脂肪组织中自噬信号通路及其功能

细胞自噬是一种真核生物中高度保守的代谢过程,包括巨自噬、微自噬以及分子伴侣介导的自噬等。自噬过程可以清除受损的细胞器,降解糖原、脂类和蛋白质等生物大分子物质,供细胞重新利用,维持细胞内代谢平衡。自噬障碍与多种疾病的病理发生过程息息相关,包括肿瘤、2型糖尿病、肥胖、骨骼肌病以及神经退行性疾病等。脂肪组织是人体脂质储存的重要场所,广泛分布于全身各处,如内脏和皮下等。脂肪组织通过储存冗余脂肪并分泌脂肪因子,防止脂肪的异位堆积和脂毒性的发生,维持机体的脂质稳态。近期的许多研究表明,自噬进程深度参与脂肪细胞的细胞分化与能量代谢。因此,深入探究脂肪组织自噬过程与机体脂质稳态的调控关系,有利于揭示机体脂质平衡的内在机制,为新型药物靶点的开发提供扎实的理论依据和数据支持。本文就近年来关于自噬影响脂肪组织脂质代谢的最新研究进展作一综述。     

Mouse models for the central melanocortin system

Obesity is characterized by an excess storage of body fat and promotes the risk for complex disease traits such as diabetes mellitus and cardiovascular diseases. The obesity prevalence in Europe is rising and meanwhile ranges from 10 to 20% in men and 15–25% in women. Body fat accumulation occurs in states of positive energy balance and is favored by interactions among environmental, psychosocial and genetic factors. Energy balance is regulated by a complex neuronal network of anorexigenic and orexigenic neurons which integrates peripheral and central hormonal and neuronal signals relaying information on the metabolic status of organs and tissues in the body. A key component of this network is the central melanocortin pathway in the hypothalamus that elicits metabolic and behavioral adaptations for the maintenance of energy homeostasis. Genetic defects in this system cause obesity in mice and humans. In this review we emphasize mouse models with spontaneous natural mutations as well as targeted mutations that contributed to our understanding of the central melanocortin system function in the control of energy balance.     

High-Fat Diet Triggers Inflammation-Induced Cleavage of SIRT1 in Adipose Tissue To Promote Metabolic Dysfunction

Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from inflammation and obesity under normal feeding conditions, and to forestall the progression to metabolic dysfunction under dietary stress and aging. Genetic ablation of SIRT1 in adipose tissue leads to gene expression changes that highly overlap with changes induced by high-fat diet in wild-type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high-fat diet induces the cleavage of SIRT1 protein in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.     

固有淋巴细胞在脂质代谢中的研究进展

由于世界范围内营养条件和生活方式的变化,肥胖及其相关的代谢性疾病已成为当前威胁人类健康的重要因素之一.在能量摄取和消耗以及体内脂肪储存、分解和脂肪组织重塑的研究中,人们逐渐认识到脂质过量及异位堆积将导致代谢组织处于慢性炎症状态,这开启了肥胖相关组织炎症研究的新方向.固有淋巴细胞(innate lymphoid cell...     

Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis

Epidemiological studies in humans suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in offspring. Animal models have allowed us to investigate the independent consequences of altering the pre- versus post-natal environments on a variety of metabolic, physiological and neuroendocrine functions as they effect the development in the offspring of obesity, diabetes, hypertension and hyperlipidemia (the 'metabolic syndrome'). During gestation, maternal malnutrition, obesity, type 1 and type 2 diabetes and psychological, immunological and pharmacological stressors can all promote offspring obesity. Normal post-natal nutrition can reduce the adverse impact of some of these pre-natal factors but maternal high-fat diets, diabetes and increased neonatal access to food all enhance the development of obesity and the metabolic syndrome in offspring. The outcome of these perturbations of the perinatal environmental is also highly dependent upon the genetic background of the individual. Those with an obesity-prone genotype are more likely to be affected by factors such as maternal obesity and high-fat diets than are obesity-resistant individuals. Many perinatal manipulations appear to promote offspring obesity by permanently altering the development of central neural pathways, which regulate food intake, energy expenditure and storage. Given their strong neurotrophic properties, either excess or an absence of insulin and leptin during the perinatal period are likely to be effectors of these developmental changes. Because obesity is associated with an increased morbidity and mortality and because of its resistance to treatment, prevention is likely to be the best strategy for stemming the tide of the obesity epidemic. Such prevention should begin in the perinatal period with the identification and avoidance of factors which produce permanent, adverse alterations in neural pathways which control energy homeostasis.     

