Inheritance Of Obesity Research Articles

EDC exposure in 3D genome memory in transgenerational obesity.

A new study reveals that exposure of pregnant mice to an endocrine disrupting chemical, bisphenol A, induces multi-transgenerational (up to six) inheritance of obesity in their descendants. This effect depends on CTCF-dependent chromatin reorganization in the sperm, a synergistic outcome of altered DNA methylation, RNA modification and long-range chromatin interactions.

The inheritance of obesity

Syndromic adiposity appears to have a predisposition to run in families suggesting a hereditary element in its transmission. Purely genetic defects and DNA sequence variants have been directly associated with the development of adiposity; however, these account for a very small proportion of cases. A stronger association has been made between the intrauterine and early childhood nutritional environment of the foetus and young child and the predisposition of childhood and subsequent adulthood obesity. The nutritional environments include both a situation of nutritional deprivation or excess working through the interplay of epigenetic changes, and pancreatic and hypothalamic development. This is further compounded by the nutritional and lifestyle attitudes of the particular at-risk family. Adiposity prevention measures must include reenforced intervention strategies stating with lifestyle education schemes during pregnancy followed through until infancy and early childhood especially in those families/individuals identified as being at a risk of developing significant adiposity.

The Obesity Pandemic: Where Have We Been and Where Are We Going?

Obesity, a new pandemic, is associated with an increased risk of death, morbidity, and accelerated aging. The multiple therapeutic modalities used to promote weight loss are outlined with caution, especially for patients who are very young or old. Except for very rare single gene defects, the inheritance of obesity is complex and still poorly understood, despite active investigations. Recent advances that have shed light on the pathophysiology of obesity are the recognition that 1) excess fat is deposited in liver, muscle, and pancreatic islets; 2) fat tissue secretes a large number of active signaling molecules including leptin, adiponectin, and resistin, as well as free fatty acids; and 3) activated macrophages colonize the adipose tissue. Other candidates for key roles in the causes and consequences of obesity include 1) metabolic programming, where food acts as a developmental regulator; 2) the constellation of defects known as the "metabolic syndrome;" 3) cortisol overproduction in the adipose tissue; and especially, 4) insulin resistance. The possible etiologies of insulin resistance include cytokine excess, elevated free fatty acids, and hyperinsulinemia itself, as with transgenic overproduction of insulin in mice.

Plasma Endothelin of Sibpairs: Variability, Inheritance, and Linkage to Obesity in Essential Hypertension

P178 A polymorphism of the endothelin (ET)-1 gene has been associated with blood pressure (BP) of obese individuals in large population studies. We explored the variability of plasma ET in essential hypertensive sibpairs (n=14 pairs, 13 with two sibs, 1 with three sibs) in relationship to their body mass index (BMI). ET levels were measured on ad libitum Na intake (AL), after a 24 hr Na load (300 mEq iv +160 mEq po, HI) and after 24 hr of Na deprivation (10 mEq po + furosemide 120 mg, LO). BP was 147±3/90±2 mmHg and BMI 35.1±1.4, with 75% of patients exceeding 30 Kg/m 2 . ET was 4.4±0.3, 4.1±0.2, and 4.3±0.3 fmol/ml for AL, HI and LO, respectively, all higher than 20 controls (3.3±0.3, ps <0.04). One way ANOVA disclosed that ET variability within pairs was significantly less than that between pairs. This was true for each diet and for all diets combined, with maximal statistical significance after the fixed Na load (F=18.9, p <0.0001). The sibpair variance of plasma ET(AL) exhibited a negative correlation with BMI (r=-0.51, p<0.01) but did not correlate with the sibpair variance for BMI. In an ANCOVA with family ID as main effect and BMI as the regressor covariate, individual ET(AL) was explained by family ID, independent of BMI (Model: R 2 =0.79, F=3.2, p<0.02; Family ID: p<0.03; BMI: ns). Our data suggest that inheritance plays a major role in determining plasma ET of essential hypertensive patients, while salt-balance has a small additional effect. The concordance of ET levels in sibpairs increases with the magnitude of obesity, but this effect of BMI is explained by family ID in the covariate analysis. These results suggest that there is a link between the inheritance of obesity and ET in hypertension, consistent with observations in population studies.

Genetic inheritance of body mass index in African-American and African families.

