Transgenerational epigenetic effects of parental high fat diet exposure

Industrialization has led to radical societal changes in the past 100 years, leading to increases in obesity, metabolic syndrome, and height in human populations across the globe. To examine whether parental high fat diet consumption contributes to this epidemic by predisposing offspring to increased adiposity, insulin insensitivity, or body size, we exposed male or female mice to a 45% fat by calories diet and bred them together with control animals to assess the extents of phenotypes present in offspring. Females exposed to high fat diet during adulthood and through the pregnancy and lactation periods produced offspring that had increased adiposity, body length, and insulin insensitivity as adults. These offspring in turn produced the second generation that exhibited both increased body length and insulin insensitivity, though only the increased body length phenotype passed into third generation female offspring through the paternal lineage. Mechanistically, first and second generation female but not male offspring exhibited alterations along the growth hormone pathway, evidence that divergent mechanisms lead to similar phenotypes in male and female offspring. The inheritance patterns suggest that traits can either be programmed somatically or in the germline, leading to some traits terminating with the first generation and others passing to the second and third. To determine the transgenerational epigenetic marks responsible for transmitting traits through the male germline, we individually injected miRNAs found to be upregulated in the sperm of males exposed to maternal high fat diet into single cell fertilized zygotes. Injections did not result in phenotypes in the subsequent generation, suggesting that individual miRNAs do not carry transgenerational epigenetic information as a result of high fat diet exposure. Furthermore, adult male mice exposed to a high fat diet do not produce offspring with any alterations in body size, insulin or glucose metabolism, macronutrient choice preference, or caloric efficiency, an indication that the male germline is not sensitive to reprogramming during adulthood. Taken together, these data indicate that parental high fat diet can program offspring in a sex, time of exposure, and tissue specific manner, resulting in phenotypes in one or more generations of offspring.