Editors' ChoiceDiabetes

Starve Now, Gain Later

See allHide authors and affiliations

Science Translational Medicine  06 Apr 2011:
Vol. 3, Issue 77, pp. 77ec46
DOI: 10.1126/scitranslmed.3002455

Some play Mozart. Others read Shakespeare aloud. But should expectant mothers focus more on their diets when attempting to boost baby’s development? In 1992, Hales and Barker hypothesized that early fetal growth restriction could impose mechanisms of “thrift” that lead to increased susceptibility for type 2 diabetes. Since then, numerous studies have demonstrated that maternal diet in the fetal and postnatal period influence an offspring’s risk of developing several chronic diseases. Nutrition and other environmental cues also have been shown to alter gene expression through the induction of epigenetic changes such as DNA methylation and histone modification. But it remains unclear how such molecular changes specify an increased diabetes risk. Now, work by Sandovici et al. provides insight into a potential mechanism for such nutritional programming.

The authors turned to a well-established rat model in which maternal protein restriction during fetal and postnatal life produces smaller-than-normal offspring that undergo age-dependent loss of glucose tolerance and late onset of type 2 diabetes. Taking a candidate gene approach, Sandovici et al. asked whether this effect could be mediated by changes in an offspring’s expression of Hnf4a, which encodes a transcriptional regulator of genes involved in pancreatic B cell differentiation and glucose homeostasis. Mutations in Hnf4a have been linked to type 2 diabetes in humans. Although several experiments involved the in vitro manipulation of histone modifications in cultured cells, the key studies were performed in primary pancreatic islet cells. Examination of the Hnf4a locus in control, nondiabetic rat, and human islets—by using immunoprecipitation, bisulphite sequencing, and quanitative polymerase chain reaction—revealed differential methylation of a pancreatic islet cell–specific promoter site that could modulate Hnf4a gene expression levels. In rats born from mothers that had been fed low-protein diets, this promoter site displayed increased DNA methylation and a reduction in open-chromatin marks, resulting in decreased Hnf4a expression, as compared with offspring of control-fed mothers. These differential effects were evident by 3 months after birth and increased with age.

Sandovici and colleagues demonstrate the induction of specific durable epigenetic changes induced by maternal diet and provide a possible mechanism for the generation of adult diabetes from fetal conditioning. Because the authors examined only one candidate gene, it remains to be seen what other genes and epigenetic modifications may be induced by maternal dietary restriction and whether these same targets are relevant in humans. Tracing the origins of disease to the womb suggests that physicians and scientists must broaden their approach to the development of methods for disease prevention and treatment.

I. Sandovici et al., Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc. Natl. Acad. Sci. U.S.A. 108, 5449–5454 (2011). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article