Hypothalamic substrates of metabolic imprinting

Abstract

The mammalian brain develops according to intrinsic genetic programs that are influenced by a variety of environmental factors. Developing neural circuits take shape in two major environments: one in utero and a second during postnatal life. Although an abundance of epidemiological and experimental evidence indicates that nutritional variables during perinatal life have a lasting effect on metabolic phenotype, the underlying mechanisms remain unclear. Peripheral hormones are widely regarded as effective signals that reflect the state of peripheral environments and can directly influence the development of a variety of functional neural systems. Recent findings suggest that the adipocyte-derived hormone leptin may play an important role in directing formation of hypothalamic neural pathways that control body weight. The arcuate nucleus of the hypothalamus (ARH) is a key site for the regulatory actions of leptin in adults, and this same hormone is required for the normal development of ARH projections to other parts of the hypothalamus. In this review, the neurobiological role of leptin is considered within the context of hypothalamic development and the possibility that variations in both prenatal and postnatal nutritional environments may impact development of neural circuits that control energy metabolism through an indirect action on leptin secretion, or signaling, during key developmental critical periods.

Introduction

Effective management of bodily energy stores is essential to survival in any environment and is best served if the energy balance of the individual is optimized so as to promote efficient utilization of available metabolic fuels. Elaborate neuroendocrine mechanisms have evolved to facilitate coordination of energy balance in a variety of organisms that inhabit environments with variable food availability. Notable examples include mammals that hibernate during winter months and migratory birds that store energy in preparation for long periods of starvation during seasonal migrations [1], [2]. In most parts of the world man has succeeded in maintaining a relatively steady source of food, so it would seem that the need for homeostatic mechanisms favoring storage of energy as fat is diminished. However, these mechanisms appear to remain intact and in modern environments, with widespread availability of energy dense food sources, may even be nonadaptive as evidenced by soaring rates of obesity and type 2 diabetes in juvenile populations [3], [4]. Like all mammals, human infants are exposed to two major successive environments: one in utero and the other postnatal. Developmental mechanisms occurring in utero have the capacity to imprint a metabolic phenotype on the offspring that promotes success in the postnatal environment. Both epidemiological and in vivo data from animal models suggests a variety of negative health outcomes ensue when these two environments are mismatched [5], [6], [7]. Thus, it is important to understand how homeostatic mechanisms established in utero predispose offspring to a favorable energy balance in its postnatal environment, and to identify the cellular and molecular events that specify metabolic phenotype.

Perinatal nutrition has been identified as a significant determining factor for predisposition to cardiovascular disease, obesity and type 2 diabetes. This relationship has been discussed extensively and in general the results of epidemiological studies indicate that fetal malnutrition can negatively impact the probability of developing metabolic disease [8], [9], [10]. Results of experiments in a variety of animal models also support a link between the perinatal nutritional environment and programming of energy balance “set points” [11], [12], [13], [14]. Maternal obesity and high fat diets during gestation and lactation appear to promote obesity and insulin-resistance in offspring, as does maternal undernutrition during gestation [12], [15], [16], [17], [18]. The signals that mediate maternal aspects of metabolic disorders in offspring have not been identified, but hormones such as insulin and leptin, or nutrients such as glucose or fatty acids, may cross the placenta and influence fetal development. For example, patients with gestational diabetes display marked increases in leptin production and these elevations are out of proportion to their adiposity [19], [20], [21]. Maternal hyperglycemia is associated with fetal hyperglycemia, which in turn may cause elevations in fetal insulin levels leading to increased growth and adiposity of the offspring. Inadequate nutrition during key developmental periods may also promote obesity, perhaps by causing the offspring to become more metabolically efficient in anticipation of reduced availability of nutrients. Later, when provided with sufficient, or even excess, availability of calories these individuals may tend toward obesity and acquisition of insulin resistance [22]. Thus, an abundance of evidence suggests that alterations in the prenatal nutritional environment and subsequent postnatal growth can predispose an individual to obesity and diabetes. However, most studies have been focused on peripheral measures and outcomes. In this review, development of the hypothalamus will be examined within the context of developmental programming of metabolic phenotype.