subscapular skinfold for the overall level of obesity, heritability was reduced but remained highly significant (0.40, p = 0.003). Heritability estimates for triceps skinfold thickness and for the two fat distribution indices were substantially lower and were not statistically significant after adjustment for overall obesity. High classical estimates of heritability were also observed for both measures of overall obesity: 0.70 for BMI and 0.73 for sum of skinfolds. However, these two estimates were biased upward because of lower total variances among monozygotic compared to dizygotic twins in this sample. The more conservative and unbiased among-component estimates also suggested substantial heritability for each measure (0.35, p = 0.08 and 0.53, p = 0.01, respectively). The heritability of overall obesity emphasizes the importance of adjusting measures of fat distribution for overall obesity before assessing its heritability.     

The influence of body composition, fat distribution, and sustained weight loss on left ventricular mass and geometry in obesity

Alterations in left ventricular mass and geometry vary along with the degree of obesity, but mechanisms underlying such covariation are not clear. In a case–control study, we examined how body composition and fat distribution relate to left ventricular structure and examine how sustained weight loss affects left ventricular mass and geometry. At the 10‐year follow‐up of the Swedish obese subjects (SOS) study cohort, we identified 44 patients with sustained weight losses after bariatric surgery (surgery group) and 44 matched obese control patients who remained weight stable (obese group). We also recruited 44 matched normal weight subjects (lean group). Dual‐energy X‐ray absorptiometry, computed tomography, and echocardiography were performed to evaluate body composition, fat distribution, and left ventricular structure. BMI was 42.5 kg/m², 31.5 kg/m², and 24.4 kg/m² for the obese, surgery, and lean groups, respectively. Corresponding values for left ventricular mass were 201.4 g, 157.7 g, and 133.9 g (P < 0.001). In multivariate analyses, left ventricular diastolic dimension was predicted by lean body mass (β = 0.03, P < 0.001); left ventricular wall thickness by visceral adipose tissue (β = 0.11, P < 0.001) and systolic blood pressure (β = 0.02, P = 0.019); left ventricular mass by lean body mass (β = 1.23, P < 0.001), total body fat (β = 1.15, P < 0.001) and systolic blood pressure (β = 2.72, P = 0.047); and relative wall thickness by visceral adipose tissue (β = 0.02, P < 0.001). Left ventricular adjustment to body size is dependent on body composition and fat distribution, regardless of blood pressure levels. Obesity is associated with concentric left ventricular remodeling and sustained 10‐year weight loss results in lower cavity size, wall thickness and mass.     

Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss

Polymorphisms in the fat mass- and obesity-associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome-wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single-nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two-hundred and four subjects participated in a lifestyle intervention program and were examined after a follow-up of 9 months. In the cross-sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P < or = 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P < or = 0.1). However, the single-nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.