Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus

Judith Korner, E. Savontaus, Streamson C. Chua, Jr., R. L. Leibel, S. L. Wardlaw

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Agouti-related protein (AGRP) is synthesized in the same neurones in the arcuate nucleus as neuropeptide Y (NPY), another potent orexigenic peptide. AGRP antagonizes the action of α-melanocyte stimulating hormone, a derivative of pro-opiomelanocortin (POMC) at the hypothalamic MC4 receptor to increase food intake. Although leptin has been shown to regulate Agrp/Npy and Pomc-expressing neurones, there are differences with respect to Agrp regulation in leptin receptor-deficient mice and rats. Unlike the obese leptin receptor-deficient db/db mouse, which exhibits upregulation of Agrp mRNA expression in the medial basal hypothalamus (MBH) compared to lean controls, the obese leptin receptor-deficient (faf; Koletsky) rat does not exhibit upregulation of Agrp expression. To determine whether this represents a general difference between leptin receptor-deficient mice and rats, neuropeptide gene expression was analysed in the MBH of lean and obese rats segregating for a different leptin receptor mutation, Leprfa (Zucker). Fasting in lean rats (+/fa) for 72 h significantly increased Agrp and Npy mRNA expression, and decreased Pomc mRNA expression as detected by a sensitive solution hybridization/S1 nuclease protection assay. Npy mRNA levels were significantly increased in fed obese fa/fa compared to lean rats, and further increased in the obese animals after fasting. In contrast, Agrp mRNA levels did not differ between fed lean and fed obese rats, and fasting did not significantly change Agrp levels in obese rats. To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin. Fasting significantly increased Agrp and Npy, and decreased Pomc mRNA levels. Leptin infusion almost completely reversed these changes such that there was no significant difference between the levels in the fasted rats and those that were fed ad libitum. Thus, in fasted lean rats, Agrp and Npy are upregulated in parallel when leptin levels fall and are downregulated by leptin infusion. By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA.

Original languageEnglish (US)
Pages (from-to)959-966
Number of pages8
JournalJournal of Neuroendocrinology
Volume13
Issue number11
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Leptin
Hypothalamus
Messenger RNA
Leptin Receptors
Fasting
Agouti-Related Protein
Middle Hypothalamus
Up-Regulation
3-nitro-2-pyridinesulfenyl
Nuclease Protection Assays
Receptor, Melanocortin, Type 4
Melanocyte-Stimulating Hormones
Neurons
Food Deprivation
Pro-Opiomelanocortin
Arcuate Nucleus of Hypothalamus
Neuropeptide Y
Neuropeptides
Sprague Dawley Rats
Down-Regulation

Keywords

  • AGRP
  • Leptin
  • NPY
  • Obesity
  • POMC

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)

Cite this

Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. / Korner, Judith; Savontaus, E.; Chua, Jr., Streamson C.; Leibel, R. L.; Wardlaw, S. L.

In: Journal of Neuroendocrinology, Vol. 13, No. 11, 2001, p. 959-966.

Research output: Contribution to journalArticle

Korner, Judith ; Savontaus, E. ; Chua, Jr., Streamson C. ; Leibel, R. L. ; Wardlaw, S. L. / Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. In: Journal of Neuroendocrinology. 2001 ; Vol. 13, No. 11. pp. 959-966.
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