脂肪组织炎症与肥胖关系的研究进展

脂肪组织是一个重要的内分泌器官,可分泌瘦素、单核细胞趋化蛋白-1（MCP-1）和脂联素等大量脂肪因子,这些因子与许多生理和病理过程有关.有研究显示,脂肪组织中的脂质代谢与激素和交感神经系统密切相关.如在禁食状态下儿茶酚胺诱导脂肪分解以提供脂肪酸,而在进食状态下胰岛素抑制脂肪分解并促进脂肪合成.当脂肪组织不能满足储存过多能量的时候,甘油三酯会在非脂肪组织储存导致异位脂肪形成,进而导致肝脏和骨骼肌胰岛素抵抗及胰腺的胰岛素分泌减少.研究表明,肥胖是一种与慢性、低度炎症相关的状态,并可导致胰岛素抵抗.腹型肥胖中具有抗炎和促炎作用的脂肪因子生成不平衡是导致多种代谢综合征的重要原因,脂肪组织在巨噬细胞浸润之前或同时均伴有胰岛素抵抗和异位脂肪沉积,说明巨噬细胞浸润对肥胖的发生有重要意义.为此,本文结合文献,就脂肪组织炎症与肥胖的关系作一综述.     

脂肪细胞的内质网应激

肥胖常伴有炎性反应、胰岛素抵抗和全身代谢紊乱,脂肪细胞内质网应激在其中发挥莺要作用,内质网有合成、折叠和运输蛋白质的作用.脂肪细胞内质网还可以合成脂肪和感受营养物质的变化.在肥胖状态下,脂肪细胞受到营养过剩、细胞内胰岛素抵抗及氧化应激等因素的刺激后,内质网的生理功能发生紊乱.导致内质网应激,内质网应激的表现主要是未折叠蛋白质反应被激活以后,可以通过炎性反应和氧化应激等通路加重胰岛素抵抗.导致全身代谢紊乱.维持和增强内质网功能可能是改善胰岛素抵抗有效的方法之一,一些可以缓解内质网应激的化学分子伴侣是有前景的治疗药物.     

阻塞性睡眠呼吸暂停低通气综合征与脂联素

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）患者多伴有肥胖和胰岛素抵抗,有学者认为,OSAHS不单单是呼吸系统的疾病,更可能是系统性代谢紊乱的一种表现。脂联素是由脂肪细胞特异性合成和分泌的细胞因子,具有降低血糖、防止骨骼肌脂质堆积和拮抗TNF—α的作用。脂联素在OSAHS、肥胖和胰岛素抵抗三者交织而成的网络中所起的作用需要更深入的探讨。     

脂肪代谢障碍与胰岛素抵抗之间的相互影响

问：脂肪代谢障碍与胰岛素抵抗（IR）之间的恶性循环是什么意思？ 答：是指体内脂肪过多特别是腹部脂肪过多会引起胰岛素抵抗。反过来，胰岛素抵抗又会引起更多的脂肪堆积，肥胖。     

瘦素与胰岛素抵抗

近年发现瘦素参与了肥胖相关的胰岛素抵抗（IR），肥胖者机体过度表达瘦素，并与IR程度呈正相关，瘦素本身可造成脂肪组织的IR，减少脂肪合成，增加脂肪分解，产生大量游离脂肪酸，而引起肝脏和肌肉的IR，使胰岛素依赖的糖处理效率受到削弱，与IR的形成与发展密切相关。     

脂肪，并不是越少越好

谈脂色变，是当代人普遍的心态，许多慢性非传染性疾病与脂肪有直接关系。糖尿病患者也应少吃脂肪，因为肥胖是引起2型糖尿病原因之一。脂肪过多，会造成胰岛素抵抗，使血糖难以得到控制，还会引起心血管疾患。但是，如果摄入的脂肪过少，对身体也会有害。     

