Maternal High-Fat Diet Programs Fetal Adipose Tissue Renin-Angiotensin System?
OK, this is a “rat” study – but given my past interest in the renin-angiontensin system (a key system in blood regulation – we were the first to describe the presence of this system in human adipose tissue), I read this paper with great interest. This study by Cristiane Guberman and colleagues from UCLA, published in the American Journal of Obstetric and Gynecology, looked at the offspring of rats raised on a high-fat or control diet, which continued throughout pregnancy. Using appropriate controls, the researchers not only demonstrated higher blood pressures in the offspring of the high-fat reared rats (which were also fatter) but also showed early and persistent activation of the adipose-tissue renin-angiotensin system, an effect that was further exacerbated when the pups were also exposed to a high-fat diet. These findings are not only important because they suggest a mechanism for why offspring of obese mothers may be more prone to developing hypertension (and other cardiometabolic risk factors) but also because they suggest that these effects may be due to epigenetic(?) “reprogramming” of renin-angiotensin system genes in adipose tissue. Unfortunately, I no longer study this system or adipose tissue in my lab but I am sure there are plenty of colleagues out there who will jump on this interesting finding. Fortunately, we do have drugs that effectively inhibit or block the renin-angiotensin system and it will be of interest to see if these may represent the best treatment for hypertension in offspring of obese mothers. Obviously, preventing or treating obesity in young women before they get pregnant may be even better! @DrSharma Edmonton, AB Guberman C, Jellyman JK, Han G, Ross MG, & Desai M (2013). Maternal high-fat diet programs rat offspring hypertension and activates the adipose renin-angiotensin system. American journal of obstetrics and gynecology PMID: 23743273
Bariatric Surgery on Moms Changes Genes in their Kids
Regular readers may recall a previous post describing the finding that bariatric surgery on obese women quite dramatically reduces the risk of subsequent obesity in their offspring. Now, the same group of investigators from Laval University, Quebec City, in a paper published in PNAS, demonstrates striking differences in the methylation of genes controlling glucose metabolism in offspring born to mothers after they underwent gastrointestinal bypass surgery. In a rather unique set up, the researchers compared gene methylation between a sibling cohort of 25 offspring (age 2-15) born before the mothers underwent bariatric surgery to 25 offspring born to the same mothers after they had surgery. Almost 6,000 genes were found to be differentially methylated between the “before” and “after” siblings, especially genes known to be involved in glucoregulatory, inflammatory, and vascular disease. Significant correlations were found between gene methylation levels and gene expression and plasma markers of insulin resistance and metabolic improvements in post-surgical offspring. As the authors note, this rather unique clinical study shows that bariatric surgery on obese women can have long-lasting (lifelong?) genetic effects on their offspring making them far less prone to obesity and metabolic disease compared to their siblings born to the very same moms prior to surgery. Not only does this study point to the importance of gestational roots of childhood obesity but also provides robust evidence to the discard the often held view that the current childhood obesity (of for that matter even obesity in young adults) cannot be explained by genetic changes in the population – clearly THE GENES HAVE CHANGED! Thankfully, as shown in this study, they can be changed back – not by intervening on the kids – but by intervening on the moms even before they become pregnant. AMS Toronto, AB Big call out to my youngest daughter, who graduated yesterday from the midwifery program at Ryerson University, Toronto – so proud of you! Guénard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, & Vohl MC (2013). Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proceedings of the National Academy of Sciences of the United States of America PMID: 23716672
Impact of High Fat Diet on Fetal Development
Regular readers of these pages are well aware of the importance of the adverse effects that environmental factors during fetal development can have on the subsequent health risks of the offspring. This is again documented in a study in rats by Emily Hayes and colleagues from McMaster University, Hamilton, Ontario, published in the latest issue of PLoS One. In their experiments, they compared the fetal development and pregnancy outcomes in female Sprague Dawley rats raised either on a high fat diet (HF – 45% of calories from fat) or a control diet (CON – 16% of calories from fat). Prior to pregnancy HF-fed dams had significant increases in body fat, serum leptin and triglycerides. In addition, the HF-fed dams exhibited altered vascular development in the placenta, as well as increased hypoxia as well as a more than 3-fold increase in fetal death and decreased neonatal survival. As the authors surmise, altered placental vasculature in animals raised on a high-fat diet may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival. Certainly in humans, increased maternal obesity and weight gain are associated with a significantly increased risk to both the mother and infant, an issue that I have previously discussed. The fact that such problems can be reproduced in experimental animal models certainly points to important biological consequences of nutrition and weight gain before and during gestation that can have important consequences for the infants. AMS Vancouver, BC Hayes EK, Lechowicz A, Petrik JJ, Storozhuk Y, Paez-Parent S, Dai Q, Samjoo IA, Mansell M, Gruslin A, Holloway AC, & Raha S (2012). Adverse fetal and neonatal outcomes associated with a life-long high fat diet: role of altered development of the placental vasculature. PloS one, 7 (3) PMID: 22442686 .
