Rats neonatally overnourished due to a reduced litter size develop persisting overweight throughout life. A presumed mechanism leading to this 'malprogramming' consists of an acquired change of the responsiveness to leptin of the neuronal system regulating feeding behavior. The study reports significant differences in the effects of leptin on single unit activity of the arcuate nucleus in brain slices of normal compared with early postnatally overfed juvenile rats. The firing rate of arcuate neurons in normal rats was inhibited by leptin (Wilcoxon test p < 0.0001, n = 42), whereas it was not changed in obese rats (Wt p = 0.24, n = 35). The reduced inhibition by leptin of arcuate neurons in neonatally overfed rats might indicate an acquired hypothalamic leptin resistance contributing to persistent hyperphagia and overweight.

Food intake and energy expenditure are regulated by neuropeptides in the hypothalamus. While cocaine- and amphetamine-regulated transcript (CART) peptide and melanocortins such as alpha-melanocyte-stimulating hormone (alpha-MSH) are anorexigenic and increase energy expenditure, the endogenous melanocortin receptor antagonist agouti gene-related protein (AGRP), melanin-concentrating hormone (MCH) and neuropeptide Y (NPY) are orexigenic, anabolic peptides. Alterations in the regulatory balance may promote excessive weight gain. The action of these peptides on paraventricular hypothalamic neurons was studied in brain slices of overweight, adult rats previously subjected to early postnatal overfeeding in small litters of only three pups per mother, compared to 12 pups per dam in control litters. CART, melanocortins and NPY significantly excited paraventricular neurons of controls, whereas neurons of small-litter rats were mainly inhibited. Inhibition was dominant following administration of AGRP, MCH and NPY. The altered responses of paraventricular neurons in adult small-litter rats might reflect a general mechanism of neurochemical plasticity and 'malprogramming' of hypothalamic neuropeptidergic systems acquired during the postnatal critical differentiation period, thus leading to permanently altered function of these regulatory systems of body weight.

Rats exposed to early postnatal overfeeding by rearing in small litters become hyperphagic, hyperleptinemic, and hyperinsulinemic throughout later life. Medial arcuate neurons are involved in body weight regulation. They were tested in brain slices of control and small-litter rats concerning differences in responses to insulin. Insulin induced suppression of firing in controls, whereas in small-litter rats inhibition was significantly reduced and activation increased. This could be observed in juvenile as well as adult rats. A gamma-aminobutyric acid type A receptor antagonist did not change the responses. Thus, negative feedback to the satiety signal insulin on medial arcuate neurons is reduced in neonatally overfed small-litter rats. This can be regarded as insulin resistance, which is induced during early development and persists in later life.