Havel P J, Hahn T M, Sindelar D K, Baskin D G, Dallman M F, Weigle D S, Schwartz M W
Department of Nutrition, University of California, Davis 95616, USA.
Diabetes. 2000 Feb;49(2):244-52. doi: 10.2337/diabetes.49.2.244.
Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.
下丘脑黑皮质素是几种与食物摄入控制密切相关的神经肽之一。促黑素细胞激素4（MC - 4）受体激动剂，如促肾上腺皮质激素原（POMC）的产物α - 黑素细胞刺激素（α - MSH），可减少食物摄入，而下丘脑刺鼠色蛋白相关蛋白（AgRP）是一种MC - 4受体拮抗剂，可增加食物摄入。为了研究黑皮质素信号减弱是否导致糖尿病失控引起的食欲亢进，对雄性Sprague - Dawley大鼠在注射链脲佐菌素（STZ）或赋形剂7天后进行了研究。此外，我们希望确定糖尿病对肌肉解偶联蛋白3（UCP - 3）的影响，UCP - 3是肌肉能量代谢的潜在调节因子。与非糖尿病对照组（9.3±0.2 mmol/l）相比，STZ糖尿病大鼠明显高血糖（31.3±1.0 mmol/l；P < 0.005）。胰岛素治疗部分纠正了高血糖（18.8±2.5 mmol/l；P < 0.005）。与对照组（3.0±0.4 ng/ml）相比，STZ糖尿病大鼠血浆瘦素明显降低（0.4±0.1 ng/ml；P < 0.005），胰岛素治疗也部分逆转了这一效应（1.8±0.3 ng/ml）。未经治疗的糖尿病大鼠食欲亢进，比对照组（34±1 g/天）多消耗40%的食物（48±1 g/天；P < 0.005）。胰岛素治疗可预防食欲亢进（32±2 g/天）。在未经治疗的糖尿病大鼠中，下丘脑POMC mRNA表达（通过原位杂交测量）降低了80%（P < 0.005），而AgRP mRNA水平增加了60%（P < 0.01），表明下丘脑黑皮质素信号明显减弱。胰岛素治疗部分逆转了POMC mRNA水平的变化，但未逆转AgRP mRNA水平的变化。相比之下，糖尿病增加下丘脑神经肽Y（NPY）表达和降低促肾上腺皮质激素释放激素（CRH）表达的效应通过胰岛素治疗恢复正常，而弓状核中瘦素受体长形式编码mRNA的表达不受糖尿病或胰岛素治疗的影响。糖尿病大鼠腓肠肌中UCP - 3 mRNA表达增加了四倍（P < 0.005），胰岛素治疗可预防这种增加。糖尿病失控导致POMC减少而AgRP基因表达增加，这表明下丘脑黑皮质素信号减弱，以及NPY增加和CRH信号减弱，可能导致糖尿病性食欲亢进。这些反应与肌肉UCP - 3表达增加共同作用，也可能导致糖尿病失控对外周组织燃料代谢的分解代谢作用。
