Pre‐ and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance

Mar 6, 2012Journal of neuroscience research

Early calorie restriction before and after birth affects brain signals that control energy balance

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Abstract

At postnatal day 21, males exhibited normal leptin levels while females showed elevated leptin levels, indicating potential leptin resistance.

Both male and female subjects showed low leptin levels at postnatal day 2 (PN2) due to intrauterine growth restriction (IUGR).
Females demonstrated activated hypothalamic leptin signaling at PN2, characterized by increased STAT3, while males remained leptin sensitive.
Increased levels of SOCS3 and PTP1B in females contributed to early leptin resistance, resulting in elevated AgRP and reduced MC3-R and MC4-R activation.
At PN21, males maintained normal leptin levels indicative of sensitivity, whereas females exhibited hyperleptinemia consistent with leptin resistance.
Postnatal growth restriction (PNGR) combined with IUGR (IPGR) led to decreased leptin levels and disrupted neuropeptide balance, favoring increased food intake and reduced energy expenditure.

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Energy balance is regulated by circulating leptin concentrations and hypothalamic leptin receptor (ObRb) signaling via STAT3 but is inhibited by SOCS3 and PTP1B. Leptin signaling enhances anorexigenic neuropeptides and receptor (POMC, MC3-R, MC4-R) activation while suppressing orexigenic neuropeptides (NPY, AgRP). We investigated in a sex-specific manner the early (PN2) and late (PN21) postnatal hypothalamic mechanisms in response to intrauterine (IUGR), postnatal (PNGR), and combined (IPGR) calorie and growth restriction. At PN2, both male and female IUGR were hypoleptinemic, but hypothalamic leptin signaling in females was activated as seen by enhanced STAT3. In addition, increased SOCS3 and PTP1B supported early initiation of leptin resistance in females that led to elevated AgRP but diminished MC3-R and MC4-R. In contrast, males demonstrated leptin sensitivity seen as a reduction in PTP1B and MC3-R and MC4-R with no effect on neuropeptide expression. At PN21, with adequate postnatal caloric intake, a sex-specific dichotomy in leptin concentrations was seen in IUGR, with euleptinemia in males indicative of persisting leptin sensitivity and hyperleptinemia in females consistent with leptin resistance, both with normal hypothalamic ObRb signaling, neuropeptides, and energy balance. In contrast, superimposition of PNGR upon IUGR (IPGR) led to diminished leptin concentrations with enhanced PTP1B and an imbalance in arcuate nuclear NPY/AgRP and POMC expression that favored exponential hyperphagia and diminished energy expenditure postweaning. We conclude that IUGR results in sex-specific leptin resistance observed mainly in females, whereas PNGR and IPGR abolish this sex-specificity, setting the stage for acquiring obesity after weaning.

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Pre‐ and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance

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