Hyperphagia and obesity produced by arcuate injection of NPY–saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes

Jun 26, 2008Peptides

Increased eating and obesity from targeting appetite neurons in the arcuate do not depend on higher levels of hunger-related genes in the side hypothalamus

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Abstract

Injection of NPY-SAP into the rat arcuate nucleus results in profound hyperphagia and obesity.

NPY-SAP injection destroys NPY and POMC/CART neurons in the arcuate nucleus.
Lesioned rats exhibited rapid increases in food intake and body weight.
Expression of orexins and melanocortin concentrating hormone in the lateral hypothalamus was not increased in lesioned rats.
Obesity and hyperphagia following NPY-SAP lesion differs from obesity related to dietary factors or leptin deficiency.
The mechanism behind the increased feeding behavior remains unidentified, potentially linked to hindbrain or endocrine factors.

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Neuropeptide Y (NPY) conjugated with a ribosomal inactivating toxin, saporin (SAP), is a toxin that targets NPY receptor-expressing cells. Injection of NPY-SAP into the rat arcuate nucleus (Arc) and basomedial hypothalamus (BMH) destroys two populations of NPY-receptor-expressing neurons important for the control of food intake and body weight, NPY and pro-opiomelanocortin (POMC) and cocaine and amphetamine related transcript (CART) neurons, and produces profound hyperphagia and obesity. Here, we investigated the contribution of lateral hypothalamus (LHA) orexigenic peptides, orexins and melanocortin concentrating hormone (MCH), to these lesion effects. We microinjected NPY-SAP into two sites on each side of the Arc, causing a loss of NPY and POMC/CART neurons that was limited to the Arc. Lesioned rats rapidly became hyperphagic and obese. However, MCH and prepro-orexin mRNA expression were not increased in the LHA in the lesioned rats, but were decreased at some levels of the LHA or were unchanged. NPY-SAP-induced obesity therefore differs from dietary obesity and from obesity associated with leptin or leptin receptor deficiency in which MCH gene expression is increased. The Arc NPY-SAP lesion produces obesity and hyperphagia that does not require overexpression of hypothalamic neuropeptides currently considered to provide major stimulatory drive for food intake: NPY, agouti gene-related protein, MCH or orexins. The source of the seemingly unregulated stimulatory drive for feeding in these animals has not been identified, but may be associated with hindbrain or endocrine mechanisms.

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Hyperphagia and obesity produced by arcuate injection of NPY–saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes

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