Abstract
Neonatal overfeeding during the first weeks of life in male rats is associated with a disruption in the peripheral and central leptin systems. Neonatally overfed male rats have increased circulating leptin in the first 2 weeks of life, which corresponds to an increase in body weight compared to normally fed counterparts. These effects are associated with a short-term disruption in the connectivity of neuropeptide Y (NPY), agouti-related peptide (AgRP), and pro-opiomelanocortin (POMC) neurons within the regions of the hypothalamus responsible for control of energy balance and food intake. Female rats that are overfed during the first weeks of their life experience similar changes in circulating leptin levels as well as in their body weight. However, it has not yet been studied whether these metabolic changes are associated with the same central effects as observed in males. Here, we hypothesized that hyperleptinemia associated with neonatal overfeeding would lead to changes in central feeding circuitry in females as it does in males. We assessed hypothalamic NPY, AgRP, and POMC gene expression and immunoreactivity at 7, 12, or 14 days of age, as well as neuronal activation in response to exogenous leptin in neonatally overfed and control female rats. Neonatally overfed female rats were hyperleptinemic and were heavier than controls. However, these metabolic changes were not mirrored centrally by changes in hypothalamic NPY, AGRP, and POMC fiber density. These findings are suggestive of sex differences in the effects of neonatal overfeeding and of differences in the ability of the female and male central systems to respond to changes in the early life nutritional environment.
Highlights
Life obesity is associated with increased risk of developing diabetes, cardiovascular complications and, increased rates of premature death [1, 2]
For the first time, we show that neonatal overfeeding in females, despite hyperleptinemia and a corresponding increased body weight, does not affect neuropeptide Y (NPY), agouti-related peptide (AgRP), and POMC mRNA or protein in the hypothalamic circuitry responsible for feeding and metabolic control
These observations are different from findings previously shown in neonatally overfed males, where overfeeding leading to hyperleptinemia and increased body weight are associated with short-term disruption of hypothalamic neuronal wiring responsible for metabolic regulation [13, 26]
Summary
Life obesity is associated with increased risk of developing diabetes, cardiovascular complications and, increased rates of premature death [1, 2]. In a neonatally overfed animal model representative of childhood obesity, both male and female rat pups raised in small litters, with greater access to their mothers’ milk, experience significantly increased body weight, accompanied by obesity-related comorbidities in adulthood compared to pups raised in normal litters. These comorbidities include hypothalamic–pituitary–adrenal (HPA) axis dysfunction, impaired reproductive function, memory. In the absence of leptin or ghrelin, or presence of a premature leptin surge or delayed ghrelin rise, neuronal connections between the relevant hypothalamic brain regions are impaired, leading to metabolic complications and obesity long term [20, 23, 24]
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