Systemic administration of leptin decreases plasma corticosterone levels: Role of hypothalamic norepinephrine

Abstract

Leptin, an adipocyte-derived hormone, is known to regulate a variety of neuroendocrine functions. It inhibits the hypothalamo-pituitary-adrenal axis (HPA) in several animal models, however, the exact mechanism by which it does so is not known. Since norepinephrine (NE) is a key regulator of the HPA axis, we hypothesized that leptin could suppress HPA activity by decreasing NE levels. To study this, we implanted adult male Sprague Dawley rats with both a push-pull cannula in the paraventricular nucleus (PVN) and a catheter in the jugular vein. Animals were treated with either 0 or 100 μg or 500 μg of recombinant rat leptin (Lep). Push-pull perfusion was performed from 1000-1600 h. Perfusate samples were collected every 30 min and analyzed for NE levels using HPLC-EC. Blood samples were collected every 60 min and analyzed for coticosterone (CS) levels. To further understand the role of NE in this phenomenon animals were treated with either an α-1 adrenergic agonist, phenylephrine (PHE; 0.5 mg/KgBW), an α-2 adrenergic agonist, clonidine (CLON; 0.6 mg/ Kg BW), or a β adrenergic agonist, isoproterenol (ISO; 0.2 mg/Kg BW) alone or in combination with 500 μg of Lep. Pretreatment and hourly posttreatment blood samples were collected, plasma was separated and analyzed for CS levels. Leptin administration decreased NE release in the PVN significantly by 30 min (p<0.05). It also significantly reduced plasma CS levels at 240 and 300 min (p<0.05). Administration of either PHE or CLON in combination with leptin prevented the leptininduced decrease in CS. In contrast, administration of ISO along with leptin did not prevent the leptininduced decrease in CS. These results indicate that leptin decreases hypothalamic NE and plasma corticosterone and that this effect is most probably mediated through alpha-adrenergic receptors.

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

“…As leptin certainly increased upon CD feeding ( Fig. 1) and leptin reveals inhibitory effects on the HPA axis (Ahima et al 1996, Bornstein et al 1997, Heiman et al 1997) via alphaadrenergic-and/or orexin-mediated pathways (Clark et al 2008, Bonnavion et al 2015, leptin itself might cause the reduced stress responses Our findings on the negative correlation between leptin and corticosterone support this notion (Fig. 8).…”

Chronic exposure to a high-fat diet affects stress axis function differentially in diet-induced obese and diet-resistant rats

“…While earlier studies attributed a stimulatory role for leptin on the HPA axis, since 1997, a substantial body of evidence indicates that leptin suppresses the HPA axis activity (24, 35–39). Recent studies suggest that this effect could be mediated by decreasing NE levels in the PVN (23, 26, 29). Results from the present study indicate that chronic exposure to a HF diet increases body weight in both DIO and DR rats, however, the increase in leptin levels is only seen in DIO rats.…”

“…Leptin receptors are found in various brainstem nuclei including A1, A2 and A6 (20–22). Since leptin has been observed to modulate HPA activity (23–26), it is possible that leptin’s direct effects in the brainstem may be involved in diet-induced obesity. Therefore, we placed DIO and DR rats on a HF diet containing higher levels of fat (45%) or chow diet for 6 weeks, measured serum leptin levels and investigated changes in key components of HPA axis.…”

Roles of Oxytocin Neurones in the Control of Stress, Energy Metabolism, and Social Behaviour

“…Activation of parvocellular oxytocin neurones by leptin contributes to leptin‐induced reduction in meal size. On the other hand, leptin has been shown to reduce noradrenaline release within the hypothalamic PVN (6,119), impair CCK‐induced Fos expression in the supraoptic nucleus (120) and reduce CCK‐induced plasma oxytocin increase (121), suggesting that leptin has inhibitory effects on magnocellular oxytocin neurones. However, leptin moderately increases, in a transient manner, the electrical activity of rat magnocellular oxytocin neurones under anaesthesia (122).…”