Article

A sensitive period for environmental regulation of eating behavior and leptin sensitivity

Laboratory of Neurobiology, Scuola Normale Superiore, 56100 Pisa, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2010; 107(38):16673-8. DOI: 10.1073/pnas.0911832107
Source: PubMed

ABSTRACT Western lifestyle contributes to body weight dysregulation. Leptin down-regulates food intake by modulating the activity of neural circuits in the hypothalamic arcuate nucleus (ARC), and resistance to this hormone constitutes a permissive condition for obesity. Physical exercise modulates leptin sensitivity in diet-induced obese rats. The role of other lifestyle components in modulating leptin sensitivity remains elusive. Environmentally enriched mice were used to explore the effects of lifestyle change on leptin production/action and other metabolic parameters. We analyzed adult mice exposed to environmental enrichment (EE), which showed decreased leptin, reduced adipose mass, and increased food intake. We also analyzed 50-d-old mice exposed to either EE (YEE) or physical exercise (YW) since birth, both of which showed decreased leptin. YEE mice showed no change in food intake, increased response to leptin administration, increased activation of STAT3 in the ARC. The YW leptin-induced food intake response was intermediate between young mice kept in standard conditions and YEE. YEE exhibited increased and decreased ratios of excitatory/inhibitory synapses onto α-melanocyte-stimulating hormone and agouti-related peptide neurons of the ARC, respectively. We also analyzed animals as described for YEE and then placed in standard cages for 1 mo. They showed no altered leptin production/action but demonstrated changes in excitatory/inhibitory synaptic contacts in the ARC similar to YEE. EE and physical activity resulted in improved insulin sensitivity. In conclusion, EE and physical activity had an impact on feeding behavior, leptin production/action, and insulin sensitivity, and EE affected ARC circuitry. The leptin-hypothalamic axis is maximally enhanced if environmental stimulation is applied during development.

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    • "Since the animals usually experience a rebound feeding the day after fasting, the total caloric balance, also in this case, is usually reduced to 70–90% of normal intake [45] [46]. More recently, environmental enrichment (EE) has been added to this list [47]. Compared to the simple physical exercise protocol, EE adds cognitive, sensory, and social stimulations by means of rearing larger groups of animals (up to ten, compared to the usual three to five) in wider cages with several objects to explore that are frequently changed [48] [49]. "
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    ABSTRACT: Regulation of feeding behavior has been a crucial step in the interplay between leptin and the arcuate nucleus of the hypothalamus (ARC). On one hand, the basic mechanisms regulating central and peripheral action of leptin are becoming increasingly clear. On the other hand, knowledge on how brain sensitivity to leptin can be modulated is only beginning to accumulate. This point is of paramount importance if one considers that pathologically obese subjects have high levels of plasmatic leptin. A possible strategy for exploring neural plasticity in the ARC is to act on environmental stimuli. This can be achieved with various protocols, namely, physical exercise, high-fat diet, caloric restriction, and environmental enrichment. Use of these protocols can, in turn, be exploited to isolate key molecules with translational potential. In the present review, we summarize present knowledge about the mechanisms of plasticity induced by the environment in the ARC. In addition, we also address the role of leptin in extrahypothalamic plasticity, in order to propose an integrated view of how a single diffusible factor can regulate diverse brain functions.
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    • "Finally, quite recent studies have shown that restriction of food can restore plasticity in the visual cortex of the adult rats, accompanied, as in the case of EE, by a decrease of inhibition and increase of BDNF (Spolidoro et al., 2011). In addition, EE is active not only in the visual cortex and hippocampus, but also in other parts of the brain, for instance in the arcuate nucleus of the hypothalamus, by altering the ratio of excitation and inhibition, with the result of increasing the sensitivity to leptin and thus regulating food intake (Mainardi et al., 2010). This experiment on the hypothalamus indicates that the effects of EE are quite general on the whole brain and with similar mechanisms. "
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    ABSTRACT: Brain development in neurodevelopmental disorders has been considered to comprise a sequence of critical periods, and abnormalities occurring during early development have been considered irreversible in adulthood. However, findings in mouse models of neurodevelopmental disorders, including fragile X, Rett syndrome, Down syndrome, and neurofibromatosis type I suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations. Furthermore, recent studies have suggested that critical period-like plasticity can be reactivated in the adult brain by environmental manipulations or by pharmacotherapy. These studies open up a tantalizing possibility that targeted pharmacological treatments in combination with regimes of training or rehabilitation might alleviate or reverse the symptoms of neurodevelopmental disorders even after the end of critical developmental periods. Even though translation from animal experimentation to clinical practice is challenging, these results suggest a rational basis for treatment of neurodevelopmental disorders in adulthood.
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    • "EE positively affects also emotional and stress reactivity, both in normal animals and in strains of mice considered pathologically anxious [43]. Interestingly, the effects of EE are not restricted to the cerebral cortex, as demonstrated by a recent work in which this paradigm has been used to investigate the effects of lifestyle change on metabolic parameters [44]. Enriched mice showed decreased leptin, reduced adipose mass, and increased food intake compared to standard-reared animals, demonstrating that the leptin-hypothalamic axis can be enhanced by environmental stimulation. "
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