瘦素与代谢综合征及临床联系

瘦素（leptin）是肥胖基因编码的一种蛋白质产物，主要由白色脂肪组织分泌，通过与其受体结合发挥抑制食欲、减少能量摄入、增加能量消耗的生物学作用。代谢综合征是一组由多种代谢相关疾病如糖耐量减低、糖尿病、冠心病、高血压、脂代谢紊乱等中的两种或两种以上的组合，胰岛紊抵抗（胰岛紊抵抗Insulin resistance，IR是指胰岛素的靶器官对胰岛索刺激的葡萄糖摄取、利用或处置的抵抗或减弱）其病因及发病机制中起关键作用。已经证实，体内存在脂肪一胰岛内分泌轴，瘦素与胰岛素抵抗、糖代谢异常、脂质代谢紊乱、高血压等密切相关，在代谢综合征和其他肥胖相关疾病的发生发展中占有重要地位。     

非酒精性脂肪性肝病中肝细胞脂肪变性分子机制的研究

肝脏在三大营养物质(包括糖、脂肪和蛋白质)的生物转化中起着重要作用。现代社会中多发的肥胖症促进了外周组织中的胰岛素抵抗,并且可能通过诱导肝脏中脂质的积累而引发严重的代谢紊乱,导致非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)。NAFLD可能导致更严重的疾病,如非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)、肝硬化甚至原发性肝癌。NAFLD的特点是肝脏中脂质增加,通常甘油三酯分子代表细胞内和血浆中脂肪酸的主要储存和运输形式,肝脏摄取和自身合成的脂肪酸以富含甘油三酯的极低密度脂蛋白的形式排出肝脏。在营养过剩和肥胖的情况下,肝脂肪酸代谢发生改变,通常导致肝细胞内甘油三酯的积累,并导致NAFLD。肝脏中脂质的累积可以通过增加游离脂肪酸摄入肝脏,减少脂肪酸β氧化或脂质从头合成的发生率增加来追踪。在本文中,我们描述了目前对肝脏中脂肪酸和甘油三酯代谢的理解及其对健康和疾病的调节,提出了未来研究的潜在方向。了解肝脏脂肪积累的分子机制对于NAFLD靶向治疗的发展至关重要。     

脂质代谢紊乱与胰岛素抵抗相关性研究进展

胰岛素抵抗在器官组织水平主要表现为肝抵抗、肌抵肮和脂抵抗。脂质代谢与胰岛素敏感性之间的关系非常密切．互相影响。即胰岛素抵抗导致脂质代谢紊乱，脂质代谢紊乱又参与胰岛素抵抗的发生。     

成纤维细胞生长因子-21对代谢的影响及可能的机制

近年来,随着社会发展和生活方式的改变,肥胖和营养相关性慢性疾病在我国的发病率迅猛上升。肥胖尤其是中心性肥胖可以导致胰岛素抵抗（IR）和脂质代谢紊乱,而IR是代谢综合征（MS）、2型糖尿病（T2DM）和心血管疾病发病的中心环节和病理生理基础。成纤维细胞生长因子-21（FGF-21）是一种肝脏、脂肪来源的细胞因子,能影响脂肪细胞及动物的葡萄糖代谢和胰岛素敏感性,     

