Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent

Abstract

Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.

Obesity after neonatal overfeeding is independent of hypothalamic microgliosis

“…In previous studies, we and others determined that the obesogenic effects of early‐life overfeeding may be related to changes in the neuropeptide Y (NPY) and agouti‐related peptide (AgRP) feeding circuitry at the level of the ARC . In rodents, a postnatal leptin surge around the first and second weeks of life stimulates growth and development of NPY/AgRP neuronal projections throughout the ARC and disruption to this leptin surge can lead to impairments in this development .…”

“…In neonatally overfed animals, it is likely that this leptin surge occurs too early and that the ghrelin “brake” on the development of this connectivity is also disrupted . In particular, neonatal overfeeding leads to elevated neonatal leptin, reduced acyl‐ghrelin, acute hypothalamic resistance to exogenous leptin, as well as increased NPY fibre density in the ARC . However, it is noteworthy that these changes to the NPY/AgRP circuitry at the level of the ARC are mostly resolved by the time the rats reach adulthood, meaning that other factors must contribute to the maintenance of excess weight throughout life after neonatal overfeeding …”

“…Early‐life diet can have a lasting impact on metabolism and feeding pathways, with early‐life overfeeding or a high‐fat diet (HFD) leading to dysregulated hypothalamic connectivity and ghrelin and leptin signalling, some aspects of which, including weight gain, can last into adulthood . Overfeeding and HFD in early development can also lead to alterations in neuroimmune function .…”

Leptin resensitisation: a reversion of leptin-resistant states

“…Early overfeeding Reduction of the litter size leads to decreased pSTAT3 and increased SOCS3 (Plagemann et al 2012) • Partial reversion in adulthood (Sominsky et al 2017).…”

“…Neonatal leptin resistance induced by litter size reduction seems to partially reverse in adulthood, as exogenous leptin injection suppresses food intake, despite body weight and circulating leptin remain elevated (Sominsky et al 2017). Interestingly, long-term energy restriction in ARH-ablated animals decreases not only adiposity and plasma leptin but also normalises peripheral sensitivity to leptin (Perello et al 2009).…”