Volume 05 · Issue 08 · 2013

There are two types of fat tissue in mammals, white fat and brown fat. White fat mainly stores energy, while brown fat consumes energy to produce heat and maintain a constant body temperature. Brown adipose tissue accounts for less than 2% of body weight. Brown adipocytes are rich in mitochondria and uncoupling protein 1 (UCP-1). Mitochondria produce a large amount of ATP, which is converted into heat release through the uncoupling effect of UCP-1. Brown adipocytes also have a large number of lipid droplets. Unlike white adipocytes, they exist in the form of multilocular lipid droplets, which are more convenient for oxidation and utilization. Especially in small mammals, the role of brown fat is even more important in order to adapt to the temperature changes of the external environment. It has long been believed that brown fat is only present in the neonatal stage and that brown adipose tissue is not present in adults. However, in 2009, five independent laboratories separately reported the presence of brown adipose tissue in adults^[1,2,3,4,5]。 Using positron emission computed tomography (PET-CT), they found fluorodeoxyglucose in the neck and supraclavicular areas (¹⁸F-FDG) uptake enhancement region; It was further confirmed by tissue biopsy that the histomorphological changes in this site tend to brown fat, and a large number of UCP-1 and peroxisome proliferator-activated receptor gamma coactivator 1 α (PGC-1 α) are expressed, with a significant increase in mitochondrial number. These studies are the first to confirm the presence of brown adipose tissue in adults, and the finding, more importantly, ignites new hope for the treatment of obesity.

Brown adipose tissue (BAT) has been shown to exist in normal adults. Its structure and function are different from white adipose tissue (WAT), but both are involved in the body's material and energy metabolism. There is evidence that the functional imbalance of BAT or WAT plays a role in the development of metabolic diseases such as obesity. At present, the prevalence of obesity and its related metabolic diseases is increasing year by year, which increases the national health and economic burden day by day. It has become one of the most serious public health crises faced by human beings in the 21st century, and there is a lack of effective prevention and treatment means. In-depth research on brown fat is expected to provide new ideas and means for the prevention and treatment of metabolic diseases such as obesity.

In recent 30 years, the prevalence of diabetes in China has increased significantly, and the epidemic situation of diabetes has become more serious in the last 10 years. From 2007 to 2008, the Diabetes Branch of Chinese Medical Association organized 14 provinces (cities) to conduct an epidemiological survey of diabetes mellitus in China. The results showed that the prevalence of diabetes mellitus in adults over 20 years old in China was 9.7%, and the total number of adults with diabetes mellitus in China reached 92.4 million. China may have become the country with the largest number of diabetes mellitus at present. What's even more worrying is that this survey also found that 60.0% of diabetic patients were not diagnosed in time. These patients are at great risk, especially those with hyperglycemic crisis as the first symptom. If the diagnosis and treatment are not timely, their lives are in danger.

To analysis the distribution of HOMA-IR, and explore the diagnostic value of leptin/adiponectin ratio (LEP/APN) on insulin sensitivity in Beijing children and adolescents.

A total of 3506 schoolchildren, selected from the Beijing Child and Adolescent Metabolic Syndrome Study(BCAM study), were included in the current study, among them 659 were overweight and 1219 were obese. Age- and sex-specific body mass index (BMI) percentiles, developed by the Working Group for Obesity in China, were used to classify participants as normal weight (BMI <85%), overweight (BMI ≥85% but <95%), or obese (BMI ≥ 95%). Examination included anthropometry, pubertal development, and levels of fasting lipid profile, insulin, LEP and APN. Insulin resistance (IR) was evaluated by HOMA-IR. Correlation analysis and receiver operating characteristic curve (ROC) were used in the statistical analysis.

According to the distribution of HOMA-IR in healthy children and adolescents, the cutoff value for IR was ≥2 .6 in pre-pubertal stage and ≥3.4 in pubertal phase, respectively. The prevalence of IR was 22.2% and 42.9% respectively in overweight and obese children and adolescences. The LEP/APN ratio was progressively increased from normal group to overweight group and to obesity group, and correlated with HOMA-IR significantly (Pearson correlation coefficient was 0.51 and partial correlation coefficient was 0.40). After adjusting for age, sex, puberty and other confounding factors, the LEP/APN ratio is an independent predicator for HOMA-IR by multivariate linear regression analysis (unstandardized coefficient was 0.273 and standardized coefficient was 0.467, P<0.01). Area under the ROC curve of LEP/APN ratio for diagnosing of IR was larger than those of LEP, APN, BMI, waist circumference and FAT%.

