Elsevier

Brain Research

Volume 949, Issues 1–2, 13 September 2002, Pages 139-146
Brain Research

Research report
Leptin regulates interleukin-1β expression in the brain via the STAT3-independent mechanisms

https://doi.org/10.1016/S0006-8993(02)02974-8Get rights and content

Abstract

Leptin is known to be an important circulating signal for regulation of food intake and body weight. These effects were suggested to be mediated through the hypothalamic center via the Ob-Rb receptor (long isoform of leptin receptor). Although short isoforms of leptin receptor exist in many regions of the brain, there has been little in vivo functional study of these areas such as for leptin’s target site. We report here that peripherally applied leptin increased interleukin (IL)-1β transcripts in many regions of the brain such as the hypothalamus, the hippocampus, the cortex, the cerebellum and the brainstem. Although leptin did not induce STAT3 activation or suppressor of cytokine signaling3 (SOCS3) expression in the hypothalamus of the db/db mice, which lack a functional Ob-Rb receptor, leptin increased the IL-1β levels to similar extents as normal mice. Therefore, a novel function of leptin is suggested as the induction of IL-1β expression in many regions of the brain via STAT3-independent mechanisms.

Introduction

Leptin, the 16-kDa protein encoded by the ob gene [65], is known to be an important energy balance regulator through its actions in the hypothalamus associated with appetite and energy expenditure [12], [51]. Leptin is mainly secreted by adipose tissue and released into the circulation to act in both the periphery and the brain.

Increasing evidence has suggested that leptin may interact with cytokines in the immune system. Intraperitoneal administration of lipopolysaccharide (LPS) or cytokines increases leptin expression in serum and adipose tissue [25], [54]. Conversely, exogenous leptin has been shown to up-regulate both phagocytosis and the production of proinflammatory cytokines in macrophages [40], and leptin increased monocyte chemoattractant protein-1 expression in endothelial cells [11]. Moreover, it has been reported that leptin modulates T-cell immune function [18], [41]. A recent study suggested that the effects of leptin on food intake and body temperature were mediated by interleukin (IL)-1β [42].

Leptin receptors (Ob-R) are found in many tissues in several alternatively spliced forms such as Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re as well as others [19], [60]. One form of the receptor, Ob-Rb (long isoform of leptin receptor) has a long cytoplasmic region with consensus amino acid sequences involved in the activation of JAK-STAT tyrosine kinases [22], [39], [61]. Leptin regulates appetite and energy expenditure through the hypothalamic center via the Ob-Rb receptor [12], [51]. However, other isoforms (short isoform) have no or short cytoplasmic domains and could not activate STAT protein [22], [61]. A large number of studies have suggested that leptin regulates feeding behavior in the hypothalamus through Ob-Rb receptor. Although other isoforms of leptin receptor exist in many regions of the brain [26], [45], leptin’s physiological function in these areas has not been elucidated.

In the present study, we show peripherally applied leptin increased IL-1β transcripts not only in the hypothalamus but also in other brain regions. Using db/db mice which lack functional Ob-Rb receptor, we found leptin’s novel function with respect to IL-1β expression was regulated through STAT3-independent mechanisms in vivo.

Section snippets

Animals

db/db mice and their respective lean littermates (C57BL/KsJ) were obtained at 7 weeks old from Central Laboratories for Experimental Animals (Japan). Mice were maintained in a room at 22–24 °C under a constant day/night rhythm and given food and water, ad libitum. All animal experiments were carried out in accordance with the NIH Guide for Care and Use of Laboratory Animals and approved by the animal care and use committee at Hokkaido University.

Leptin injection and sample preparation

Murine Leptin (Pepro Tech., London) was dissolved

Effect of leptin on IL-1β transcripts in the brain

IL-1β mRNA does not abundantly exist in the brain, therefore, it may be difficult to detect without amplification by RT–PCR. In line with previous findings [21], [38], we detected basal levels of IL-1β mRNA in the hypothalamus, the hippocampus, the cortex, the cerebellum and the brainstem as assessed by RT–PCR (Fig. 1). IL-1β transcripts were increased 2 h after the application of leptin (5 mg/kg, i.v.) in all the brain regions tested (Fig. 1). The effect of leptin was not due to endotoxin

Discussion

The effect of leptin in the regulation of appetite and energy expenditure is mediated through the hypothalamic center via the Ob-Rb receptor (long isoform of leptin receptor). Although other isoforms of leptin receptor exist in many regions of the brain, there has been no in vivo functional study of these areas such as for leptin’s target site. The findings of the present study demonstrate that peripheral leptin increased IL-1β transcripts in many regions of the brain even in the region which

Acknowledgements

This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (Y.O., Y.N.), and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (T.H.).

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