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

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.environmental enrichment | arcuate nucleus | AgRP | POMC | synaptic plasticity I t is widely accepted that the prevalent lifestyle model of Western societies characterized by limited physical activity, excessive caloric intake, and repetitive behavioral patterns contributes to the dysregulation of the otherwise homeostatic control of body weight (BW) (1). The main player in this system is leptin, a hormone secreted in the periphery by fat cells (2), which signals the status of body energy stores, down-regulates feeding behavior, and promotes energy expenditure by activating signal transduction mediated by the JAK-STAT pathway in the hypothalamic arcuate nucleus (ARC) through its receptor (Ob-Rb). This, in turn, promotes excitation and inhibition of neurons expressing, respectively, POMC, which is a precursor of α-melanocyte-stimulating hormone (MSH), the most potent anorexigenic peptide, and the orexigenic peptides agouti-related peptide (AgRP)/Neuropeptide Y (NPY) (3, 4).Such a seemingly clear view of the complex regulation of feeding behavior and BW is challenged by the fact that the majority of obese people exhibit high levels of circulating leptin (5), to which they are apparently resistant. Leptin resi...

Childhood maltreatment and obesity: systematic review and meta-analysis

“…Because they act on developing, plastic systems, [8][9][10] childhood stressors like maltreatment may exert enduring effects, presumably through epigenetic mechanisms. 75,76 Future research will need to clarify the biological mechanisms underlying these clinical findings, for example, by directly testing the adipogenic effects of neurobiological, endocrine and immune abnormalities previously described in maltreated individuals.…”

“…[8][9][10][11][12]15,16 Because childhood psychosocial experiences influence obesity risk, obesity should be seen not only as a clinical problem but also as a societal problem. Public health solutions to this problem might be important for at least two reasons.…”

“…Experimental research in animal models starting in the womb showed that brain regions regulating energy balance continue to develop till early postnatal life in response to environmental stimuli and endocrine signals. [8][9][10] Similarly, the development of energy balance regulation in humans may be significantly influenced by environmental influences starting in the prenatal period and continuing throughout childhood. 11,12 Diet in childhood has long been investigated as an important determinant of later obesity.…”

Feed Your Head: Neurodevelopmental Control of Feeding and Metabolism

“…For example, a 3-week period of wheel running in rats fed HFD in early postnatal life leads to sustained increases in leptin sensitivity in adulthood (184). Enriched environmental conditions (EEC) are even more potent in reversing prenatal HFD-induced leptin resistance, triggering ArcN synaptic changes that increase Pomc neuron excitability and decrease Agrp neuron excitability (185). The impact of EEC is age dependent, with the greatest impact on the leptin-hypothalamic axis when environmental stimulation is applied during postnatal development.…”

Environmental Influences on Visual Cortex Development and Plasticity

“…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.…”