Quantitative comparison of transient growth of Saccharomyces cerevisiae,Saccharomyces kluyveri,and Kluyveromyces lactis

A multitude of metabolic regulations occur in yeast, particularly under dynamic process conditions, such as under sudden glucose excess. However, quantification of regulations and classification of yeast strains under these conditions have yet to be elucidated, which requires high-frequency and consistent quantification of the metabolic response. The present study aimed at quantifying the dynamic regulation of the central metabolism of strains Saccharomyces cerevisiae, S. kluyveri, and Kluyveromyces lactis upon sudden glucose excess, accomplished by a shift-up in dilution rate inside of the oxidative region using a small metabolic flux model. It was found that, under transient growth conditions, S. kluyveri behaved like K. lactis, while classification using steady-state conditions would position S. kluyveri close to S. cerevisiae. For transient conditions and based on the observation whether excess glucose is initially used for catabolism (energy) or anabolism (carbon), we propose to classify strains into energy-driven, such as S. cerevisiae, and carbon-driven, such as S. kluyveri and K. lactis, strains. Furthermore, it was found that the delayed onset of fermentative catabolism in carbon-driven strains is a consequence of low catabolic flux and the initial shunt of glucose in non-nitrogen-containing biomass constituents. The MFA model suggests that energy limitation forced the cell to ultimately increase catabolic flux, while the capacity of oxidative catabolism is not sufficient to process this flux oxidatively. The combination of transient experiments and its exploitation with reconciled intrinsic rates using a small metabolic model could corroborate earlier findings of metabolic regulations, such as tight glucose control in carbon-driven strains and transient changes in biomass composition, as well as explore new regulations, such as assimilation of ethanol before glucose. The benefit from using small metabolic flux models is the richness of information and the enhanced insight into intrinsic metabolic pathways without a priori knowledge of adaptation kinetics. Used in an online context, this approach serves as an efficient tool for strain characterization and physiological studies.     

Advanced omics techniques shed light on CD1d-mediated lipid antigen presentation to iNKT cells

Invariant natural killer T cells (iNKT cells) can be activated through binding antigenic lipid/CD1d complexes to their TCR. Antigenic lipids are processed, loaded, and displayed in complex with CD1d by lipid antigen presenting cells (LAPCs). The mechanism of lipid antigen presentation via CD1d is highly conserved with recent work showing adipocytes are LAPCs that, besides having a role in lipid storage, can activate iNKT cells and play an important role in systemic metabolic disease. Recent studies shed light on parameters potentially dictating cytokine output and how obesity-associated metabolic disease may affect such parameters. By following a lipid antigen's journey, we identify five key areas which may dictate cytokine skew: co-stimulation, structural properties of the lipid antigen, stability of lipid antigen/CD1d complexes, intracellular and extracellular pH, and intracellular and extracellular lipid environment. Recent publications indicate that the combination of advanced omics-type approaches and machine learning may be a fruitful way to interconnect these 5 areas, with the ultimate goal to provide new insights for therapeutic exploration.     

Adipocytokine Orosomucoid Integrates Inflammatory and Metabolic Signals to Preserve Energy Homeostasis by Resolving Immoderate Inflammation

Orosomucoid (ORM), also called α-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-α, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-κB and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-α-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.     

Bariatric surgery to unload the stressed heart: a metabolic hypothesis

Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.     

基于调节肠道菌群的功能性低聚糖改善肥胖的研究进展

肥胖是机体脂肪积聚过多的一种典型的能量过剩疾病,是导致2型糖尿病和心血管疾病等一系列代谢性疾病的主要原因之一,已成为威胁全球健康的重大公共卫生问题。肠道菌群作为机体能量代谢调控的重要参与者,在肥胖及相关代谢性疾病的发生发展中起着关键作用,通过饮食干预调节肠道菌群,进而改善机体健康状况将是未来的研究热点之一。已有研究表明,功能性低聚糖作为一类典型的新型益生元,可调节肠道菌群结构及其代谢产物的水平,影响机体能量代谢过程,改善肥胖及相关代谢性疾病。本文主要对肠道菌群在肥胖中的潜在作用机制,以及常见功能性低聚糖调节肠道菌群改善肥胖的作用效果进行综述,以期为通过靶向肠道菌群精准干预肥胖及相关代谢性疾病提供一些新的潜在防治策略。

     

Fat breakdown: a function for CGI-58 (ABHD5) provides a new piece of the puzzle

The hydrolysis of fat stored in adipose tissues is crucial for providing energy during fasting and exercise, and dysregulation of fat breakdown may contribute to metabolic disease. In this issue of Cell Metabolism, report that CGI-58/ABHD5, a lipid-droplet-associated protein that is mutated in a rare disease characterized by excess lipid storage, activates adipose triglyceride lipase and thus may regulate fat mobilization.     

