Glucose Metabolism in Healthy Subjects and in Patients with Carbohydrate and Lipid Metabolic Disorders

The rate of glucose oxidation was studied by measurement of the ¹³C concentration in expired air with simultaneous detection of the activity of the pyruvate dehydrogenase complex in subjects with obesity and patients with type II diabetes. Intake of small amounts of glucose did not change the rate of glucose oxidation in subjects with obesity as compared to healthy controls. However, intake of large amounts of glucose resulted in a considerable increase in the rate of glucose oxidation without a hypoxic shift. In patients with diabetes mellitus, the rate of glucose oxidation decreased with increasing tissue hypoxia.     

脂肪代谢的整合调控

脂肪组织是人体内甘油三酯的主要储存场所,脂肪分解产生的甘油和游离脂肪酸对机体能量代谢起着至关重要的作用。肝脏在脂类运输和代谢中起重要作用。在餐后、饥饿不同状态机体内脂肪代谢不同。脂肪代谢失调是肥胖发生发展的重要原因,内脏脂肪和胰岛素抵抗等与疾病关系密切。     

Lipid Metabolism in Photoreceptor Membranes: Regulation and Mechanisms

Lipid metabolism in photoreceptor rod outer segments has attracted considerable attention because of its importance in providing the appropriate environment for supporting an efficient phototransduction mechanism. Recent studies suggest that lipid metabolism in these membranes is involved in the generation of second messengers and in signal transduction mechanisms. Phospholipid turnover is tightly regulated by phosphorylation-dephosphorylation reactions and light, and provides, in turn, with molecules capable of activating protein kinases and cellular processes such as membrane fusion or light-adaptation. These findings suggest that photoreceptor membrane lipids are more than just important structural components of the visual cell rod outer segment.     

Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity

A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart. To better understand the interactions of CB1, CPT1 and PPARs in these tissues, 30 diet-induced obese (DIO) C57BL/6J male mice were obtained, weight-matched and divided into two groups (15 in each group): (i) DIO/vehicle mice (D-Veh) and (ii) DIO/SR141716 mice (D-SR) treated with SR141716 (or rimonabant, a selective CB1 receptor blocker) administered orally (10 mg/kg daily). Another 15 mice fed standard diet (STD) formed the STD/vehicle group (S-Veh). At the end of 3-week treatment, mean body weight was 28.4 ± 0.5, 36.5 ± 0.8, and 30.3 ± 1.2 g for the S-Veh, D-Veh, and D-SR group, respectively (p < 0.05; D-Veh vs. D-SR). Liver weight in the D-SR group was also decreased significantly compared to the D-Veh group (p < 0.05). Serum levels of total cholesterol, high-density lipoprotein cholesterol, leptin and adiponectin in the D-SR group were ameliorated compared to the D-Veh group (p < 0.05). Both qRT-PCR and Western blot assay revealed that CB1 expression levels were efficiently blocked by SR141716 in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscles and liver (D-SR vs. D-Veh; p < 0.05), whereas there was no significant difference between S-Veh and D-Veh mice (p > 0.05). Simultaneously with the reduction of CB1 expression in the D-SR group, the expression levels of CPT1A isoform (protein) in the liver and heart and CPT1B isoform (protein) in the SAT, VAT, liver and skeletal muscles were significantly increased (p < 0.05; D-SR vs. D-Veh). Interestingly, the CPT1A and CPT1B expression levels in heart were detected slightly. The expression levels of PPARα in the SAT, VAT, liver and skeletal muscles and PPARγ in the SAT and skeletal muscles in the D-SR group were significantly increased compared to the D-Veh mice (p < 0.05). However, the PPARβ expression level differed from that of PPARα and PPARγ. Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1. Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.     

