Dore Riccardo, Levata Luka, Gachkar Sogol, Jöhren Olaf, Mittag Jens, Lehnert Hendrik, Schulz Carla
Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
Center of BrainBehavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
J Endocrinol. 2017 Nov;235(2):111-122. doi: 10.1530/JOE-17-0151. Epub 2017 Aug 29.
Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.
内脂素-1是一种在大脑和外周组织中均有表达的生物活性多肽，通过减少食物摄入量参与能量平衡的调控。中枢给予内脂素-1可显著增加能量消耗，这表现为更高的干热散失；然而，中枢内脂素-1产热效应的潜在机制仍不清楚。因此，在本研究中，我们试图探究内脂素-1诱导的能量消耗增加是否由中枢黑皮质素途径介导，此前有报道称该途径介导中枢内脂素-1对进食及许多其他生理功能的影响。通过直接量热法，我们发现脑室内注射内脂素-1（25 pmol）可增加干热散失，并且同时给予等摩尔剂量的黑皮质素3/4受体拮抗剂SHU9119可完全阻断这一效应。有趣的是，内脂素-1诱导的干热散失增加与体重减轻呈正相关。此外，通过热成像评估发现，脑室内注射内脂素-1（100 pmol）可增加肩胛间棕色脂肪组织（iBAT）以及尾部温度，提示iBAT产热增加以及尾部表面散热增加。最后，内脂素-1上调了下丘脑前阿黑皮素原和黑皮质素3受体mRNA表达，同时iBAT中碘甲腺原氨酸脱碘酶2显著增加，解偶联蛋白1和过氧化物酶体增殖物激活受体γ共激活因子-1α mRNA有非显著性增加。总体而言，我们明确证明内脂素-1需要激活中枢黑皮质素系统来增加iBAT产热，进而增加总体能量消耗。
