Medical Research

Cell Metabolism 在自2005年创刊以来，在CELL BIOLOGY (细胞生物学)同类期刊中的影响因子排名第10位。期刊为了庆祝十周年，推出了2005至2014年最受读者关注的十大综述文章。

 

1. AMP-Activated Protein Kinase: Ancient Energy Gauge Provides Clues to Modern Understanding of Metabolism

AMPK是一个进化保守的细胞能量状态感应器，近来的研究表明AMPK也在系统性能量平衡中起到了关键的作用。AMPK在周边组织和下丘脑中整合能量和激素信号，介导脂肪因子（瘦素、脂联素和resistin）对进食、体重、葡萄糖和脂质稳态的调控效果。人们还首次发现，AMPK受到上游激酶LKB1（肿瘤抑制子）的调控。AMPK能通过信号传导、代谢和基因表达，增强胰岛素敏感性，形成能降低肥胖和二型糖尿病风险的代谢环境。

文章摘要：

The AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status, and recent data demonstrate that it also plays a critical role in systemic energy balance. AMPK integrates nutritional and hormonal signals in peripheral tissues and the hypothalamus. It mediates effects of adipokines (leptin, adiponectin, and possibly resistin) in regulating food intake, body weight, and glucose and lipid homeostasis. AMPK is regulated by upstream kinases of which the tumor suppressor, LKB1, is the first to be identified. Complex signaling networks suggest that AMPK may prevent insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. Through signaling, metabolic, and gene expression effects, AMPK enhances insulin sensitivity and fosters a metabolic milieu that may reduce the risk for obesity and type 2 diabetes.

 

2. The Biology of Incretin Hormones

GLP-1（glucagon-like peptide-1）和GIP（glucose-dependent insulinotropic polypeptide）等肠道多肽以营养依赖的方式分泌，能刺激葡萄糖依赖的胰岛素分泌。GIP和GLP-1都能促进β细胞增殖和抑制凋亡，增加β细胞的量。这篇文章总结了这些肠促胰岛素的作用，探讨了GLP-1受体激动剂和DPP-4抑制剂的治疗潜力。

文章摘要：

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote β cell proliferation and inhibit apoptosis, leading to expansion of β cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.

 

3. The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation

细胞增殖需要营养、能量和生物合成活性来复制所有的大分子成分。而非增殖细胞和增殖细胞的代谢活性存在着根本差异。这篇文章提出，一些核心过程（比如有氧糖酵解、从头脂类合成、谷氨酰胺依赖的回补反应）形成了模式化的平台，为不同细胞的增殖提供支持。此外，文章还探讨了生理性细胞增殖和肿瘤发生过程中的信号传导和基因表达调控，包括HIF-1、Myc和(PI3K)/Akt/mTOR系统。

文章摘要：

Cell proliferation requires nutrients, energy, and biosynthetic activity to duplicate all macromolecular components during each passage through the cell cycle. It is therefore not surprising that metabolic activities in proliferating cells are fundamentally different from those in nonproliferating cells. This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types. We also consider regulation of these fluxes by cellular mediators of signal transduction and gene expression, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR system, hypoxia-inducible factor 1 (HIF-1), and Myc, during physiologic cell proliferation and tumorigenesis.

4. Autophagy in the Cellular Energetic Balance

自噬促使溶酶体降解细胞成分，从而去除异常蛋白和细胞器。实际上自噬不止在细胞受损时激活，饥饿也是一个很强的刺激因素。在营养匮乏的时候激活自噬，细胞就能重新利用自身组分的能量。自噬除了促进蛋白分解，还会调动细胞的各种能量储备。自噬与脂质、碳水化合物代谢之间的互作，揭示了自噬与细胞能量平衡之间的动态反馈。

文章摘要：

Autophagy mediates the degradation of cellular components in lysosomes, assuring removal of altered or dysfunctional proteins and organelles. Autophagy is not only activated in response to cellular damage; in fact, one of its strongest and better-characterized stimuli is starvation. Activation of autophagy when nutrients are scarce allows cells to reutilize their own constituents for energy. Besides protein breakdown, autophagy also contributes to the mobilization of diverse cellular energy stores. This recently discovered interplay between autophagy and lipid and carbohydrate metabolism reveals the existence of a dynamic feedback between autophagy and cellular energy balance.

5. Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways

癌性恶病质（Cancer cachexia）表现为脂肪组织和骨骼肌缺失引起的体重显著下降，这会降低患者对癌症治疗的耐受，影响他们的生活质量和生存期。由于调节子、信号传导和代谢通路发生了显著改变，癌性恶病质的治疗并不顺利。理解骨骼肌萎缩/肥大的保守分子机制，为人们提供了一个绕过上游复杂通路的下游平台，有望转化成为新的靶向疗法。

文章摘要：

Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.