Evaluation of IR needs to consider puberty status and prevalence of IR is obvious in overweight and obese children and adolescents. The LEP/APN ratio is expected to be early biomarker of IR state, and an early potent predicator of metabolic disorders.

To investigate the association of serum irisin level with fat mass percentage.

A total of 1204 subjects with obesity(waist circumference: male ≥90 cm, female ≥85 cm) were recruited from Lianqian Community in Xiamen city from April, 2011 to August, 2012. All the participants received questionnaire survey, physical examination, blood chemistry tests and serum irisin levels measurement, and the fat mass percentage was measured by using a bioelectrical impedance analyzer. The data were analyzed using student-t test, ANOVA and logistic regression.

Total of 807 women and 397 men with central obesity took part in the study, the age was (53±7) yrs(35 to 65 yrs). A higher fat mass percentage and serum irisin levels were shown in women as compared with those in men ((39±4)% vs (26±4)% and 8.9(4.7-17.2) μg/L vs 7.6(4.0-14.4) μg/L, t=-53.50, -2.87, both P<0.05). Serum irisin levels were correlated with fat mass percentage in total subjects. Fat mass percentage, serum total cholesterol(TC) and low density lipoprotein-cholesterol (LDL-C) levels increased as serum irisin levels increased by tertiles (F=4.49, 3.63, 4.88, all P for trend<0.05). Serum irisin levels were increased as fat mass percentage increased by tertiles (F=3.33, P<0.05). Logistic regression analysis showed that serum irisin levels were increase by 13% as fat mass percentage increased by one percent after all metabolic markers (such as age, sex, body mass index, waist circumference, physical activity, systolic blood pressure, diastolic blood pressure, current smoking and drinking, triglyceride, TC, LDL-C, high density lipoprotein-cholesterol, glycated hemoglobin A1c, fasting blood glucose and homeostasis model of assessment for insulin resistence index) were adjusted (OR=1.13, 95%CI: 1.01-1.25, χ ²=4.83, P<0.05).

Serum irisin levels in obese adults were associated with fat mass percentage.

To investigate the prevalence and association factors of secondary diabetes in Chinese hospitalized children.

A case-control design, retrospective study on pediatric patients <18 years, who were hospitalized in Beijing Children's Hospital between Jan.2002 and Dec.2010 was carried out. Diabetes was diagnosed according to the criteria of World Health Orgnization(WHO), 1999. Control cases were chosen with 1∶4 ratio and matched in the primary diseases, age, gender. The associated risk factors of secondary diabetes was investigated with logistic analysis.

Total 33 cases (aged 7.1-16.4 years, 15 boys and 18 girls) of secondary diabetes were identified among 9657 inpatients suffering the corresponding primary diseases. The total prevalence of secondary diabetes was 0.34%, the highest was 4.17% in lymphoma leukemia, then 3.70% in acute lymphoblastic leukemia after hematopoietic stem cell transplantation, 1.67% in multiple sclerosis and less than 1.0% in systemic lupus erythematosus, dermatomyositis, acute lymphoblastic leukemia without hematopoietic stem cell transplantation, histocytosis, idiopathic thrombocytopenic purpura, nephropathy and purpuric nephritis. The prevalence of secondary diabetes was lower in boy than that in girls(0.24% vs 0.53%, χ ²=4.79, P<0.05). There were 18 cases of secondary diabetes suffering hematological malignancies and 12 cases of them developed diabetes within 6 days after L-asparaginase treatment; 2 cases with chemotherapy with non-L-asparaginase-based regimens developed diabetes at day 45 and 210 respectively, and the rest 4 patients developed diabetes during days 60 to 450 after hematopoietic stem cell transplantation. Of the patients treated mainly with corticosteroid, 15 cases were identified with diabetes 2 days to 4.7 years after the treatment. None of them had typical symptoms and diabetic ketone acidosis. Logistic regression showed that age and obesity or overweight were the risk factors for secondary diabetes(the odds ratio was 1.24 and 5.08 respectively, bothP<0.05).

