Divergent Leptin Signaling in Proglucagon Neurons of the Nucleus of the Solitary Tract in Mice and Rats

Nov 3, 2007Endocrinology

Different Leptin Responses in Sugar-Regulating Neurons in the Brainstem of Mice and Rats

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Abstract

Leptin induced phosphorylation of a signaling protein in 100% of GLP-1 neurons in the caudal brainstem of mice.

Leptin acts on neurons in the nucleus of the solitary tract (NTS), affecting food intake regulation.
Injection of leptin into the NTS suppresses food intake in rats.
In mice, leptin administration prevents a decrease in proglucagon mRNA levels during fasting.
In contrast, fasting or leptin does not affect proglucagon mRNA levels in rats.
These findings indicate a direct regulatory effect of leptin on proglucagon neurons in mice, but not in rats.
Species differences exist in the interaction mechanisms between leptin and NTS proglucagon neurons.

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The central targets mediating the anorectic and other actions of leptin have yet to be fully identified. Although previous studies focused on the hypothalamus, leptin also acts on neurons in extrahypothalamic sites, including the nucleus of the solitary tract (NTS). Moreover, injection of leptin into the NTS of rats suppresses food intake. Within the central nervous system, glucagon-like peptide (GLP-1), a product of proglucagon, is synthesized almost exclusively in neurons of the NTS. Intracerebroventricular administration of GLP-1 inhibits energy intake, and GLP-1 receptor antagonists attenuate the anorexic effects of leptin in rats. To examine whether NTS proglucagon neurons are directly regulated by leptin, we performed double GLP-1 and phosphorylation of signal transducer and activator of transcription-3 immunohistochemistry on brain sections from ip leptin-treated mice and rats. Leptin induced phosphorylation of signal transducer and activator of transcription-3 in 100% of GLP-1 cells in the caudal brainstem of mice. In striking contrast, 0% of GLP-1-positive neurons in rats responded to leptin. We then measured regulation of NTS proglucagon mRNA using real-time RT-PCR in mice and rats fed ad libitum, fasted, or fasted and treated ip with leptin. In mice, proglucagon mRNA fell by fasting, and this was prevented by leptin administration. In rats, by contrast, proglucagon mRNA was unaffected by either fasting or leptin. Taken together, our studies reveal direct regulation of proglucagon neurons by leptin in mice but not rats along with corresponding species differences in the regulation of proglucagon mRNA expression. These data, combined with previous results, suggest a different mechanism of interaction between leptin and NTS proglucagon neurons in mice and rats.

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Divergent Leptin Signaling in Proglucagon Neurons of the Nucleus of the Solitary Tract in Mice and Rats

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