MicroRNA在脂肪细胞分化中的调节作用

MicroRNA(miRNA)是一类内源性、短小、大小为～22核苷酸的单链非编码RNA.miRNA广泛分布于真核细胞内,能够通过与靶mRNA3'末端非翻译区(3'-untranslated region,3'UTR)特异性结合来降解或抑制靶mRNA的翻译,从而对基因进行转录后基因表达的调控.miRNA不仅调控生物体的生长和发育过程,而且参与调控多种生理学和病理学过程,如细胞分化、细胞增殖、胰岛素的分泌、脂肪代谢以及肿瘤的形成.研究表明miRNA在肿瘤、糖尿病、代谢等多种疾病中发挥着重要的作用.本文对miRNA在脂肪细胞分化及脂类代谢中的调节作用进行综述.     

Alterations of Choroidal Blood Flow Regulation in Young Healthy Subjects with Complement Factor H Polymorphism

A common polymorphism in the complement factor H gene (rs1061170, Y402H) is associated with a high risk of age-related macular degeneration (AMD). In the present study we hypothesized that healthy young subjects homozygous for the high-risk haplotype (CC) show abnormal choroidal blood flow (ChBF) regulation decades before potentially developing the disease. A total of 100 healthy young subjects were included in the present study, of which 4 subjects were excluded due to problems with genotyping or blood flow measurements. ChBF was measured continuously using laser Doppler flowmetry while the subjects performed isometric exercise (squatting) for 6 minutes. The increase in ChBF was less pronounced than the response in ocular perfusion pressure (OPP), indicating for some degree of choroidal blood flow regulation. Eighteen subjects were homozygous for C, 47 subjects were homozygous for T and 31 subjects were heterozygous (CT). The increase in OPP during isometric exercise was not different between groups. By contrast the increase in ChBF was more pronounced in subjects homozygous for the high risk C allele (p = 0.041). This was also evident from the pressure/flow relationship, where the increase in ChBF in homozygous C carriers started at lower OPPs as compared to the other groups. Our data indicate that the regulation of ChBF is abnormal in rs1061170 CC carriers. So far this polymorphism has been linked to age related macular degeneration (AMD) mainly via inflammatory pathways associated with the complement system dysfunction. Our results indicate that it could also be related to vascular factors that have been implicated in AMD pathogenesis.     

瘦素在糖脂代谢中的调控作用

瘦素（leptin）是OB基因的编码产物,由脂肪细胞分泌,具有广泛的生理学功能.瘦素可通过作用于中枢神经系统与外周组织等途径在糖脂代谢调控、能量代谢、生殖发育及免疫调节过程中起重要作用.不同剂量、不同作用时间,也可导致瘦素产生不同的生理学作用.近年来,随着肥胖及糖尿病在全球范围内成为流行病,瘦素在糖脂代谢中的调控作用引起了人们的广泛关注.现有的研究已发现,瘦素抵抗与胰岛素抵抗之间具有重要的关联性,揭示瘦素功能异常在肥胖诱发的糖脂代谢紊乱过程中起着重要的作用.本文将对瘦素在机体糖脂代谢中的调控作用进行综述和讨论.     

Regulation of Metamorphosis-Associated Changes in the Lipid Metabolism of Selected Vertebrates

SYNOPSIS. The life histories of many vertebrates include complex,postembryonic developmental pathways that involve morphologicaland physiological changes that adapt juveniles to a new habitat.A survey of such developmental pathways, including lamprey metamorphosis,salmonid smoltification, and anuran metamorphosis, reveals acommon strategy of lipid metabolism consisting of two distinctphases. The first phase is characterized by lipid accumulationin storage sites and resultsfrom lipogenesis prevailing overlipolysis. The second phase is characterized by lipid depletionfrom storage sites and results from lipolysis prevailing overlipogenesis. Regulation of lipid deposition and lipid mobilizationis essential for ensuring availability of lipid during timesof need. Lipogenesis is promoted by insulin and, in lampreyand anurans, also by thyroid hormones. Lipolysis is promotedby a number of hormones, including prolactin, growth hormone,adrenocorticotropic hormone, corticosteroids, somatostatins,and thyroid hormones. The coordinate regulation of development-associatedchanges in lipid metabolism results from interactions amonghormones and other internal and environmental cues.     