Diabetic dyslipidemia and pathogenesis of ischemic heart disease

BACKGROUND: Type II diabetes is associated with high risk of ischemic heart disease (IHD), diabetes and IHD have similar risk factors, abdominal obesity as well as interrelated disturbances of lipid and carbohydrate metabolism play important roles in pathogenesis of both diseases. AIM: To elucidate characteristics of metabolism and transport of lipids and carbohydrates in patients with type II diabetes and IHD with normal and excessive body mass with abdominal type of fat distribution. MATERIAL AND METHODS: Parameters of carbohydrate metabolism, blood serum levels of free fatty acids, lipid and apoprotein (apo-) parameters of lipoprotein spectrum were evaluated in subjects without diabetes or IHD (group 1), patients with IHD and normal body mass (group 2), patients with IHD combined with diabetes with normal body mass (group 3), patients with IHD, diabetes and abdominal obesity (group 4). RESULTS: Patients with combination of diabetes and IHD compared with those of groups 1 and 2 in addition to higher blood glucose had lower growth hormone, higher triglycerides, lower high density lipoprotein cholesterol (CH) and apo-A1, higher low/high density lipoprotein CH and apo-B/apo-A1 ratios. These atherogenic changes were more pronounced in patients of group 4 who had highest levels of insulin, free fatty acids, low density lipoprotein CH and apo-B and lowest glucose/insulin ratio and level of apo-A1. CONCLUSION: Insulin resistance and hyperinsulinemia are most important features of disturbed carbohydrate and lipid metabolism. Insulin resistance and hyperinsulinemia are most pronounced in subjects with abdominal obesity in whom they create conditions for impaired glucose utilization, development of atherogenic dyslipidemia and eventually emergence of IHD.     

苏州社区人群血脂现状分析及研究

目的：了解苏州地区社区居民目前脂代谢紊乱的流行现状及危险因素,为相应防治提供依据.方法：在苏州2个社区随机选取20岁及以上的居民,对其进行问卷调查、体格检查和生化指标检测.结果：苏州地区2009年脂代谢紊乱总患病率为48.4%,其中高甘油三酯（TG）11.3%,高总胆固醇（TC）25.8%,低密度脂蛋白胆固醇（LDL-C）升高22.9%,高密度脂蛋白胆固醇（HDL-C）降低24.0%,混合型脂代谢紊乱8.0%.其发生与性别无明显关系,年龄增加对女性患者的血脂影响较大,随年龄增加有明显升高,对男性患者影响不大.而体重、腰围、血压、血糖、尿酸等皆与脂代谢紊乱有密切关系.结论：苏州地区的脂代谢紊乱发生水平已较高,需早期防治,对绝经期女性、老年患者、肥胖患者及患有高血压、高血糖、高尿酸等人群需重点筛查.     

肥胖者内脏脂肪蓄积与脂代谢的关系

目的:研究内脏脂肪蓄积与脂代谢的相关性。方法:选择首次就诊的163名单纯性肥胖病人。采用CT测定腹腔内脂肪面积,依据腹腔内脂肪面积分为内脏型肥胖组(腹腔内脂肪面积≥100cm2,115例)及皮下型肥胖组(腹腔内脂肪面积<100cm2,48例),并进行人体指标、脂代谢指标测定。结果:与皮下型肥胖组比较,内脏型肥胖组甘油三酯[TG,(1.69±1.51)mmol/L比(2.67±2.61)mmol/L]、总胆固醇[TC,(5.07±1.03)mmol/L比(5.65±1.19)mmol/L]水平显著升高(P<0.01),高密度脂蛋白胆固醇[HDL-C,(1.17±0.48)mmol/L比(1.02±0.22)mmol/L]水平显著降低(P<0.05)。直线相关分析显示,腹腔内脂肪面积与TG呈正相关(r=0.235,P=0.003),与HDL-C负相关(r=-0.162,P=0.039)。结论:内脏脂肪蓄积与脂代谢紊乱密切相关。     

Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome

Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.     

男性老年中心型肥胖与血脂及载脂蛋白的关系

分析84名中心型肥胖、104名外周型肥胖及101名正常体重老年人血脂和载脂蛋白资料。结果发现，中心型肥胖与外周型肥胖者血脂紊乱类型一致，均表现为血清胆固醇、甘油三酯及载脂蛋白B升高，高密度脂全白胆固醇、载脂蛋白AI降低，但中已心型肥胖者紊乱更为严重；随着腰围臀围比值水平升高，胆固醇和甘油三酯值亦升高；中心型肥胖者高脂血症患病率为82．2％，明显高于外周型肥胖者（476％，P＜0．01）。提示，腹部脂肪堆积与高脂血症密切相关，在血脂异常的预防和控制中，应重视对人体脂肪分布的观察与调整。     

Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage

We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARgamma, or PPARgammaalpha agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening.     

