Differential Expression and Regulation of Leptin Receptor Isoforms in the Rat Brain: Effects of Fasting and Oestrogen

Abstract

Leptin affects body weight and reproduction mainly via receptors in the central nervous system. Different isoforms of the leptin receptor (leptin-R) exist, including a long isoform (leptin-R_L) with signalling capacity and short isoforms (leptin-R_S) with unknown function. The aim of this study was to examine leptin-R gene expression in different regions of the brain under conditions with altered body weight, in the female rat, including ovariectomy (OVX), oestradiol (E₂) treatment, fasting and a genetic model of obesity (Zucker fa/fa). Leptin-R gene expression was analysed by in situ hybridization using probes recognizing all receptor isoforms (leptin-R) or specifically leptin-R_L. Transcripts recognized by the leptin-R probe were abundant in the choroid plexus (CP), arcuate nucleus (ARC), ventromedial nucleus (VMN), thalamus (TH) and piriform cortex (PC). Leptin-R_L transcripts were detected in the ARC, VMN, TH and PC but not in the CP. Although no sex difference was observed, leptin-R gene expression was reduced by E₂ administration and increased by OVX. Administration of E₂ reduced leptin-R_L gene expression in the ARC and VMN but did not alter the expression in the TH or PC. OVX had no effect on the expression of leptin-R_L mRNA. Fasting also caused a differential regulation of leptin-R mRNAs, with an increase in abundance of leptin-R_L transcripts in the TH despite a decrease in leptin-R in this area. Obese Zucker rats had a similar pattern of expression with an increased expression of leptin-R_L transcripts in all brain areas analysed and a decrease in leptin-R gene expression. These results demonstrate a differential regulation of leptin-R_L and leptin-R_S which could provide a mechanism for regulating access to, and sensitivity of, discrete regions of the brain for circulating leptin. We suggest that fasting and E₂ alter the balance between leptin-R_L and leptin-R_S and that this could increase tissue sensitivity to leptin.

Seasonal and dose-dependent effects of intracerebroventricular leptin on lh secretion and appetite in sheep

“…The disparity may be resolved when such studies are conducted in controlled artificial photoperiods rather than in natural photoperiods. Nonetheless, unlike in the present study, the sheep used by Clarke et al (2001) did not have gonadal steroid replacement and it is suggested that oestradiol is required to facilitate leptin actions in the brain (Bennett et al 1998, Pelleymounter et al 1999, Ainslie et al 2001, Kimura et al 2002. Photoperiodic modulation of leptin-induced body weight (or fat) loss is seen in the Siberian hamster, with sensitivity to leptin in two separate studies found to be greatest in a short-as opposed to a long-day photoperiod (Atcha et al 2000.…”

Leptin increases in vivo GH responses to GHRH and GH-releasing peptide-6 in food-deprived rats

“…These findings indicate that the blunted GH responses to GHRH induced by food deprivation reflect a functional and reversible state, and suggest that the primary alteration could be mediated by decreased leptin activation of the hypothalamic-GH axis. It is also possible that the effect of leptin in food-deprived rats could be the result of increased gene expression of the long isoform of the leptin receptor in the hypothalamus, in response to fasting (36). However, this stimulatory effect of leptin on GH responses to GHRH resembles that obtained by others who assessed the same response after passive immunization with antisomatostatin antiserum (31).…”

Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism

“…Several studies suggested that the estrogen and leptin systems are related via functional cross talk. For example, estrogens have been shown to regulate the expression of leptin (Casabiell et al, 1998;Tsuruta et al, 2004) and its receptor (Bennett et al, 1998) in adipose tissue and brain, respectively. Reciprocally, leptin stimulates ovarian cancer cell growth involving ERα transcriptional activation via the STAT-3 signaling pathways (Choi et al, 2011).…”