ReviewNeurodevelopmental actions of leptin
Introduction
Leptin is a 16-kDa protein secreted from white adipose tissue that acts as a crucial signal for body energy stores. It is found in the blood circulation in proportion to fat mass and functions to blunt feeding behavior and promote energy expenditure. It is now widely recognized that leptin primarily acts on the brain to mediate its effects on feeding and energy balance. The observation that central nervous system-specific deletion of leptin receptors results in a phenotype that is a virtual carbon copy of whole-body leptin receptor-deficient (Leprdb/db) mice strongly supports this idea (Cohen et al., 2001). The hypothalamus has traditionally been the focus of studies on obesity, owing not only to its central role in neuroendocrine functions and feeding behavior, but also to the fact that it contains the highest density of leptin receptors of any brain region (Caron et al., 2010, Elmquist et al., 1998). Accordingly, leptin acts directly on neurons located in various parts of the hypothalamus, including the ARH, the VMH, and the LHA, to induce its effects on feeding and energy balance regulation in mature animals (Balthasar et al., 2004, Coppari et al., 2005, Dhillon et al., 2006, Leinninger et al., 2009). An emerging concept in the field of leptin neurobiology also implicates other non-hypothalamic brain regions in mediating the central effects of leptin. These regions include, but are not limited to, the midbrain (Fulton et al., 2006, Hommel et al., 2006), the hippocampus (Lu et al., 2006), and the hindbrain (Hayes et al., 2010).
It is broadly recognized that hormones can produce pleiotropic effects, especially in the brain, on functions that are well outside those they have traditionally been thought to regulate. Consistent with this idea, although the effects of leptin in the brain were previously thought to be limited to the neural control of feeding behavior in mature animals, it is now becoming increasingly clear that leptin can also influence a variety of developmental processes in the immature brain. This review summarizes the neurodevelopmental changes that have been observed in response to alterations in leptin levels during critical periods of development.
Section snippets
Leptin secretion during important periods of brain development
Leptin is one of the first major metabolic hormones to appear during development. White adipose tissue (the main source of leptin production in adult animals) is minimal at early ages, yet mouse fetuses do contain significant leptin levels in their blood as early as E12.5 (Udagawa et al., 2006a) (Ishii and Bouret, unpublished data). Various tissues produce leptin during embryonic development. On embryonic day 13.5, high levels of leptin gene expression are found in the fetal liver and
Developmental regulation of CNS leptin receptor expression
The leptin receptor exists in multiple alternatively-spliced isoforms, of which only the long form (LepRb) associates with Janus kinase 2 (JAK2) to mediate intracellular signaling. Upon leptin binding, LepRb initiates multiple intracellular signal transduction pathways that result in the activation of STAT family transcription factors, extracellular signal-regulated kinases (ERK), and phosphoinositol-3 kinase. Leptin receptors, including LepRb, are detected in the mouse brain as early as
Early studies of the neurodevelopmental actions of leptin
Over 30 years ago, Bereiter and Jeanrenaud, 1979, Bereiter and Jeanrenaud, 1980 reported that the brains of genetically obese and diabetic mice (Lepob/Lepob and Leprdb/Leprdb mice, respectively) were structurally different from those of control mice. They observed a reduction in cell density in various brain regions, including the hypothalamus, and found alterations in the dendritic orientation of hypothalamic neurons. These structural abnormalities of Lepob/Lepob and Leprdb/Leprdb mice were
Hypothalamic actions
The hypothalamus undergoes tremendous growth beginning early in gestation and continuing during the postnatal period (see (Bouret, 2010) and (Markakis, 2002) for review). During this developmental period, a variety of processes shape the hypothalamic nuclei involved in the control of feeding and energy balance. The cellular mechanisms proposed to explain how hypothalamic circuits are formed fall into five main categories: neurogenesis, neuronal migration, cell death, axon growth, and synapse
Nutritional manipulations of perinatal leptin: impact on hypothalamic development
The majority of research on nutritional manipulations of perinatal leptin levels has been focused on metabolic abnormalities, a natural bias given the obvious importance of leptin in metabolic regulation. There is also a growing appreciation that nutritional alterations in leptin levels during early life may have structural consequences on hypothalamic feeding circuits. For instance, maternal obesity increases leptin levels throughout postnatal life and reduces the hypothalamic response to
Extra-hypothalamic actions
The neurodevelopmental actions of leptin are not limited to hypothalamic development. Soon after the discovery that leptin influences the establishment of hypothalamic neural projections, various groups reported a role for leptin in hippocampal and cortical development (Fig. 2). O'Malley et al. showed that exposure of hippocampal neurons to leptin enhances the motility and density of dendritic filopodia, with consequences on synapse morphology (O'Malley et al., 2007). Furthermore, they showed
Evidence in humans
The majority of what we know about the influence of leptin on brain development and plasticity comes from rodent models, predominantly rats and mice. Nevertheless, there is increasing evidence suggesting that leptin may also influence neuroplastic events in the human brain. Much of our knowledge of the neural actions of leptin in humans has been inferred from non-invasive magnetic resonance imaging studies. Using voxel-based morphometry analysis, Matochick et al. reported that leptin
Conclusion
Tremendous progress has been made in elucidating the effects of leptin on the developing brain and the cellular and molecular mechanisms by which those effects are achieved. There is still no evidence that leptin influences very early developmental events such as neural induction and the establishment of polarity; however, accumulating evidence indicates that leptin regulates later developmental processes such as neurogenesis, axon growth, dendrite proliferation, and synapse formation. Less
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