Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve

Abstract

Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.

The vagus nerve, food intake and obesity

“…Leptin is produced in the mucosa of the stomach and rapidly mobilized by feeding and high doses of exogenous cholecystokinin (Bado et al, 1998), and it appears to activate vagal afferents (Wang et al, 1997), shown to express the long form of leptin receptor (Buyse et al, 2001;Burdyga et al, 2002). Small doses of leptin infused into the celiac artery significantly decreased sucrose intake and this effect was not observed in rats with subdiaphragmatic vagotomy or perivagal capsaicin-treatment aimed to selectively ablate vagal afferent fibers.…”

Physiological mechanisms for food-hoarding motivation in animals

“…In these studies, peripherally administered leptin prevented food-deprivation-induced decreases in circulating leptin (figure 2a,b; Keen-Rhinehart & Bartness 2008) and attenuated food-deprivationinduced increases in food hoarding, being most effective in hamsters with the lowest foraging effort requirement (figure 1c-e; Keen-Rhinehart & Bartness 2008). It is generally accepted that leptin penetrates into the brain to act centrally to affect ingestive behaviour (Elmquist 2001), although evidence of leptin receptors on vagal sensory nerves (Buyse et al 2001) suggests an additional means by which peripheral leptin could affect food intake (but ultimately acting centrally as well). Indeed, in our studies, leptin more effectively blocked food-deprivation-induced increases in food hoarding when given centrally, inhibiting fooddeprivation-induced increases in food hoarding up to 48 h post-injection regardless of foraging requirement (figure 3a -c; Keen-Rhinehart & Bartness 2008).…”

Leptin and cancer

“…ObRl is highly expressed in the hypothalamus (Bjorbaek et al, 1997). However, lower levels of ObRl have been identified in many peripheral organs (Morton et al, 1999;Frank et al, 2000;Buyse et al, 2001;Goiot et al, 2001;Akerman et al, 2002;Ebenbichler et al, 2002;Lee et al, 2002;Kim et al, 2003).…”