Metabolic programming in the immediate postnatal period Malathi Srinivasan and Mulchand S. Patel Department of Biochemistry, University at Buffalo, The State University of New York, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA In recent decades, there has been a dramatic increase in the incidence of obesity in all age groups of the popu- lation in the USA. In addition to genetics and life style changes, the important role of metabolic programming effects in the etiology of the obesity epidemic is being increasingly recognized. Although the role of a com- promised intrauterine environment in fetal metabolic programming is well documented to contribute to the development of adult-onset diseases, vulnerability in the immediate postnatal period to similar conditions has also been shown. Metabolic programming effects induced by altered nutritional experiences in the immediate postnatal period can give rise to long- term consequences in the context of the current obesity epidemic. The obesity epidemic The prevalence of overweight and obesity among adults remained relatively stable until 1980 in the USA [1]. Since then, there has been a progressive increase in the number of overweight and obese individuals. According to the National Health and Nutrition Examination Surveys, the prevalence of obesity (body mass index >30) in the adult population increased from 15% in the period from 1976–1980, to 32.9% in the period from 2003–2004 [2] (Figure 1). Concomitantly, a dramatic increase (approxi- mately threefold) in the incidence of obesity (defined as body weight in the 95th percentile) was observed for chil- dren and adolescents [2] (Figure 1). Obesity is associated with a significantly increased risk for a cluster of associ- ated pathologies, which include type 2 diabetes and car- diovascular disease. Fetal metabolic programming There is an increasing recognition of an early developmen- tal component in the etiology of the obesity epidemic. Barker’s fetal origins of adult-onset diseases hypothesis (derived from retrospective analysis of human epi- demiological data) was instrumental in the recognition of the role of malnourishment during pregnancy in the predisposition of the offspring for adult-onset diseases [3]. The underlying principle of Barker’s hypothesis is the phenomenon of metabolic programming, which refers to the altered development of a somatic structure, resetting of a physiological system and/or an imbalance in normal homeostatic mechanisms in response to a nutritional stimulus or insult experienced during crucial periods of development. These early responses have an impact on whole-body metabolic processes, resulting in functional aberrations and metabolic diseases in adulthood. The reader is referred to the several excellent reviews on animal models investigating the long-term effects of a malnourished pregnancy [4–12]. Metabolic programming in the immediate postnatal period It is important to recognize that crucial windows of tissue and/or organ development also extend into the immediate postnatal period. Several regulatory mechanisms are not functionally mature at the end of gestation and continue development during the immediate postnatal period. Therefore, altered nutritional experiences (under-, over- and modified nutrition) in the immediate postnatal period are important and independent cues for inducing meta- bolic programming effects. Using the small litter (SL; three pups per dam) rat model, the Plagemann laboratory has demonstrated that overnourishment during the suckling period causes meta- bolic programming effects resulting in permanent changes in plasma levels of insulin and leptin, body weight and food intake in adult SL rats [13]. Electrophysiological studies performed on brain slices indicated altered neuronal activity of various hypothalamic regulatory centers in response to insulin, leptin and several neuropeptides, providing a mechanistic basis for the persistent hyperpha- gia and overweight observed in adult SL rats. Some of the recent significant observations of the Plagemann labora- tory include: (i) increased inhibition of paraventricular nucleus (PVN) neurons by neuropeptide Y (NPY), mela- nin-concentrating hormone, agouti gene-related protein (AgRP) and orexin B, and decreased activation of these neurons by cocaine- and amphetamine-regulated tran- script (CART) and a-melanocyte-stimulating hormone (a-MSH) [14,15]; (ii) reduced response of PVN neurons to the adiposity signals insulin, leptin and amylin [16]; (iii) inhibition of ventromedial nucleus (VMN) neurons by dopamine and AgRP, and altered expression and/or activity of dopamine receptors [17,18]; (iv) reduced inhi- bition of arcuate nucleus (ARC) neurons by amylin [19] and lack of inhibition, but observed activation of, these neurons by insulin [20], and (v) inhibition of dorsomedial VMN and medial parvocellular PVN neurons by corticotropin-releas- ing hormone receptor-2 agonist [21] and inhibition of both dorsomedial and ventromedial neurons by CART in adult SL rats [22]. These findings collectively indicate that a Review Corresponding author: Patel, M.S. (mspatel@buffalo.edu). 146 1043-2760/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2007.12.001 Available online 7 March 2008