非编码RNA与肝脏糖脂代谢调控

随着经济的迅速发展、人们饮食习惯的改变和身体活动的减少,糖尿病成为了现代社会的非传染性的流行病,给家庭和社会造成了极大的危害和经济负担。其中以全身性胰岛素抵抗及胰岛功能衰竭为主要发病特征的2型糖尿病(type 2 diabetes,T2D)已在世界范围引起广泛关注。T2D的发生发展涉及许多组织及糖代谢的各个环节,遗传因素和环境因素共同引起的糖脂代谢通路任一环节的失调均可导致T2D的发生。近年来,包括microRNA(miRNA)及长非编码RNA(LncRNA)在内的非编码RNA(ncRNA)的发现及其在人体生理和病理生理过程中的重要调控作用不断被揭示,为进一步了解T2D的发病机制注入了新理念和信息。miRNAs及LncRNAs的表达具有组织特异性,其表达水平的异常通常与疾病相关。本文主要对miRNAs和LncRNAs在肝脏糖脂代谢调控及T2D的发生发展中的作用及机制的最新研究进展作简要综述。     

Diurnal Regulation of Lipid Metabolism and Applications of Circadian Lipidomics

The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles （e.g., in shift work） results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.     

microRNAs——脂质代谢调控新机制

综述了近年来microRNAs,尤其是miR-33在脂质代谢调控方面的功能研究进展.脂质代谢在细胞水平进行有规律的调控,主要参与者有肝X受体(LXRs)和固醇调节元件结合蛋白(SREBPs)等.最近研究发现,非编码RNAs家族成员microRNAs在转录后水平调节脂质代谢相关基因表达,参与胆固醇、甘油三酯和脂肪酸代谢.其中miR-33可靶向沉默三磷酸脂苷结合盒(ABC)转运体家族成员ABCA1和ABCG1,抑制胆固醇流出和高密度脂蛋白(HDL)合成;通过靶向沉默脂肪酸β-氧化相关基因,如CPT1A、CROT和HADHB表达,抑制脂肪酸氧化;还可沉默AMPK和RIP140的表达,影响甘油三酯代谢.其他microRNAs如miR-122、miR-370、miR-125a-5p、miR-27、miR-320等,也参与调控胆固醇、甘油三脂、脂肪酸代谢及脂肪细胞分化.     

Acylation Stimulating Protein,Complement C3 and Lipid Metabolism in Ketosis-Prone Diabetic Subjects

Background

Ketosis-prone diabetes (KPDM) is new-onset diabetic ketoacidosis without precipitating factors in non-type 1 diabetic patients; after management, some are withdrawn from exogenous insulin, although determining factors remain unclear.

Methods

Twenty KPDM patients and twelve type 1 diabetic patients (T1DM), evaluated at baseline, 12 and 24 months with/without insulin maintenance underwent a standardized mixed-meal tolerance test (MMTT) for 2 h.

Results

At baseline, triglyceride and C3 were higher during MMTT in KPDM vs. T1DM (p<0.0001) with no differences in non-esterified fatty acids (NEFA) while Acylation Stimulating Protein (ASP) tended to be higher. Within 12 months, 11 KPDM were withdrawn from insulin treatment (KPDM-ins), while 9 were maintained (KPDM+ins). NEFA was lower in KPDM-ins vs. KPDM+ins at baseline (p = 0.0006), 12 months (p<0.0001) and 24 months (p<0.0001) during MMTT. NEFA in KPDM-ins decreased over 30–120 minutes (p<0.05), but not in KPDM+ins. Overall, C3 was higher in KPDM-ins vs KPDM+ins at 12 months (p = 0.0081) and 24 months (p = 0.0019), while ASP was lower at baseline (p = 0.0024) and 12 months (p = 0.0281), with a decrease in ASP/C3 ratio.

Conclusions

Notwithstanding greater adiposity in KPDM-ins, greater NEFA decreases and lower ASP levels during MMTT suggest better insulin and ASP sensitivity in these patients.     

