Chronic consumption of a low-fat diet leads to increased hypothalamic agouti-related protein and reduced leptin.

Objective: This study examined the hypothesis that dietary fat under ad libitum feeding conditions influences expression levels (mRNA) of the mouse agouti-related protein (AgRP), leptin, leptin receptor (OBRb), and neuropeptide Y (NPY) at early stages of development.

Methods: C57Bl/6J male mice were placed on a high-fat diet (HFD) or a low-fat diet (LFD) shortly after weaning. Groups of mice were euthanized at various ages and real-time one-step reverse transcriptase polymerase chain reaction was used to analyze gene expression in the hypothalamus (AgRP, NPY, OBRb), the adrenal gland (AgRP), the testis (AgRP), and epididymal fat (leptin).

Results: Leptin expression increased linearly with age but only under the HFD despite body weight gain under both diets. This pattern of expression coincided with reduced expression of hypothalamic AgRP under an HFD, whereas OBRb and NPY did not fluctuate in response to diet. By contrast, consumption of an LFD (i.e., high carbohydrate) increased hypothalamic AgRP and suppressed adipose leptin, which is consistent with the notion that leptin could regulate AgRP centrally. In contrast, AgRP expression in the adrenal gland initially decreased and then increased with age under both diets.

Conclusions: Dietary fat can have a tissue-dependent effect on AgRP that may be unfettered by leptin under an HFD.