Epigenetic Germline Inheritance of Diet-Induced Obesity and Insulin Resistance EDITORIAL COMMENT

Several genetic risk factors for diabetes and obesity have been identified. In addition to genetic risk factors, it has been proposed that epigenetic alterations in gametes are another potential mechanism of disease risk inheritance. A number of epidemiological and mouse studies suggested that diet-induced susceptibility to obesity and diabetes, acquired during parents' lifetimes, can be inherited. Previous studies examining potential epigenetic inheritance relied on in vivo fertilization to produce offspring. Such studies were limited by the inability to distinguish heritable, epigenetic determinants in the gametes from other factors that can influence offspring development such as the composition of paternal seminal fluid or diet-induced changes in the uterus during pregnancy. In this study, the investigators used in vitro fertilization (IVF) to ensure exclusive inheritance via the gametes. Male and female inbred mice were fed 1 of 3 diets for 6 weeks: high fat, low-fat control, or normal. Mice fed the high-fat diet developed obesity, severe glucose intolerance, and type 2 diabetes (as would be expected). The IVF was performed using egg and sperm cells from various pairings of mice fed the same or different diets; the resulting embryos were then implanted into healthy surrogate females, which eliminated parental influence on offspring beyond the contribution of gametes. This new generation of mice was fed a normal diet for 9 weeks after birth. All offspring were challenged with a fatty diet, and the animals' weight over the next 6 weeks was recorded as well as the response of these mice to injected glucose. All mice grew fatter, but weight gain was strongly dependent on the parental diet, especially among female offspring. Compared with offspring of both parents on a control diet, female offspring from 2 parents fed high-fat diets were 20% heavier. Male and female offspring of mothers fed a high-fat dietmaintained insulin production, but these animals had significantly higher glucose intolerance than other members of the cohort regardless of the paternal diet. This indicates primarily egg-cell transmission of insulin resistance. These findings provide new evidence in support of the epigenetic inheritance theory. The data show that diet-induced obesity and diabetes can be epigenetically inherited by the offspring via both the oocytes and the sperm. Epigenetic inheritance due to an unhealthy diet could be responsible for the dramatic global increase in both obesity and prevalence of diabetes in the last 5 decades.