It's indicated that the prevalence of secondary diabetes in hospitalized children was lower in China than that in western countries and differs with gender, age and various primary diseases. Secondary diabetes can be easily miss-diagnosed due to the atypical symptoms. It is necessary to monitor glucose during the whole course of the primary diseases.

To investigate the effect of exenatide on serum insulin and plasma glucose in obese subjects with impaired glucose regulation(IGR).

A total of 75 obese subjects with IGR were enrolled from May 2011 to November 2012 in Quanzhou First Hospital Affiliated Fujian Medical University. A total of 62 eligible subjects were divided into the hyperinsulinemia group (HIns, fasting serum insulin ≥15 mU/L and(or)2-hour serum insulin ≥80 mU/L post glucose load, n=32) and the non-hyperinsulinemia group (NHIns, n=30) by the serum insulin level. Fasting and 2h plasma glucose in OGTT, insulin , C-peptide and body weight were measured at the baseline, D5 and D14 of exenatide treatment. Insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR) and the gutt insulin sensitivity index. Paired t test was used to test within group change. One-way ANOVA was applied to compare differences of continuous variables between subgroups. Rates were compared by using the χ² test.

Compared with the baseline, fasting and 2 h glucose significantly improved at D5 in the two groups, but without further decrease at D14 in the two groups(t=4.42, 9.78, 4.00, 8.66 with all P<0.05). Compared with the baseline, the fasting insulin significantly decreased at D5 in the HIns group(t=2.07, P<0.05). The 2 h insulin level significantly decreased at D5 with further reduction at D14 in the HIns group(F=24.17, P<0.05). No significant decrease was observed with the fasting and 2 h insulin in the NHIns group at D5 and D14. HOMA-IR significantly decreased at D5 in the HIns groups(t=3.27, P<0.05), while showed no change at D5 and D14 in the NHIns group(allP>0.05). Gutt insulin sensitivity index increased at D5 in the HIns groups(t=-9.84, P<0.05)with further increase at D14(F=55.96, P<0.05). Compared with the baseline, the Gutt insulin sensitivity index significantly increased at D5 in the NHIns group(t=-4.27, P<0.05). Body weight significantly decreased in the HIns group and the NHIns group at D14(t=14.13, 12.00, all P<0.05), while showed no change at D5 in both groups. None of the subjects withdrew because of adverse event including hypoglycemia.

Exenatide short-term treatment in obese subjects with IGR can benefit glucose regulation, improve insulin resistance and control body weight.

To investigate the effects of hypoxia on adiponectin mRNA transcription and protein expression in adipose tissue of obese mice.

The mRNA and protein of adiponectin and peroxisome proliferator activated receptor -γ(PPAR-γ) in epididymal fat tissues of genetic obese mice (ob/ob) and high fat diet-induced (HFD) obese mice were examined through quantitative real-time PCR (qRT-PCR) and western blotting. mRNA expression and promoter activity of adiponectin was measured with real-time qRT-PCR and luciferase reporter assay in 3T3-L1 adipocytes. Adiponectin mRNA stability was checked with real-time RT-PCR. mRNA and mRNA stability of PPAR-γ were examined with qRT-PCR in 3T3-L1 adipocytes after hypoxia treatment and then nuclear accumulation of PPAR-γ and peroxisome proliferator response element (PPRE) transcriptional activity were determined in mature adipocytes.Comparison of data between groups was applied by usingt test.

(1) Adiponectin expression was inhibited in white adipose tissue of obese mice at both mRNA and protein levels(P<0.01). In mature 3T3-L1 adipocytes, the qRT-PCR data showed that mRNA expression of adiponectin was reduced by hypoxia, compared with control group, especially after hypoxia for 8 and 24 hours, the level of adiponectin mRNA was reduced from 1.00±0.04 to 0.65±0.05 and 0.29±0.05 (t=11.548, 24.893, both P<0.01). Half life of mRNA was not reduced by hypoxia. A luciferase reporter driven by the adiponectin gene promoter was inhibited by hypoxia in 3T3-L1 adipocytes. (2)Protein and mRNA expression of PPAR-γ were decreased in white adipose tissue of obese mice and in 3T3-L1 adipocytes after hypoxia treatment. After hypoxia for 8 and 24 hours, compared with control group, level of PPAR-γ mRNA was significantly reduced from 1.00±0.09 to 0.72±0.09 and 0.54±0.07(t=5.134, 9.876, both P<0.01). PPAR-γ mRNA stability was reduced in 3T3-L1 adipocytes after hypoxia treatment. Nuclear translocation of PPAR-γ protein and transcriptional activity of PPAR-γ was also inhibited by hypoxia.

