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The Role of Intracerebroventricular Administration of Leptin in the Stimulation of Prothyrotropin Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus

Division of Endocrinology (M.P., R.C.S., E.A.N.), Department of Medicine, Brown Medical School/Rhode Island Hospital, Providence, Rhode Island 02903; and Department of Molecular Biology, Cell Biology and Biochemistry (E.A.N.), Brown University, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Dr. Eduardo A. Nillni, Division of Endocrinology, Brown Medical School/Rhode Island Hospital, 55 Claverick Street, 4th Floor, Room 430, Providence, Rhode Island 02903. E-mail: Eduardo_Nillni{at}Brown.edu.

We previously have shown that leptin regulates proTRH in the paraventricular nucleus (PVN) of the hypothalamus through two pathways. The first one acts directly on proTRH neurons, and the second one (indirect) acts through the melanocortin system (arcuate nucleus). However, it is unknown whether the direct or the indirect pathways of leptin action on proTRH neurons occurs on separated or on the same subsets of neurons within the PVN region. We used immunostaining for the phosphorylated signal transducer and activator of transcription 3 to localize direct leptin signaling, and the phosphorylated cAMP response element binding protein to localize indirect signaling on proTRH neurons in animals intracerebroventricularly injected with leptin. With this approach we were able to identify two subsets of neuronal populations responsive to leptin, which are distributed in different regions within the PVN. ProTRH neurons directly responsive to leptin were located mainly in the medial and posterior part of the PVN, and they were not primarily related to the hypothalamic pituitary thyroid axis. Whereas, proTRH neurons indirectly responsive (through -MSH) to leptin were located mainly in the anterior, medial, and periventricular part of the PVN, and related to the hypothalamic pituitary thyroid axis. In addition, -MSH showed to affect the processing of proTRH and up-regulated the prohormone convertase 1/3. In this study, we show evidence supporting the hypothesis that in the PVN there are subpopulations of proTRH neurons responding to leptin, which is dependent upon the way leptin reaches its primary target(s) in the hypothalamus. These findings are critical to a better understanding of leptin-mediated actions in energy expenditure.

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