Adaptive responses in hypothalamic neuropeptide Y in the face of prolonged high‐fat feeding in the rat

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Abstract
While a dysregulation in neuropeptide Y (NPY) signaling has been described in rodent models of obesity, few studies have investigated the time‐course of changes in NPY content and responsiveness during development of diet‐induced obesity. Therefore we investigated the effect of differing lengths (2–17 weeks) of high‐fat diet on hypothalamic NPY peptide content, release and NPY‐induced hyperphagia. Male Sprague–Dawley rats (211 ± 3 g) were fed either a high‐fat diet (30% fat) or laboratory chow (5% fat). Animals were implanted with intracerebroventricular cannulae to investigate feeding responses to NPY (0.5 nmol, 1 nmol) after 4 or 12 weeks of diet. At the earlier stage of obesity, NPY‐induced hyperphagia was not altered; however, animals maintained on the high‐fat diet for the longer duration were hyper‐responsive to NPY, compared to chow‐fed control rats (p < 0.05). Overall, hypothalamic NPY peptide content tended to be decreased from 9 to 17 weeks of diet (p < 0.05). Total hypothalamic NPY content was negatively correlated with plasma leptin concentration (p < 0.05), suggesting the hypothalamic NPY system remains responsive to leptin's inhibitory signal. In addition, hypothalamic NPY overflow was significantly reduced in high‐fat fed animals (p < 0.05). Together these results suggest a reduction in hypothalamic NPY activity in high‐fat fed animals, perhaps in an attempt to restore energy balance.