The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes?

Abstract

Obesity and type 2 diabetes arise from a set of complex gene-environment interactions. Explanations for the heritability of these syndromes and the environmental contribution to disease susceptibility are addressed by the "thrifty genotype" and the "thrifty phenotype" hypotheses. Here, the merits of both models are discussed and elements of them are used to synthesize a "thrifty epigenotype" hypothesis. I propose that: (1) metabolic thrift, the capacity for efficient acquisition, storage and use of energy, is an ancient, complex trait, (2) the environmentally responsive gene network encoding this trait is subject to genetic canalization and thereby has become robust against mutational perturbations, (3) DNA sequence polymorphisms play a minor role in the aetiology of obesity and type 2 diabetes-instead, disease susceptibility is predominantly determined by epigenetic variations, (4) corresponding epigenotypes have the potential to be inherited across generations, and (5) Leptin is a candidate gene for the acquisition of a thrifty epigenotype.

Duration of breastfeeding and gender are associated with methylation of the LEPTIN gene in very young children

“…Articles thrifty phenotype (4,7,8). We observed significant associations between the methylation of LEP and the duration of breastfeeding, birth weight, BMI, gender, leptin concentration in the child and maternal education.…”

“…In particular, the mismatch between prenatal and postnatal nutrition is emphasized in association with obesity (3). Epigenetics may be one of the major links between the periconception and perinatal periods in association with health and disease in later life (4). It is described as a biological mechanism to explain gene-environment interactions, in which (heritable) changes in gene expression occur without changes in the DNA sequence (5).…”

“…The gene leptin (LEP) has been proposed as an important candidate gene for thrifty phenotypes because it displays epigenetic variation and is involved in the development of obesity and insulin resistance (4,7,8). LEP is primarily expressed in differentiated adipocytes of white fat tissue, and its product, the hormone leptin, has several functions, including the regulation of food intake and the expression of energy-regulating peptides.…”

Gene–environment interplay in Drosophila melanogaster : Chronic food deprivation in early life affects adult exploratory and fitness traits

“…Similarly, in fruit flies, levels of hemolymph carbohydrate affected by 3 h of food deprivation return to normal levels after just 2 h of refeeding (8). Moreover, not all individuals are affected equally by early nutritional adversity (9,10), and these individual differences arise from GEIs.…”

Nutrition, Genes and Modern Disease: A Current Dilemma or a Legacy of our Past

“…Consequently, during times of famine, the 'thrifty' genotype would allow for increased fat storage and thus represent a survival advantage over a less 'thrifty' genotype [2]. While this thrifty genotype would have been beneficial during times of regular famine, it would also pose a liability in modern westernized societies that have regular access to food sources [9]. Accordingly, sedentary lifestyles and positive caloric imbalances through the selection of highly processed foods rich in carbohydrates, are suggested to be implicated in a discordance between our ancestral genes and modern circumstances leading to the dysregulation of ancestral homeostatic processes and contributing to modern diseases such as obesity and type 2 diabetes [1,2,7,10].…”