Nesfatin-1 in the Lateral Parabrachial Nucleus Inhibits Food Intake, Modulates Excitability of Glucosensing Neurons, and Enhances UCP1 Expression in Brown Adipose Tissue

Abstract

Nesfatin-1, an 82-amino acid neuropeptide, has been shown to induce anorexia and energy expenditure. Food intake is decreased in ad libitum-fed rats following injections of nesfatin-1 into the lateral, third, or fourth ventricles of the brain. Although the lateral parabrachial nucleus (LPBN) is a key regulator of feeding behavior and thermogenesis, the role of nesfatin-1 in this structure has not yet been delineated. We found that intra-LPBN microinjections of nesfatin-1 significantly reduced nocturnal cumulative food intake and average meal sizes without affecting meal numbers in rats. Because glucose sensitive neurons are involved in glucoprivic feeding and glucose homeostasis, we examined the effect of nesfatin-1 on the excitability of LPBN glucosensing neurons. In vivo electrophysiological recordings from LPBN glucose sensitive neurons showed that nesfatin-1 (1.5 × 10−8 M) excited most of the glucose-inhibited neurons. Chronic administration of nesfatin-1 into the LPBN of rats reduced body weight gain and enhanced the expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) over a 10-day period. Furthermore, the effects of nesfatin-1 on food intake, body weight, and BAT were attenuated by treatment with the melanocortin antagonist SHU9119. These results demonstrate that nesfatin-1 in LPBN inhibited food intake, modulated excitability of glucosensing neurons and enhanced UCP1 expression in BAT via the melanocortin system.

Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis

“…These observations, together with the present data, suggest that nesfatin-1, when given acutely, may affect responsiveness to UCP1 rather than its production. This view is supported by another recent study showing that UCP1 protein levels are significantly increased upon a 5-day site-specific central application of nesfatin-1 [27]. Alternatively, the time-window at which the UCP1 mRNA was increased may have simply been overlooked.…”

Current Understanding of the Role of Nesfatin-1

“…Interestingly, ICV injected nesfatin-1 30–59 , described as the active core of nesfatin-1 [ 2 ], increased satiety as well whereas satiation was not altered in mice [ 32 ], giving rise to differential receptor binding or activation. Lastly, in rats nesfatin-1 30–59 induced satiation but not satiety [ 33 ], pointing toward species differences, a finding confirmed after microinjection of nesfatin-1 into the lateral parabrachial nucleus in rats [ 34 ]. Although the effect of nesfatin-1 30–59 was retained during diet-induced obesity (DIO) in rats [ 33 ], giving rise to a leptin-independent signaling as suggested before [ 1 , 2 ], the underlying microstructure differed, with increased satiety [ 33 ] suggesting different downstream signaling under conditions of obesity.…”

“…This finding was also confirmed in chicks with astressin-B, a CRF 1/2 antagonist [ 35 ]. Because the melanocortin receptor 3/4 antagonist SHU9119, with anorexigenic melanocortin 4 signaling being well established upstream of CRF [ 36 , 37 ], attenuated [ 34 ] or blocked [ 1 ] nesfatin-1’s anorexigenic effect, nesfatin-1 might act via melanocortin → CRF signaling to inhibit food intake.…”

The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system

“…Nevertheless, UCP1 protein levels could be affected at a different time-point. Of note, a recent study showed that subchronic central nesfatin-1 treatment resulted in increased UCP1 protein levels (Yuan et al 2017).…”