The adiponectin mRNA expression is reduced by hypoxia and the inhibition happened at the transcriptional level. It might be the result of suppression of PPAR-γ, an important transcription activator for adiponectin, at both mRNA expression level and its transcriptional activity.

To investigate the abnormal glucose metabolism in acute coronary syndrome (ACS) inpatients without diagnosed history of diabetes mellitus (DM) of Han, Uygur and Kazak people in Xinjiang.

Five hundred and eighty-one ACS cases without DM were collected from September 2010 to September 2012 in three ethnic inpatients.Oral glucose tolerance (OGTT) were underwent to determine the glucose metabolism if they could not be clearly diagnosed as diabetes by fasting plasma glucose.

Total of 428 cases (73.7%) had abnormal glucose metabolism, including 245 patients (42.2%) with DM and 183 cases (31.5%) with abnormal glucose regulation. There were 337 Han cases with ACS, including 146 cases (43.3%) with diabetes mellitus and 114 cases (33.8%) with glucose regulation abnormality. There were 219 Uygur cases, including 96 cases (43.8%) with DM and 65 cases (29.7%) with abnormal glucose regulation. There were 25 Kazak cases, including 3 cases (12.0%) with DM and 4 cases (16.0%) with abnormal glucose regulation. Without OGTT test, only recognized by fasting blood glucose, 38.0% diabetes mellitus patients would be missed and 43.7% impaired glucose regulation patients would be missed in patients without diagnosed history of DM. There was no statistically significant difference in follow-up after 3 months (P<0.05).

There are 428 cases (73.7%) with abnormal glucose metabolism in Han, Uygur and Kazak ACS patients without diagnosis history of DM in Xinjiang, and the incidence is the lowest in kazak patients.Only relying on fasting blood glucose, a considerable number of ACS patients with abnormal glucose metabolism would be missed.

To investigate the effects of active vitamin D₃ on the expression of vitamin D receptor(VDR)and angiotensin Ⅱ in the human proximal tubular epithelial cells HK-2 induced by high glucose.

Cultured HK-2 cells were divided into the following five groups: (1)control group (5.5 mmol/L glucose), (2)mannitol group (5.5 mmol/L glucose + 19.5 mmol/L mannitol), (3)high glucose group (25.0 mmol/L glucose), (4)high glucose + 1, 25-(OH)₂D₃ group (25.0 mmol/L glucose + 1, 25-(OH)₂D_3,for 1.0×10^-6, 1.0×10^-7, 1.0×10^-8 mol/L respectively), (5)high glucose + 1, 25-(OH)₂D₃+ siRNA VDR group(25.0 mmol/L glucose + 1, 25-(OH)₂D_3,10^-6 mol/ L + siRNA VDR) . The expression of VDR mRNA and protein were detected by real-time quantitative PCR and western blot, respectively. Dual luciferase reporter gene assay was used to detect VDR gene transcription activity. Radioimmunoassay was used to examine the expression of angiotensin Ⅱ. Significance between different groups was compared by one-way analysis of variance. The q-test was used to evaluate the differences in means between groups. P<0.05 were considered to be statistically significant.

Compared with the control group, the mRNA, protein expression and gene transcription activity of VDR in the high glucose group were lower(1.34±0.22 vs 2.47±0.31, 0.51±0.06 vs 1.14±0.13, 0.51±0.21 vs 1.42±0.28, all P<0.05). The mRNA expression, protein expression and gene transcription activity of VDR were up-regulated by 1, 25-(OH)₂D₃ in a dose dependent manner in HK-2 cells induced by high glucose(1.96±0.31 vs 1.34±0.22, 0.93±0.08 vs 0.51±0.06, 1.12±0.23 vs 0.51±0.21, all P<0.05). Compared with the control group, high glucose significantly induced the expression of angiotensin Ⅱ in HK-2 cells((88±10) vs (17±2) ng/L,P<0.05). The expression of angiotensin Ⅱ was significantly down-regulated by 1, 25-(OH)₂D₃ in a dose dependent manner in HK-2 cells induced by high glucose((44±5) vs (88±10) ng/L, P<0.05), while the effect was abolished after silencing VDR by siRNA((87±12) vs (88±10) ng/L,P>0.05).