脂联素对肝脏糖脂代谢调节作用的研究进展

脂联素因其具有抗糖尿病作用而备受关注,它能控制血糖,并且在肝脏、脂肪和胰腺中能影响脂质代谢。脂联素通过刺激脂肪细胞,对抗炎症、控制脂质过氧化和脂肪分解的速率来调控脂质流入非脂肪组织。肝脏是脂联素发挥作用的重要靶器官;在肝脏中,脂联素与脂联素受体1、2或T-钙黏着蛋白结合,激活下游的AMPK、APPL1、神经酰胺酶等发挥其调节作用。我们总结了脂联素改善肝脏胰岛素敏感性和糖脂代谢的相关机制。     

Gaze Holding in Healthy Subjects

Eccentric gaze in darkness evokes minor centripetal eye drifts in healthy subjects, as cerebellar control sufficiently compensates for the inherent deficiencies of the brainstem gaze-holding network. This behavior is commonly described using a leaky integrator model, which assumes that eye velocity grows linearly with gaze eccentricity. Results from previous studies in patients and healthy subjects suggest caution when this assumption is applied to eye eccentricities larger than 20 degrees. To obtain a detailed characterization of the centripetal gaze-evoked drift, we recorded horizontal eye position in 20 healthy subjects. With their head fixed, they were asked to fixate a flashing dot (50 ms every 2 s)that was quasi-stationary displacing(0.5 deg/s) between ±40 deg horizontally in otherwise complete darkness. Drift velocity was weak at all angles tested. Linearity was assessed by dividing the range of gaze eccentricity in four bins of 20 deg each, and comparing the slopes of a linear function fitted to the horizontal velocity in each bin. The slopes of single subjects for gaze eccentricities of ±0−20 deg were, in median,0.41 times the slopes obtained for gaze eccentricities of ±20−40 deg. By smoothing the individual subjects'' eye velocity as a function of gaze eccentricity, we derived a population of position-velocity curves. We show that a tangent function provides a better fit to the mean of these curves when large eccentricities are considered. This implies that the quasi-linear behavior within the typical ocular motor range is the result of a tuning procedure, which is optimized in the most commonly used range of gaze. We hypothesize that the observed non-linearity at eccentric gaze results from a saturation of the input that each neuron in the integrating network receives from the others. As a consequence, gaze-holding performance declines more rapidly at large eccentricities.     

类法尼醇X受体对脂代谢的调控作用

类法尼醇X受体（famesoid X receptor,FXR）属于于配体激活的核转录因子,是核受体超家族中的一员。受配体激活后．FXR在胆汁酸、脂质代谢中具有重要调控作用。随着FXR特异性配体及拮抗剂的发现,其在代谢及相关疾病中的调控作用日趋明显。最近发现,FXR在心血管系统中有表达活性,开辟了FXR调控网络的新领域。     

High Energy Digestion Efficiency and Altered Lipid Metabolism Contribute to Obesity in BFMI Mice

To constitute a valuable resource to identify individual genes involved in the development of obesity, a novel mouse model, the Berlin Fat Mouse Inbred line 860 (BFMI860), was established. In order to characterize energy intake and energy expenditure in obese BFMI860 mice, we performed two independent sets of experiments in male BFMI860 and B6 control mice (10 per line). In experiment 1, we analyzed body fat content noninvasively by dual‐energy X‐ray absorptiometry and measured resting metabolic rate at thermoneutrality (RMRt) and respiratory quotient (RQ) in week 6, 10, and 18. In a second experiment, energy digested (energy intake minus fecal energy loss) was determined by bomb calorimetry from week 6 through week 12. BFMI860 mice were heavier and had higher fat mass (final body fat content was 24.7% compared with 14.6% in B6). They also showed fatty liver syndrome. High body fat accumulation in BFMI860 mice was restricted to weeks 6–10 and was accompanied by hyperphagia, higher energy digestion, higher RQs, and abnormally high blood triglyceride levels. Lean mass–adjusted RMRt was not altered between lines. These results indicate that in BFMI860 mice, the excessive accumulation of body fat is associated with altered lipid metabolism, high energy intake, and energy digestion. Assuming that BFMI860 mice and their obese phenotypes are of polygenic nature, this line is an excellent model for the study of obesity in humans, especially for juvenile obesity and hyperlipidemia.