Numerous studies have shown recessive major gene inheritance of body mass index (BMI) in white populations; few have examined the inheritance of BMI in the African-American population where obesity is more prevalent, nor in African populations where obesity is comparatively rare. To evaluate the inheritance of obesity in two different populations of African origin, we used segregation analysis to determine the transmission of BMI in 95 African-American families and 400 Nigerian families. Probands were selected from participants in the population-based International Collaborative Study on Hypertension in Blacks. Using class D regressive models, results from the segregation analysis of the African-American data showed evidence of a major gene effect on BMI. The Nigerian results were strikingly similar, with comparable estimates for the genotype frequencies and means and strong evidence for a major effect in the transmission of BMI. The high BMI allele frequency estimate of 24% is consistent with estimates in other studies, but the mode of transmission appeared codominant, which differs from studies involving predominantly white populations. In the Nigerian analysis, however, the probability of a high BMI homozygote parent transmitting a low BMI allele to his/her offspring was significantly different from the Mendelian expectation of zero (estimated tau(BB) = 0.45), suggesting that additional complexities exist in the major gene inheritance of BMI in this population. The strong similarity of the genotype frequencies and means obtained from the African-American and Nigerian samples suggests that a common codominant major gene effect may contribute to the variation in BMI in both populations.

Obesity QTLs on Mouse Chromosomes 2 and 17

The inheritance of obesity has been analyzed in an intercross between the mouse strains AKR/J and C57L/J. Two novel obesity quantitative trait loci (QTLs) have been identified using the strategy of selective DNA pooling. One QTL affecting adiposity,Obq3,was mapped to a 39-cM segment near the middle of Chromosome 2, with a peak lod score (5.1) just distal to theD2Mit15locus. The AKR/JObq3allele confers increased adiposity in a nearly additive manner, and males are more affected than females. A second obesity QTL (Obq4) maps to the centromeric end of Chromosome 17, with a lod score peak of 4.6 atD17Mit143.The obesity-conferring allele is contributed by C57L/J and acts in a recessive or an additive manner.Obq4also has more influence in males and affects the inguinal fat depot differentially.Obq3andObq4account for 7.0 and 6.1% of the phenotypic variance in adiposity (gender-merged data), respectively. The possible relationships between these QTLs and previously described obesity QTLs and candidate genes are discussed. The large number of different obesity QTLs that have been described in mice and the relatively small effects contributed by individual loci suggest considerable genetic complexity.

Detection of Obesity QTLs on Mouse Chromosomes 1 and 7 by Selective DNA Pooling

The inheritance of obesity has been analyzed in an intercross between the lean 129/Sv mouse strain and the obesity-prone EL/Suz mouse strain. The weights of three major fat pads were determined on 4-month-old mice, and the sum of these weights, divided by body weight, was used as an adiposity index. The strategy of selective DNA pooling was used as a primary screen to identify putative quantitative trait loci (QTLs) affecting adiposity index. DNA pools representing the leanest 15% and fattest 15% of the F2 progeny were compared for differential allelic enrichment using widely dispersed microsatellite variants. To evaluate putative QTLs, individual genotyping and interval mapping were employed to estimate QTL effects and assess statistical significance. One QTL affecting adiposity index, which accounted for 12.3% of phenotypic variance in gender-merged data, was mapped to the central region of Chromosome (Chr) 7. The QTL allele inherited from EL conferred increased adiposity. A second QTL that accounts for 6.3% of phenotypic variance was identified on Chr 1 nearD1Mit211.At both QTLs, the data are consistent with dominant inheritance of the allele contributing to obesity. The possible relationships between these QTLs and previously described obesity QTLs, major obesity mutations, and candidate genes are discussed.

Growth and development in man as bioindicator of adaptation, adaptability and ecosensitivity

The inheritance of obesity has been analyzed in an intercross between the lean 129/Sv mouse strain and the obesity-prone EL/Suz mouse strain. The weights of three major fat pads were determined on 4-month-old mice, and the sum of these weights, divided by body weight, was used as an adiposity index. The strategy of selective DNA pooling was used as a primary screen to identify putative quantitative trait loci (QTLs) affecting adiposity index. DNA pools representing the leanest 15% and fattest 15% of the F2 progeny were compared for differential allelic enrichment using widely dispersed microsatellite variants. To evaluate putative QTLs, individual genotyping and interval mapping were employed to estimate QTL effects and assess statistical significance. One QTL affecting adiposity index, which accounted for 12.3% of phenotypic variance in gender-merged data, was mapped to the central region of Chromosome (Chr) 7. The QTL allele inherited from EL conferred increased adiposity. A second QTL that accounts for 6.3% of phenotypic variance was identified on Chr 1 nearD1Mit211.At both QTLs, the data are consistent with dominant inheritance of the allele contributing to obesity. The possible relationships between these QTLs and previously described obesity QTLs, major obesity mutations, and candidate genes are discussed.