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Departments of Internal Medicine and Molecular and Integrative Physiology (M.G.M., R.L.L.), University of Michigan Medical School, Ann Arbor, Michigan 48109, and, Research Division (M.E.P.), Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Martin G. Myers, Jr., M.D., Ph.D., University of Michigan, Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Molecular and Integrative Physiology, 1150 West Medical Center Drive, 4301 MSRB III, Box 0638, Ann Arbor, Michigan 48109. E-mail: mgmyers{at}umich.edu.
The prevalence of obesity in the United States and other developed countries approximates one third of the adult population and continues to climb at an alarming rate (http://www.cdc.gov/nccdphp/dnpa/obesity/). Particularly concerning is the increasing prevalence of obesity in children and adolescents, and the expected future associated risks to health, including diabetes, cardiovascular disease, and other features of the metabolic syndrome. Thus, it is critical to understand the pathophysiology of obesity to develop effective preventive and therapeutic strategies.
Both genetic and environmental contributors to obesity have been identified. Mutations in the melanocortin 4 receptor may be responsible for up to 4% of severe obesity (1), but other genetic factors contributing to common forms of obesity are poorly understood. Environmental factors likely to play a major role in the explosion of obesity over the past decade include decreased physical activity and increased calorie intake, facilitated by access to palatable, calorie-dense foods. Additionally, alterations in the fetal or perinatal nutritional or metabolic environment can predispose to the later development of obesity and diabetes (2, 3, 4). Examples of this phenomenon in humans include the experience of the Dutch Hunger Winter of 1944–45, in which exposure of fetuses to maternal caloric restriction during pregnancy predisposed to various aspects of the metabolic syndrome later in life (2, 5, 6). Current concerns focus on the role of fetal overnutrition (including maternal diabetes) in the induction of infant macrosomia and predisposition to subsequent diabetes and obesity (3, 7). These relationships in human populations have been confirmed by experimental manipulations in rodents and other mammals, in which caloric restriction, gestational diabetes, or overnutrition of pregnant mothers results in increased adiposity and decreased glucose tolerance in their offspring later in life (8, 9, 10).
Although suboptimal antenatal/perinatal nutritional status is now accepted as a risk factor for the metabolic syndrome, we do not yet have an understanding of the mechanisms linking these processes. In this issue of Endocrinology, Vickers et al. (9) present data supporting a role for perinatal leptin levels as modulators of the development of adult obesity. Leptin is an adipose-derived hormone that acts in the central nervous system to suppress feeding and increase energy use (11, 12). Throughout much of life, leptin production and circulating levels mirror fat storage. In the study by Vickers, dams were calorie restricted during the last week of pregnancy, and their offspring (CR) were fed either standard chow or high-calorie diets and followed until 170 d of age (9). While control (NN) mice that had not been exposed to caloric restriction in utero increased in adiposity on a high-calorie diet compared with standard chow, the CR mice that had experienced in utero caloric restriction gained even more adipose mass. Whereas daily leptin treatment for postnatal d 3–13 had no effect in NN mice, this leptin treatment significantly blunted the increased adiposity in CR offspring compared with NN controls on the high-calorie diet. These data suggest that circulating leptin concentrations during perinatal development in CR mice influence the later propensity to weight gain and obesity on high-calorie chow.
Several other recent observations also support this potential role for postnatal leptin in influencing the tendency toward obesity in later life: leptin levels in mice surge in the first 2 wk after birth before diminishing toward (
10-fold lower) adult values (13). This neonatal surge in leptin levels occurs at a time when the developmental wiring of hypothalamic circuits that control feeding is incomplete, and leptin is largely ineffective at decreasing feeding during this time (14, 15, 16). Furthermore, although some plasticity in neural connectivity remains later in life, leptin action during this neonatal window is crucial for the development of the brain, including many hypothalamic circuits important for leptin regulation of feeding and energy expenditure (14, 15, 17). Thus, although many of the details of this model have yet to be explicitly tested, it is reasonable to hypothesize that the postnatal leptin surge in mice is responsible (and required) for the correct development and later functioning of hypothalamic circuits that control feeding and energy expenditure (and thus adiposity). A corollary of this hypothesis is that alteration of the amplitude or timing of this surge (as might be expected in the face of fetal or perinatal nutritional restriction or excess) could alter the development of these hypothalamic circuits so as to predispose to weight gain/increased adiposity later in life, especially in the face of palatable high-calorie foods. It is also tempting to speculate that postnatal leptin exposure may also link to risk for ß-cell dysfunction and diabetes risk because modulation of early postnatal nutrition can reverse diabetes risk in offspring of pregnancies complicated by nutrient stress (18).
The compelling results of Vickers et al. (9), notwithstanding, the ultimate picture of how leptin levels may act to control the later predisposition to obesity are likely to be quite a bit more complex than the simple proposition that more postnatal leptin improves hypothalamic wiring and combats subsequent obesity. In another recent study, Yura et al. (10) used a similar model of in utero caloric restriction followed by high-calorie diet, which similarly resulted in increased postnatal weight gain and adiposity in the CR offspring compared with NN controls. These investigators then treated NN mice with leptin for a shorter, slightly different, postnatal period. In contrast to the results of Vickers et al., with leptin treatment of CR mice (9), this treatment of NN mice resulted in a modestly increased risk for obesity as compared with vehicle-treated NN controls. Thus, the exact timing and dose of leptin treatment likely determines the nature of the subsequent developmental program. Indeed, whereas the serial examination of circulating leptin levels in neonatal mice (which are very small with a correspondingly miniscule blood volume) is technically challenging, some data in the Yura study suggested alteration of the amplitude and timing of the postnatal leptin surge after in utero caloric restriction (10).
The notion that the exact amplitude and timing of the leptin surge may impact the direction of the subsequent development of hypothalamic feeding and satiety networks is attractive for a variety of reasons. Not only are both prenatal under- and overnutrition associated with subsequent obesity and diabetes (3), but also the magnitude and timing of catch-up growth is more tightly linked to obesity risk than is prenatal nutritional status (19). Furthermore, leptin likely promotes the development of both anorectic (appetite reducing) and orexigenic (appetite stimulating) neurons in the hypothalamus. Thus, it is reasonable to suppose that relatively subtle alterations in timing or amplitude of leptin action during the key developmental window might result in an imbalance in the relative strength of these networks.
Although data derived from rodent models are likely to apply to human biology, it is also important to consider species-specific differences. For instance, although we know neither the timing of a leptin surge during development nor the role that leptin plays in the development of feeding circuits in humans, it is clear that no postnatal leptin surge exists in human children. Leptin levels are high in cord blood during the later part of pregnancy and at birth but fall during the first few days after birth and remain relatively low thereafter (20, 21).
Clearly, future work will be required to determine the mechanisms by which leptin acts during development to influence adult adiposity. Moreover, additional nutrient and growth-related factors related to catch-up growth are likely to be important in influencing the final phenotype in high-risk offspring. To fully understand the mechanisms by which leptin hits the desired developmental target, it will be crucial to understand the mechanisms governing the timing and amplitude of the neonatal leptin surge in rodents, the optimal timing and amplitude for the developmental response, and the detailed mechanisms by which leptin controls the development of individual neural circuits.
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Received July 29, 2005.
Accepted for publication August 4, 2005.
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