Angiotensin Ⅱ could be reversely regulated by 1, 25-(OH)₂D₃ in the human proximal tubular epithelial cells induced by high glucose via a VDR-mediated mechanism. The finding could be of particular value in the prevention of diabetic nephropathy.

To explore the effect of sterol regulatory element-binding protein-1c (SREBP-1c) on the transcription of patatin like phospholipase domain containing 3(PNPLA3) in rat.

Seven-week male weight matching Sprague-Dawley rats were assigned to fed ad libitum group(n=3), fasting group(n=3, fasting for 24 h), refeeding group(n=4, fasting for 24 h and refeeding 48 h) and normal control group(n=5), high-fat-diet and streptozotocin-induced diabetic group(n=6). Reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were performed to determine the expression of SREBP-1c and PNPLA3 in rats' liver. Three nested deletions of the 5' end of the 1.0 kbPNPLA3 promoter were generated and introduced into the luciferase reporter gene(R-PNPLA3-1, R-PNPLA3-2, R-PNPLA3-3), and then transfected into human normal hepatic cell line LO2 respectively to compare the basal and post-stimulate luciferase activity after transfected with SREBP-1c plasmid. The PNPLA3 promoter which was shown the highest luciferase activity might contain a putative SREBP-1c binding sites (SRE). Then wild-type and mutant SRE reporter vectors were constructed to compare their luciferase activity. Statistical analysis was performed with one-way ANOVA of variance, followed by the Student'st test.

Compared with the fed ad libitum group, the gene expression of SREBP-1c, PNPLA3 and fatty acid synthase(FAS) in liver decreased significantly in fasting group, and recovered in refeeding group (F=114.14, 334.11, 754.20, all P<0.05).Compared with normal control group, the gene and protein expression of SREBP-1c and PNPLA3 increased markedly in diabetic group(t=-18.39, -30.07 and 4.58, 6.81, all P<0.05).The basal luciferase activity of R-PNPLA3-1 increased for 51.13 folds when compared with that in the control group(t=-28.93, P<0.05),while no notable changes was found with R-PNPLA3-2 and R-PNPLA3 -3; transfection of SREBP-1c plasmid into LO2 cells caused 2.63 folds activation of R-PNPLA3-1(t=-7.64, P<0.01),while no changes in R-PNPLA3-2and R-PNPLA3-3 groups was found. A putative SRE located in -97/-88 bp of rat PNPLA3 gene promoter, the luciferase activity of mutant SRE reporter vectors(MUT-R-PNPLA3-1) decreased for 40.8% when compared with that in wild-type(R-PNPLA3-1) ( t=4.99, P<0.05).

SREBP-1c trans-activates rat PNPLA3 via a proximal SRE (-100/-91 bp) of PNPLA3 promoter.

Previous views suggest that there are two main types of adipose tissues in mammals-white fat (WAT) and brown fat (BAT)^[1]。 The main function of WAT is to store energy in the form of triglycerides, while BAT maintains the energy metabolism balance of the body through heat production. In recent years, a so-called "beige cell" with the same thermogenic function as BAT has been found in WAT. This phenomenon is also considered to be WAT browning^[2]。 Beige fat plays an important role in the regulation of energy metabolism and has become a new obesity therapeutic target. This article will expound the cognitive process of WAT browning, and the signaling pathways that play an important role in the differentiation and metabolism of beige adipose tissue, and discuss the feasibility of using WAT browning to treat obesity.

