Linking maternal obesity to early insulin resistance☆

The current epidemics of obesity and type 2 diabetes are major concerns to our health and health care systems and project major public health problems in future generations. In addition to genetics, lifestyle and nutrition, increasing attention is focused on the non-genetic, transgenerational effects of maternal obesity on the offspring, as risk factors for obesity [1]. While the principle associations between maternal obesity and increased risk of obesity and its metabolic consequences in the offspring are well established in rodents and humans, the underlying molecular mechanisms are under active investigation [2]. In this issue of Molecular Metabolism, Fernandez-Twinn and colleagues demonstrate that maternal obesity during pregnancy and lactation results in hyperinsulinemia, characteristic for insulin resistance, in the male offspring prior to the development of obesity [3]. Thus, the authors show that insulin resistance in the offspring is not a consequence of obesity, which has been previously observed as a result of maternal adiposity [4], but presents either an independent trait or even a predisposition for the development of obesity later in life. Interestingly, Tsuduki and colleagues [5] previously reported that feeding a high fat diet during lactation also increases serum insulin levels at weaning. However, this effect was only observed transiently as no differences in serum insulin levels were observed later in life. Fernandez-Twinn and colleagues focused their study on the early consequences of maternal obesity on the offspring, thus it will be interesting to see if in this mouse model insulin levels normalize over time too. This is of great interest as a transient insulin resistance early in life could cause a predisposition to obesity or other components of the metabolic syndrome later on and most likely would not be recognized if not specifically tested. However, a direct translation of these findings from mice to humans is complex as mice are born at a developmental stage comparable to the beginning of the third trimester in humans. Therefore the lactation period in mice overlaps with the final developmental/ growth phase in-utero in humans. The adverse effects of maternal obesity on the offspring later in life have been previously demonstrated and linked to a dysregulation of key signaling molecules of the insulin signaling pathway in the liver and skeletal muscle [1,4,6]. However, these studies were performed after the development of obesity and impaired glucose tolerance. Thus, any molecular changes could be a consequence of the maternal obesity or the metabolic syndrome in the offspring. As the authors were investigating mechanisms to explain the obesity independent hyperinsulinema in their mouse model, they turned to