Ahima Rexford S
University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, PA 19104, USA.
Obesity (Silver Spring). 2006 Aug;14 Suppl 5:242S-249S. doi: 10.1038/oby.2006.317.
Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.
脂肪组织在能量平衡中起着关键作用，不仅能储存甘油三酯，还能对营养、神经和激素信号作出反应，并分泌控制进食、产热、免疫和神经内分泌功能的脂肪因子。瘦素通过下丘脑和脑干神经元中的受体向大脑发出饱腹感信号。瘦素激活酪氨酸激酶、Janus激酶2以及信号转导和转录激活因子3，导致厌食肽水平升高，如α-黑素细胞刺激素和可卡因及苯丙胺调节转录物，并抑制食欲肽，如神经肽Y和刺鼠相关肽。肥胖的特征是高瘦素血症和下丘脑瘦素抵抗，部分原因是细胞因子信号抑制因子-3的诱导。禁食期间瘦素迅速下降，并强烈刺激食欲、减少产热，介导甲状腺和生殖激素的抑制以及下丘脑-垂体-肾上腺轴的激活。这些作用由下丘脑室旁核整合。瘦素还通过涉及AMP激活蛋白激酶（AMPK）的中枢和外周途径降低血糖并刺激脂肪分解。脂联素仅由脂肪细胞分泌，与葡萄糖、脂质和心血管调节有关。肥胖、糖尿病和动脉粥样硬化与脂联素水平降低有关，而脂联素治疗可部分通过激活肝脏和肌肉中的AMPK来逆转这些异常。在大脑中给予脂联素可重现外周作用，以增加脂肪酸氧化和胰岛素敏感性并降低血糖。尽管假定的脂联素受体广泛存在于外周器官和大脑中，但脂联素是否仅通过这些靶点起作用尚不确定。与瘦素一样，脂联素需要中枢黑皮质素途径。此外，脂联素至少部分地通过激活肌肉和肝脏中的AMPK来刺激脂肪酸氧化并降低葡萄糖和脂质水平。