Adipose tissue in mammals is mainly divided into white adipose tissue (WAT) and brown adipose tissue (BAT) according to their function^[1]。 WAT mainly stores the energy ingested by the body in the form of triglycerides. When the energy intake exceeds the storage capacity of fat cells, the body will produce obesity. Unlike WAT, BAT mainly consumes energy by oxidizing fatty acids. On the one hand, BAT maintains the body temperature through non-trembling thermogenesis, on the other hand, it can consume the excess energy of the body and maintain the energy balance^[2]。 Based on the role of BAT in energy consumption, activating BAT activity can increase energy consumption in obese patients, achieve weight loss and improve metabolism. Therefore, the research on BAT has become a hot spot in obesity research at present. The author will summarize the major progress and breakthroughs in the research field of BAT in recent years.

In the 1850s, Mertz and Schwarz discovered that chromium regulated blood sugar^[1]； Later, some scholars gave chromium supplements to patients who received long-term parenteral nutrition, and found that they could reverse the impaired glucose tolerance state^[2]Therefore, the theory that "chromium is an essential trace element of human body" is put forward. In recent years, numerous studies have found that chromium has the effect of reversing insulin resistance and improving type 2 diabetes^[3,4]。 This article reviews the molecular mechanism of chromium and insulin resistance.

The age-standardized prevalence of diabetes in people over 20 years old in China reaches 9.7%^[1]The results of the 2010 survey on the prevalence of overweight and obesity among adults in China showed that the overweight rate [24 kg/m²≤ body mass index (BMI)<28 kg/m²] was 30.6%, and the obesity rate (BMI ≥28 kg/m²) was 12.0%^[2]。 Obesity is an important cause of insulin resistance and a major risk factor in the development of type 2 diabetes mellitus (T2DM). Therefore, the substantial increase of obese and overweight people is undoubtedly one of the basic reasons for the high incidence of diabetes in China. Weight management for the general population and diabetic patients is of great significance for the prevention and control of diabetes.

At present, the best exercise mode to reduce the risk of abdominal obesity and type 2 diabetes in adolescents is still unclear. Lee and others from the University of Pittsburgh School of Medicine in the United States explored the effects of aerobic exercise (AE) and resistance exercise (RE) on abdominal fat, ectopic fat deposition, insulin sensitivity and insulin secretion in adolescents without caloric intake restriction. The study included obese [body mass index (BMI) ≥95th percentile] adolescents recruited from November 2007 to October 2011 at the University of Pittsburgh Medical Center Children's Hospital. The inclusion criteria included: 12-18 years old, no exercise (did not participate in systematic physical exercise except school physical education class in the past 3 months). Those who participated in systemic physical exercise in the past 3 months and those with obvious changes in body weight (BMI change>2~3 kg/m²), endocrine disorders, patients with pathological obesity (such as Prader-Willi syndrome), patients with mental illness, and those who take drugs that may affect glucose metabolism and body composition for a long time.

Exercise is one of the cornerstones of diabetes treatment, and it is also an important means of non-drug treatment of cardiovascular diseases and other metabolic diseases. However, the mechanism of exercise improving human metabolism has been unclear. Peroxisome proliferator-activated receptor gamma coactivator 1 α (PGC-1 α) is a class of transcriptional coactivators that can mediate energy metabolism. Exercise can induce the expression of PGC-1 α in muscle tissue, which in turn can promote fat burning and help to prevent and improve muscle atrophy. Interestingly, although the expression of PGC-1 α in muscle tissue of certain mice is increased by transgenic technology, if mice are lazy, high-fat diet can still increase their insulin resistance, which may be related to the glucose metabolism rate and muscle tissue. Impaired glucose uptake is related.

Skeletal muscle fat accumulation and decreased mitochondrial oxidative capacity are associated with insulin resistance. Athletes with high training intensity are highly sensitive to insulin and have stronger mitochondrial oxidative capacity despite higher levels of lipids in their muscle cells. Phielix et al. from Maastricht University Medical Center in the Netherlands explored whether high oxidative capacity can reduce insulin resistance caused by lipids.

Childhood obesity and overweight are prevalent among children in the United States. One-third of elementary school-age children are overweight or obese, and childhood obesity is closely related to several adverse conditions that were previously thought to occur only in adults, including type 2 diabetes. The latest results of the recently published China Health and Nutrition Survey (CHNS) also show that 11% of children ≥7 years old in China are overweight; About 42% of obese children are associated with at least one cardiometabolic risk factor; Among them, prediabetes and diabetic children have reached 27.7 million and 1.7 million respectively.