Edwards C M, Abbott C R, Sunter D, Kim M, Dakin C L, Murphy K G, Abusnana S, Taheri S, Rossi M, Bloom S R
ICSM Endocrine Unit, Hammersmith Hospital, W12 0NN, London, UK.
Brain Res. 2000 Jun 2;866(1-2):128-34. doi: 10.1016/s0006-8993(00)02257-5.
The melanocortin-4 receptor (MC4-R) appears to be an important downstream mediator of the action of leptin. We examined to what extent the anorectic effects of cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1) and corticotrophin releasing factor (CRF) might be mediated via MC4-R. alpha-Melanocyte stimulating hormone (alpha-MSH), the MC4-R agonist, administered intracerebroventricularly (ICV) at a dose of 1 nmol reduced food intake by approximately half. Agouti-related protein (Agrp) (83-132), a biologically active fragment of the endogenous MC4-R antagonist, administered ICV at a dose of 1 nmol completely blocked the anorectic effect of 1 nmol alpha-MSH. CART (55-102) (0.2 nmol), GLP-1 (3 nmol) and CRF (0.3 nmol) produced a reduction in feeding of approximately the same magnitude as 1 nmol alpha-MSH. Agrp (83-132) (1 nmol) administered ICV did not block the anorectic effects of CART (55-102) (1 h food intake, 0.2 nmol CART (55-102), 2.7+/-0.8 g vs. CART (55-102)+Agrp (83-132), 2.6+/-0.6 g, P=0.87; saline control 5.4+/-0.3 g, P<0.001 vs. both groups). Agrp (83-132) also did not block the anorectic effects of GLP-1 or CRF (1 h food intake, 0.3 nmol CRF, 0.7+/-0.3 g vs. CRF+Agrp (83-132), 0.7+/-0.3 g, P=0.91; 3 nmol GLP-1, 1.9+/-0.4 g vs. GLP-1+Agrp (83-132), 1.1+/-0. 5 g, P=0.23; saline control 5.0+/-0.6 g, P<0.001 vs. all four groups). Thus, as previous data suggests, GLP-1 and CRF do not appear to reduce food intake predominantly via MC4-R, we here demonstrate for the first time that CART, in addition to GLP-1 and CRF primarily acts via Agrp independent pathways.
黑皮质素-4受体（MC4-R）似乎是瘦素作用的重要下游介质。我们研究了可卡因和苯丙胺调节转录物（CART）、胰高血糖素样肽-1（GLP-1）和促肾上腺皮质激素释放因子（CRF）的厌食作用可能通过MC4-R介导的程度。α-黑素细胞刺激素（α-MSH），即MC4-R激动剂，以1 nmol的剂量脑室内（ICV）给药可使食物摄入量减少约一半。刺鼠相关蛋白（Agrp）（83-132），即内源性MC4-R拮抗剂的生物活性片段，以1 nmol的剂量ICV给药可完全阻断1 nmol α-MSH的厌食作用。CART（55-102）（0.2 nmol）、GLP-1（3 nmol）和CRF（0.3 nmol）产生的进食减少幅度与1 nmol α-MSH大致相同。ICV给药的Agrp（83-132）（1 nmol）并未阻断CART（55-102）的厌食作用（1小时食物摄入量，0.2 nmol CART（55-102），2.7±0.8 g；CART（55-102）+Agrp（83-132），2.6±0.6 g，P = 0.87；生理盐水对照5.4±0.3 g，与两组相比P<0.001）。Agrp（83-132）也未阻断GLP-1或CRF的厌食作用（1小时食物摄入量，0.3 nmol CRF，0.7±0.3 g；CRF+Agrp（83-132），0.7±0.3 g，P = 0.91；3 nmol GLP-1，1.9±0.4 g；GLP-1+Agrp（83-132），1.1±0.5 g，P = 0.23；生理盐水对照5.0±0.6 g，与所有四组相比P<0.001）。因此，如先前数据所示，GLP-1和CRF似乎并非主要通过MC4-R减少食物摄入量，我们在此首次证明，除了GLP-1和CRF外，CART主要通过不依赖Agrp的途径发挥作用。