Fructose-mediated stress signaling in the liver: implications for hepatic insulin resistance

Organisms reprogram metabolic pathways to adapt to changes in nutrient availability. This requires that nutrient-based stimuli are sensed, signals are transmitted, and highly specific responses are engaged. We propose that in the liver, the mitogen-activated protein kinase, c-jun N-terminal kinase (JNK), links excessive nutrient metabolism with impaired insulin regulation of glucose production. The liver, by virtue of its anatomic position and selective regulatory features, buffers and is highly responsive to changes in nutrient delivery. In particular, sugars such as sucrose and fructose uniquely regulate and are selectively metabolized by the liver. We propose that when hepatic fructose uptake exceeds requirements for glycogen and energy (hepatic sugar excess), the JNK-signaling pathway is engaged as part of the adaptive response.     

Super-size flies

The increasing prevalence of obesity and other nutrition-related chronic diseases has prompted considerable efforts to understand their pathogenesis and treatment. One experimental approach is to overexpress, inactivate, or manipulate specific genes that regulate energy metabolism and fat storage. Many such techniques are fully established, routine tools in Drosophila and C. elegans, which provide elegant models for dissecting endocrine problems and metabolic pathways.     

The Fat Controller: Adipocyte Development

Obesity is a condition characterized by excess adipose tissue that results from positive energy balance and is the most common metabolic disorder in the industrialized world. The obesity epidemic shows no sign of slowing, and it is increasingly a global problem. Serious clinical problems associated with obesity include an increased risk for type 2 diabetes, atherosclerosis, and cancer. Hence, understanding the origin and development of adipocytes and adipose tissue will be critical to the analysis and treatment of metabolic diseases. Historically, albeit incorrectly, adipocytes were thought to be inert cells whose singular function was lipid storage. It is now known that adipocytes have other critical functions; the most important include sensitivity to insulin and the ability to produce and secrete adipocyte-specific endocrine hormones that regulate energy homeostasis in other tissues. Today, adipocytes are recognized as critical regulators of whole-body metabolism and known to be involved in the pathogenesis of a variety of metabolic diseases. All cells come from other cells and many cells arise from precursor cells. Adipocytes are not created from other adipocytes, but they arise from precursor cells. In the last two decades, scientists have discovered the function of many proteins that influence the ability of precursor cells to become adipocytes. If the expansion of the adipose tissue is the problem, it seems logical that adipocyte development inhibitors could be a viable anti-obesity therapeutic. However, factors that block adipocyte development and limit adipocyte expansion also impair metabolic health. This notion may be counterintuitive, but several lines of evidence support the idea that blocking adipocyte development is unhealthy. For this reason it is clear that we need a better understanding of adipocyte development.     

Polysaccharide reserve material in the acetotrophic methanogen,Methanosarcina thermophila strain TM-1: accumulation and mobilization

The ability of Methanosarcina thermophila strain TM-1 to store a reserve polysaccharide was studied using both biochemical methods and thin-section electron microscopy. When grown under conditions of excess carbon and energy (either methanol or acetate) and limiting nitrogen, M. thermophila accumulated a polysaccharide which could be hydrolyzed to glucose by the enzyme amyloglucosidase. This polysaccharide reached levels of 20 mg polysaccharide per g protein in nitrogen-limited cells, while cells limited for carbon, as well as cells in the exponential phase of growth, did not accumulate significant amounts of this polysaccharide. Thin-section electron micrographs of M. thermophila showed glycogen-like inclusion granules in nitrogen-limited cells but not in carbon-limited or exponential-phase cells. These granules were stained by a polysaccharide-specific staining procedure, the PATO stain. The polysaccharide was purified from cell extracts, the iodine-polysaccharide complex gave a maximum absorption at between 500 and 510 nm. The polysaccharide was mobilized within 21 h by cells starved for a carbon/energy source. N-Limited (polysaccharide-containing) acetategrown cells could shift to methanogenesis from methanol more quickly than did C-limited acetate-grown cells lacking polysaccharide, and ATP levels remained higher in N-limited cells. The results are consistant with the hypothesis that this polysaccharide can provide carbon and energy for metabolic shifts but other storage compounds, such as polyphosphate, may also play a similar role.     

PPARgamma in human and mouse physiology

The peroxisome proliferator activated receptor gamma (PPARgamma) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARgamma also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARgamma has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARgamma activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARgamma. It is now evident that the full activation of PPARgamma is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARgamma signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARgamma biology.