Regulatory role of hypothalamic AMP-kinase in body energy metabolism

AMPK是一种代谢感受器，调节能量代谢。我们之前已经证明，瘦素通过AMPK刺激骨骼肌中的脂肪酸氧化。AMPK广泛表达，表达部位包括神经元和神经胶质细胞。我们推测下丘脑AMPK可能介导了激素和营养对食物摄取和能量平衡的影响。包括瘦素在内的许多厌氧剂抑制了小鼠弓状核和室旁核的α-2AMPK活性，而包括AGRP在内的许多厌氧剂增加了下丘脑核的α-2AMPK活性。下丘脑内侧的结构性活性(CA)-AMPK和显性负性(DN)-AMPK的表达相互调节摄食量和体重，CA-AMPK在下丘脑内侧的表达可抑制瘦素引起的厌食。此外，CA-AMPK在PVH中的慢性表达也增加了摄食量，从而导致大量肥胖。我们利用C2C12细胞进一步研究了瘦素诱导骨骼肌细胞脂肪酸氧化的分子机制。Leptin可促进C2C12细胞的脂肪酸氧化和A2 AMPK活性。α-2AMPK的小干扰RNA可阻断瘦素诱导的脂肪酸氧化。此外，我们还发现，α2β2γ1 AMPK转位到细胞核并刺激瘦素反应的PPARA基因表达，而α2β1γ1AMPK保留在细胞质中，并磷酸化乙酰辅酶A羧基酶，在线粒体中诱导脂肪酸氧化。我们的研究证实，α-2-β-2-γ-1AMPK的核转位是由a2亚基的核定位信号介导的，而β-1的肉豆蔻化作用将a2AMPK保留在线粒体膜上，并刺激脂肪酸氧化。因此，瘦素-AMPK系统在控制食物摄入和脂肪酸代谢中起着至关重要的作用。

AMP kinase (AMPK) is a metabolic sensor that regulates energy metabolism. We have previously shown that leptin stimulates fatty acid oxidation in skeletal muscle via AMPK. AMPK is widely expressed-locations include neurons and glial cells. We hypothesized that hypothalamic AMPK might mediate hormonal and nutrient effects on food intake and energy balance.Many anorexigens including leptin suppressed α2 AMPK activity in the arcuate (ARH) and paraventricular (PVH) hypothalamus in mice, while many orexigens including AGRP increased α2 AMPK activity in the hypothalamic nucleus. Expression of constitutively active (CA)-AMPK and dominant negative (DN)-AMPK in the medial hypothalamus reciprocally regulated food intake and body weight, and CA-AMPK in the medial hypothalamus inhibited leptin-induced anorexia. Moreover, chronic expression of CA-AMPK in the PVH also increased food intake, then causing massive obesity.We further examined the molecular mechanism of leptin-induced fatty acid oxidation in skeletal muscle cells, using C2C12 cells. Leptin stimulated fatty acid oxidation and a2 AMPK activity in C2C12 cells. Leptin-induced fatty acid oxidation is abolished by siRNA of α2 AMPK. Furthermore, we found that α2β2γ1 AMPK translocated to the nucleus and stimulated PPARa gene expression in response to leptin, while α2β1γ1AMPK retained in the cytoplasm and phosphorylated acetyl-CoA carboxylase, where it induced fatty acid oxidation in mitochondria. Our studies identified that nuclear translocation of α2β2γ1AMPK is mediated by the nuclear localization signal in the a2 subunit, and myristoylation of β1 retains the a2AMPK to the mitochondrial membrane and stimulates fatty acid oxidation. Thus, leptin-AMPK system plays a crucial role in the control of food intake and fatty acid metabolism.