Childhood Predictors of Adult Obesity
There are good reasons to believe that for a significant number of people, the foundations of adult obesity may well be established in early childhood or even in utero. This topic is the focus of an extensive review by Tristin Brisbois and colleagues from the University of Alberta, just published in OBESITY REVIEWS. In their paper, the researchers screen the literature on data supporting a role for a wide range of factors in early childhood (≤5 years of age) that potentially predict the development of obesity in adulthood. Factors of interest included exposures/insults in the prenatal period, infancy and early childhood, as well as other socio-demographic variables such as socioeconomic status (SES) or birth place that could impact all three time periods. Their review of over 8,000 citations, resulted in relevant 135 studies, which reported a total of 42 variables as being associated with obesity in adulthood. Of these, however, only seven variables made the cut as potential early markers of obesity. These included maternal smoking and maternal weight gain during pregnancy, maternal body mass index, childhood growth patterns (early rapid growth and early adiposity rebound), childhood obesity and father’s employment (a proxy measure for SES in many studies). Notably, neither early childhood nutrition or physical activity were identified as possible predictors. Although such association studies alone by no means imply causality, the identified variables are nevertheless worth considering as reasonable targets in the development of health promotion programmes to reduce the risk of adult obesity. Clearly, the feasibility and effectiveness of such measures remains to be demonstrated. AMS Dallas, TX Brisbois TD, Farmer AP, & McCargar LJ (2011). Early markers of adult obesity: a review. Obesity reviews : an official journal of the International Association for the Study of Obesity PMID: 22171945 . .
Intergenerational Transmission of Obesity and Diabetes
Regular readers should by now be quite familiar with the accumulating data suggesting that your risk for future development of obesity, diabetes, and possibly other metabolic diseases, may begin in the womb. This topic is nicely reviewed in a paper by Marie-Claude Battista and colleagues from the University of Sherbrooke, Quebec, published in Experimental Diabetes Research. In this paper, the authors not only discuss the relationship between maternal obesity and pregnancy risk (for both mother and child) but also discuss the complex factors that link excess weight to gestational diabetes. They then extensively review the animal data that shows how intra-uterine epigenetic modifications can lead to a (permanent) metabolic adaptation that substantially increases the risk for obesity and diabetes in the offspring. Finally, they critically discuss the emerging human data demonstrating the impact of lifestyle and bariatric surgery on both maternal and fetal health and the ability of these interventions to possibly break the vicious circle that perpetuates the transmission of obesity and metabolic conditions to the next generations As the authors conclude: “Fetal programming of metabolic function induced by obesity and GDM may have intergenerational effect and thus, perpetuate the burden of such conditions. Mechanisms by which reprogramming of fetal function might occur is directly through maternal metabolic and hormonal effects, epigenetic alterations or impaired placental function. Periconceptional weight loss interventions have demonstrated their ability to reverse the impacts of maternal obesity and GDM on the child and are of great importance for the prevention of future cardiometabolic risks in the offspring, and may thus be the best approach to break the vicious circle of intergenerational propagation of obesity and diabetes.” They, however also caution that: “…the nature and the timing of intervention should be carefully considered because it could also by itself induce organ reprogramming and potential long-term effect on the offspring.” Not an easy topic (and certainly not an easy read) given the complexity of the emerging molecular, metabolic and genetic animal and human data on this issue. However, certainly a topic that cannot be ignored in any discussion about finding solutions to the obesity epidemic. AMS Leipzig, Germany Battista MC, Hivert MF, Duval K, & Baillargeon JP (2011). Intergenerational cycle of obesity and diabetes: how can we reduce the burdens of these conditions on the health of future generations? Experimental diabetes research, 2011 PMID: 22110473
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