Abstract
ObjectiveLeptin resistance is a common hallmark of obesity. Rats on a free-choice high-fat high-sugar (fcHFHS) diet are resistant to peripherally administered leptin. The aim of this study was to investigate feeding responses to central leptin as well as the associated changes in mRNA levels in hypothalamic and mesolimbic brain areas.Design and MethodsRats on a CHOW or fcHFHS diet for 8 days received leptin or vehicle intracerebro(lateral)ventricularly (ICV) and food intake was measured 5 h and 24 h later. Four days later, rats were sacrificed after ICV leptin or vehicle and mRNA levels were quantified for hypothalamic pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) and for preproenkephalin (ppENK) in nucleus accumbens and tyrosine hydroxylase (TH) in ventral tegmental area (VTA).ResultsICV leptin decreased caloric intake both in CHOW and fcHFHS rats. In fcHFHS, leptin preferentially decreased chow and fat intake. Leptin increased POMC and decreased NPY mRNA in CHOW, but not in fcHFHS rats. In CHOW rats, leptin had no effect on ppENK mRNA and decreased TH mRNA. In fcHFHS, leptin decreased ppENK mRNA and increased TH mRNA.ConclusionDespite peripheral and arcuate leptin resistance, central leptin suppresses feeding in fcHFHS rats. As the VTA and nucleus accumbens are still responsive to leptin, these brain areas may therefore, at least partly, account for the leptin-induced feeding suppression in rats on a fcHFHS diet.
Highlights
Since the discovery of leptin in 1994 [1] a wealth of studies has been generated on leptin’s role in feeding behavior and metabolism
Despite peripheral and arcuate leptin resistance, central leptin suppresses feeding in free-choice high-fat high-sugar (fcHFHS) rats
As the ventral tegmental area (VTA) and nucleus accumbens are still responsive to leptin, these brain areas may at least partly, account for the leptininduced feeding suppression in rats on a fcHFHS diet
Summary
Since the discovery of leptin in 1994 [1] a wealth of studies has been generated on leptin’s role in feeding behavior and metabolism. Leptin resistance is the process occurring in human obesity and in several models of rodent obesity in which synthesis and secretion of leptin are increased, while inhibition of feeding or activation of energy expenditure by leptin are decreased [2,3]. Leptin’s actions in the brain have been best characterized in the arcuate nucleus of the hypothalamus, where leptin suppresses feeding by acting on leptin receptors on neuropeptide Y (NPY)/ Agouti related protein (AgRP) neurons and pro-opiomelanocortin (POMC) neurons. Both NPY and AgRP stimulate feeding, whereas alpha-MSH, which is a product of the POMC gene after splicing, suppresses feeding. Leptin exerts its inhibitory effects on feeding by changing the excitability of the POMC and NPY/ AgRP neurons and by increasing and decreasing their expression levels, respectively [4]
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