Obesity—A Disease With Many Aetiologies Disguised in the Same Oversized Phenotype

Has the Overeating Theory Failed?

Peter Stenvinkel

Disclosures

Nephrol Dial Transplant. 2015;30(10):1656-1664. 

In This Article

Epigenetics as a Cause of Obesity—The Original Sin

Although ~150 genetic loci have been linked to obesity in genome-wide association studies (GWAS), genetic associations as such do not explain more than ~2% of changes in BMI.[78] Thus, as gene–environment interactions may represent the most important regulators of obesity risk, this should increase the attention to epigenetic processes, i.e. the environment influences the expression of susceptible genes.[79] As genes associated with obesity risk are susceptible to epigenetic alterations[12] and obese patients have an epigenetic pattern different from non-obese subjects,[80] studies of the dietary impact on the epigenome are of interest.[12] The experience from the Dutch Hunger winter 1944 during which individuals exposed to prenatal famine had a markedly higher risk for metabolic syndrome and heart disease in adulthood elegantly demonstrated the impact of the nutritional in utero environment on adult disease.[81] The importance of nutrients in affecting the epigenome via methyl groups that silence genes was first demonstrated in a study of the yellow obese agouti mice prone to diabetes. When pregnant mice were fed methyl-rich food (choline, folic acid, betaine and vitamin B12), this increased the methylation of the locus and silenced the gene expression, which resulted in lean brown Agouti mice with low disease risk.[82] In another study, genistein (the major phytoestrogen in soy) induced hypermethylation that persisted into adulthood and decreased ectopic Agouti expression, which protected the offspring from obesity.[83] Recent studies link changes in the epigenome to risk of obesity. As long-term, high-fat diet decreases methylation of the MCR-4 receptor gene,[84] this change in the epigenetic machinery could stimulate appetite (Figure 2). Also acute exercise affects the epigenome via promoter hypomethylation and increases the expression of PGC-1α, PDK4 and PPAR in skeletal muscle.[85] The differential methylation in glucoregulatory, inflammatory and vascular disease genes demonstrated in offsprings born before versus after maternal gastrointestinal bypass surgery[86] suggests that obesity and over-nutrition during pregnancy affect fetal programming and the risk for obesity during adult disease. As epigenetic modulations, like DNA and histone methylation, are stable enough to be transmitted to future generations, the impact of our parents and grandparents lifestyle (i.e. the original sin) on the risk of overweight deserves further studies.

Figure 2.

Instead of being a simple caloric overshooting problem, overweight is caused by a complex sum of coexisting alterations. Specific nutrients, such as fructose in sucrose and high fructose corn syrup, may via generation of uric acid cause intracellular adenosine triphosphate depletion and mitochondrial exhaustion, which promote weight gain and insulin resistance independent of calories. Other nutrients, such as plant food, antioxidants, nuts and marine oils may, on the other hand, counter insulin resistance and fat accumulation via antioxidative effects and stimulation of mitochondrial health. In addition, nutrients that affect the gut microbiota, such as artificial sweeteners, pro- and prebiotics, might also promote fat mass accumulation indirectly via changes in gene expression in target tissues. As genetic variations and single nucleotide polymorphisms (SNPs) in obesity genes, such as the 'fat mass and obesity' (FTO), melanocortin receptor 4 (MC4R) and transmembrane protein 18 (TMEM18) genes only play a minor part in variations in BMI, the familial aggregation of obesity may be caused by other factors, such as changes in the epigenome. There are reasons to believe that the composition of nutrients during fetal development in utero may have trans-generational effects on the epigenome and thereby affect the risk of overweight. Physical exercise may also affect the epigenome and via decreased promoter methylation it increases expression of both the peroxisome proliferator-activated receptor (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) in muscle. Recent data also indicate a link between the gut microbiota and epigenetic regulations. Hypomethylation of the MC4R gene following high-fat intake has been shown to increase appetite. One of many links not depicted in the figure is the direct appetite stimulating effects of fructose.

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