Free fatty acid metabolism and obesity in man: in vivo in vitro comparisons

We have examined the relationship of free fatty acid (FFA) turnover and lipid oxidation rates in vivo to the size of body triglyceride stores and compared these findings with the in vitro lipolytic rates of isolated abdominal fat cells. The studies were performed in 20 Pima Indian women 18 to 35 years of age, both lean and obese. FFA turnover rate was measured using a 1-14C-palmitate infusion, lipid oxidation rate by indirect calorimetry using a ventilated hood, body composition by underwater weighing with correction for residual lung volume, and fat cell lipolytic rates in vitro by published methods. Both FFA turnover and lipid oxidation rates, expressed per kg of body fat, decreased with increasing degree of obesity (as measured by percent body fat) (r = -0.90, and r = -0.75, P less than or equal to 0.0001, respectively). In contrast, the rate of lipolysis determined in vitro, expressed per kg of fat, increased with increasing degree of obesity (r = 0.58, P less than 0.01). A ratio of FFA turnover/lipolysis, which directly compares these in vivo and in vitro measurements, decreased significantly with increases in the degree of obesity (r = -0.81, P less than or equal to 0.0001). Furthermore, there were no positive correlations between the measures of in vivo FFA metabolism and in vitro lipolysis when both were expressed per fat mass, per fat cell number, or per fat cell surface area. The in vivo data also demonstrated that lipid oxidation could only account for 50% of the FFA disappearance rate. While lipid oxidation rate adjusted to the metabolic size increased with increasing plasma FFA concentration (r = 0.75, P less than 0.0003), the nonoxidative component of the FFA turnover failed to increase with increases in plasma FFA concentration (P = 0.5). We conclude that FFA is not available in vivo in proportion to the size of the triglyceride stores. The reason for this is not due to an inability of fat cells to release their stored triglyceride as assessed in vitro. Hence, in vitro measurements of fat cell lipolysis cannot be used to directly predict in vivo FFA metabolism. The large nonoxidative FFA disposal is likely to be important in the regulation of plasma FFA concentrations.     

Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis

ObjectiveLecithin cholesterol acyltransferase (LCAT) plays a pivotal role in HDL metabolism but its influence on atherosclerosis remains controversial for decades both in animal and clinical studies. Because lack of cholesteryl ester transfer protein (CETP) is a major difference between murine and humans in lipoprotein metabolism, we aimed to create a novel Syrian Golden hamster model deficient in LCAT activity, which expresses endogenous CETP, to explore its metabolic features and particularly the influence of LCAT on the development of atherosclerosis.MethodsCRISPR/CAS9 gene editing system was employed to generate mutant LCAT hamsters. The characteristics of lipid metabolism and the development of atherosclerosis in the mutant hamsters were investigated using various conventional methods in comparison with wild type control animals.ResultsHamsters lacking LCAT activity exhibited pro-atherogenic dyslipidemia as diminished high density lipoprotein (HDL) and ApoAI, hypertriglyceridemia, Chylomicron/VLDL accumulation and significantly increased ApoB100/48. Mechanistic study for hypertriglyceridemia revealed impaired LPL-mediated lipolysis and increased very low density lipoprotein (VLDL) secretion, with upregulation of hepatic genes involved in lipid synthesis and transport. The pro-atherogenic dyslipidemia in mutant hamsters was exacerbated after high fat diet feeding, ultimately leading to near a 3- and 5-fold increase in atherosclerotic lesions by aortic en face and sinus lesion quantitation, respectively.ConclusionsOur findings demonstrate that LCAT deficiency in hamsters develops pro-atherogenic dyslipidemia and promotes atherosclerotic lesion formation.     

