Examining the fetal origins of obesity

The mechanisms

The programming mechanisms that predispose offspring to obesity are similar in infants of obese mothers and intrauterine growth restricted newborns, though they involve different epigenetic signals. Both involve dysregulation of appetite/satiety and of adipogenesis.

Appetite is primarily controlled by a complex circuit of neurons in the hypothalamus of the brain called the hypothalamic arcuate nucleus. Some neurons are orexigenic and stimulate or increase appetite, while others are anorexigenic and suppress appetite by promoting satiety.

During fetal development, hypothalamic neural stem cells proliferate and differentiate into various cell types. Neurons destined for the arcuate nucleus then differentiate into these so-called appetite neurons and satiety neurons. Though there is continued neural development and maturation during newborn life, hypothalamic control of appetite and satiety is largely set during this period.

Differentiation to appetite or satiety neurons is regulated by a complex interplay of pathways that may be significantly altered by the nutrient environment. Research in our laboratory and others has shown that both limited and excess nutrition can program the structure and function of the arcuate nucleus – changing its wiring, in essence – such that there is an increased ratio of appetite to satiety neurons (Clin Obstet Gynecol. 2013 Sep;56[3]:529-36).

There also appears to be a programmed down-regulation in the reward pathway of the brain, and some studies have shown that children of obese mothers and children who were born with low birth weights have a higher preference for sweet and high-calorie foods. This all begins at the neural stem cell level.

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With more appetite neurons and fewer satiety neurons, as well as a down-regulation of reward – and an abundance of available food – a newborn is at high risk of becoming obese. Eating for this child will not only be pleasurable; it will be driven by an enhanced appetite, an inability to feel full after reasonable amounts of food, and a down-regulation of reward (potentially requiring greater amounts of food or a shift in preference for high fat/sweet food to achieve the pleasure from eating).

In addition to alterations in appetite/satiety, the nutrition environment in utero can alter adipose tissue development and function.

Like neural development, adipogenesis – the process by which preadipocytes proliferate and differentiate into mature adipocytes – is tightly regulated by a cascade of transcription factors that are expressed in response to stimuli, including nutrients. In animal studies we have found an up-regulation of adipogenic and lipogenic transcription factors in intrauterine growth restricted offspring as well as in offspring of obese mothers (Reprod Sci. 2008 Oct;15[8]:785-96 and Curr Diab Rep. 2013 Feb;13[1]:27-33).

This up-regulation leads to greater proliferation of preadipocytes and greater lipid synthesis and storage in mature adipocytes. Not only will the newborn have an increased number of adipocytes, but he or she will have an increased number of hypertrophic lipid-filled fat cells. The enhanced adipogenesis will contribute to the newborn’s programmed propensity for obesity, and the directive to “just eat less” will likely be ineffective throughout childhood and beyond.

Programmed offspring are resistant to both central and peripheral effects of leptin and insulin, resulting in impaired satiety (i.e., overeating) and manifestations of GDM. Responses to an array of additional energy regulatory factors (e.g., ghrelin) demonstrate a similar programmed dysfunction.

In practice

There are several approaches that ob.gyns. can take to prevent childhood and lifelong obesity. Most importantly, we must counsel our obese patients to lose weight before pregnancy. In doing so, it may be meaningful and effective to ask the patient to think about her baby’s future as an obese adult.

Patients who have experienced the challenges of trying to lose weight, and who are told about the developmental origins of obesity and how obesity can be programmed, may be more motivated to lose weight to avoid passing on to their children the burden and challenges that they’ve experienced. We can tell obese patients that their children may well be predisposed through the current in utero environment to have an increased appetite and a propensity to store body fat, and that they subsequently will face higher risks of diabetes and other serious chronic conditions.

We should also appropriately counsel women on healthy weight gain during pregnancy, and urge them not to gain excessive weight.

Newborn feeding strategies are also important for babies exposed to gestational programming of obesity, but especially small babies given the high risk of obesity when there is rapid catch-up growth. We must encourage good growth of both the low-birth-weight and macrosomic infant during the newborn period, but not overgrowth.