6. Unraveling the Biological Roles of Reactive Oxygen Species

活性氧并不只是造成氧化损伤的有害物质，它们实际上在多种生物学现象中起到了重要的调节作用。如何更好的理解活性氧的重要性及其氧化损伤，是生物医学领域面临的一大挑战。这篇文章总结和回顾了这一热点课题近来的一些显著进展。

文章摘要：

Reactive oxygen species are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. The relatively recent development of this more nuanced view presents a challenge to the biomedical research community on how best to assess the significance of reactive oxygen species and oxidative damage in biological systems. Considerable progress is being made in addressing these issues, and here we survey some recent developments for those contemplating research in this area.

7. Transcriptional Control of Brown Fat Determination by PRDM16

负责消耗能量的棕色脂肪能够防止肥胖，不过人们并不清楚形成棕色脂肪的转录基础。这篇文章指出，与白色脂肪相比，锌指蛋白PRDM16在棕色脂肪细胞高度富集。在白色脂肪前体细胞中表达PRDM16，激起了很强的棕色脂肪表型。在白色脂肪中转基因表达PRDM16，促进了棕色脂肪细胞的形成。去除棕色脂肪细胞的PRDM16，会使其几乎完全丧失棕色脂肪的特性。这些数据说明，PRDM16能够决定棕色脂肪的命运。

文章摘要：

Brown fat cells are specialized to dissipate energy and can counteract obesity; however, the transcriptional basis of their determination is largely unknown. We show here that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. When expressed in white fat cell progenitors, PRDM16 activates a robust brown fat phenotype including induction of PGC-1α, UCP1, and type 2 deiodinase (Dio2) expression and a remarkable increase in uncoupled respiration. Transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells. Depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics. PRDM16 activates brown fat cell identity at least in part by simultaneously activating PGC-1α and PGC-1β through direct protein binding. These data indicate that PRDM16 can control the determination of brown fat fate.

8. Crosstalk between Components of Circadian and Metabolic Cycles in Mammals

哺乳动物绝大多数代谢过程受到生物钟和进食节律的影响。然而，将细胞代谢和昼夜节律偶联起来的机制才刚刚浮出水面，比如NAD依赖的酶、氧化还原或温度依赖的转录因子、营养感知的转录调节蛋白和蛋白激酶。

文章摘要：

In mammals, most metabolic processes are influenced by biological clocks and feeding rhythms. The mechanisms that couple metabolism to circadian oscillators are just emerging. NAD-dependent enzymes (e.g., Sirtuins and poly[ADP-ribose] polymerases), redox- and/or temperature-dependent transcription factors (e.g., CLOCK, NPAS2, and HSF1), nutrient-sensing transcriptional regulatory proteins (e.g., CREB-CBP-CRCT2, FOXO-p300, nuclear receptors, PGC-1, and SP1 family members) and protein kinases (e.g., AMPK), are plausible candidates for conveying a cell's metabolic state to the core clock circuitry. The intertwining between these acute regulators and circadian clock components is so tight that the discrimination between metabolic and circadian oscillations may be somewhat arbitrary.

9. Replicative and Chronological Aging inSaccharomyces cerevisiae

酿酒酵母是一种重要的模式生物，可以帮助人们鉴定更多影响衰老的哺乳动物基因。酵母衰老研究主要是检测其复制或时序寿命。这篇文章回顾了与这种衰老有关的基因和机制，探讨了有待解决的关键问题。由于酿酒酵母很容易进行遗传学操作和高通量筛选，它将继续作为研究人类衰老和相关疾病的理想模型。

文章摘要：

Saccharomyces cerevisiaehas directly or indirectly contributed to the identification of arguably more mammalian genes that affect aging than any other model organism. Aging in yeast is assayed primarily by measurement of replicative or chronological life span. Here, we review the genes and mechanisms implicated in these two aging model systems and key remaining issues that need to be addressed for their optimization. Because of its well-characterized genome that is remarkably amenable to genetic manipulation and high-throughput screening procedures,S. cerevisiaewill continue to serve as a leading model organism for studying pathways relevant to human aging and disease.

10.Immunological Goings-on in Visceral Adipose Tissue

肥胖症和二型糖尿病的发病率正在持续上升，而这两种疾病与内脏脂肪组织和全身性的低等级慢性炎症有关。在肥胖诱导的脂肪组织炎症中，巨嗜细胞一直被认为是关键的因素。近年来人们发现，先天免疫和适应性免疫中的其他细胞类型也在脂肪组织炎症中起到了正面或负面的作用。这篇文章回顾了与这些新成员有关的研究数据，探讨了相关实验中存在的不确定性、矛盾性和复杂性，并提出了一个简明的综合性体系。

文章摘要：

Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme.

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