Statins and diabetes

Lipid abnormalities play an important part in raising the cardiovascular risk in diabetic subjects. The main components of diabetic dyslipidemia are increased plasma triglycerides, low concentration of high-density lipoprotein cholesterol, preponderance of small, dense low-density lipoprotein, and excessive postprandial lipemia. Small, dense low-density lipoprotein, the elevation in remnant triglyceride-rich lipoprotein particles, and the low high-density lipoprotein are the most powerful atherogenic components. The coexistence of these three factors strongly aggravates the lipid accumulation in the arterial wall and the formation of atherosclerotic plaques. The position of diabetes in cardiovascular risk assessment has been recently reviewed in the Harmonized Clinical Guidelines on Prevention of Atherosclerotic Vascular Disease. In general, patients with diabetes carry a high risk for cardiovascular disease, but the absolute risk varies depending on the type of diabetes, age, and population baseline risk. The Adult Treatment Program III (ATP III) and the American Heart Association have designated diabetes as a high-risk condition and recommended intensive risk-factor management. Concerning therapeutic targets, both ATP III and the American Diabetes Association (ADA) guidelines have identified low-density lipoprotein cholesterol as the first priority of lipid lowering, and the optimal level was set at less than 2.6 mmol/L (100 mg/dL). There is strong evidence, coming from landmark secondary prevention studies, that LDL lowering in people with diabetes is associated with significant clinical benefits. The benefits of statin therapy in type 2 diabetics can no longer be questioned. Ongoing clinical trials will help clarify the question of whether increasing high-density lipoprotein cholesterol with fibrates in the presence of low low-density lipoprotein levels (lower than 3.4 mmol/L, or 130 mg/dL) will be more beneficial than statin therapy alone. The new paradigms in risk-reduction therapies for type 2 diabetic subjects are focused on cardiovascular disease prevention, rather than only on glucose or lipid control. Therapeutic lifestyle changes are considered primary therapies for hyperglycemia and coexisting metabolic syndrome, which can be diagnosed in more than half of type 2 diabetes subjects. New perspectives of lipid management in type 2 diabetes should take into account that insulin resistance, increased lipolysis, and overproduction of large, buoyant, very low density lipoprotein particles are at the base of diabetic dyslipidemia. Accordingly, drugs acting in the regulatory steps of very low density lipoprotein assembly should be developed. Activation of peroxisome proliferator activated receptor alpha (PPARalpha), as occurs with fibrates, lowers free fatty acids (FFAs) and triglyceride levels. PPARgamma agonism, as demonstrated by the thiazolidinediones, increases triglyceride lipolysis, FFA transport, and conversion of FFAs to triglycerides. As separate activation of PPARalpha and PPARgamma improves lipid metabolism, the development of new drugs integrating PPARalpha and PPARgamma activity (PPAR-alpha/gamma agonists) is a promising line that may further improve insulin resistance, FFA metabolism, and consequently, atherogenic diabetic dyslipidemia.     

实验性Ⅱ型糖尿病大鼠主动脉早期超微结构改变及影响因素

本实验测定了实验性Ⅱ型糖尿病大鼠血脂、血浆过氧化脂质及超氧化物歧化酶，观察了１０周时大鼠主动脉超微结构的改变。结果表明：糖尿病组及单纯肥胖组大鼠均有主动脉内膜病变，前者较明显。与对照组大鼠比较，前二者过氧化脂质、甘油三脂及低密度脂蛋白胆固醇均增高，而高、低密度脂蛋白胆固醇比值下降，差异非常显著（Ｐ＜０．０１），糖尿病组大鼠超氧化物歧化酶下降而单纯肥胖组大鼠则升高。以上结果提示，实验性Ⅱ型糖尿病大鼠主动脉内膜有早期超微病理改变，这种病变与过氧化脂质升高及超氧化物歧化酶活性下降有关。与脂代谢紊乱也有一定的关系。