OBJECTIVE-Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans. RESEARCH DESIGN AND METHODS-A newly developedimmunoassay was used to measure serum FGF21 levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF21 in the liver and adipose tissues were quantified by real-time PCR.RESULTS-Serum FGF21 levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF21 correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF21 and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF21 was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations in humans.CONCLUSIONS-FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF21, warrants further investigation.

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

Background: Lipocalin-2, a 25-kDa secreted glycoprotein, is a useful biomarker for early detection of various renal injuries. Because lipocalin-2 is abundantly expressed in adipose tissue and liver, we investigated its relevance to obesity-related pathologies. Methods: We used real-time PCR and in-house immunoassays to quantify the mRNA and serum concentrations of lipocalin-2 in C57BL/KsJ db/db obese mice and their age-and sex-matched lean littermates. We analyzed the association between serum lipocalin-2 concentrations and various metabolic and inflammatory variables in 229 persons (121 men and 108 women) recruited from a previous cross-sectional study, and we evaluated the effect of the insulin-sensitizing drug rosiglitazone on serum lipocalin-2 concentrations in 32 diabetic patients (21 men and 11 women). Results: Compared with the lean littermates, lipocalin-2 mRNA expression in adipose tissue and liver and its circulating concentrations were significantly increased in db/db diabetic/obese mice (P <0.001). These changes were normalized after rosiglitazone treatment. In humans, circulating lipocalin-2 concentrations were positively correlated (P <0.005) with adiposity, hypertriglyceridemia, hyperglycemia, and the insulin resistance index, but negatively correlated (P ‫؍‬ 0.002) with HDL cholesterol. There was also a strong positive association

Background-Adipocyte-fatty acid binding protein (A-FABP), a major cytoplasmic protein in adipocytes, plays a central role in the development of diabetes and atherosclerotic cardiovascular disease in experimental animals. We have previously shown that A-FABP is present in the bloodstream and that its circulating levels correlate with metabolic risk factors in a cross-sectional study. In the present study, we further evaluated the prospective association of A-FABP with the metabolic syndrome (MetS) as defined by the updated National Cholesterol Education Program criteria. Methods and Results-In the present study, 495 nondiabetic adults from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study were prospectively followed up for 5 years. The relationship of serum A-FABP with the MetS and its components was investigated. At baseline, high A-FABP levels were associated with the MetS (odds ratio, 4.0; 95% CI, 1.5 to 10.4; highest versus lowest sex-specific tertile, adjusted for age, body mass index, the homeostasis model assessment index for insulin resistance, C-reactive protein, and adiponectin, Pϭ0.005). On long-term follow-up, subjects with higher baseline A-FABP levels had progressively worse cardiometabolic risk profile and increasing risk of the MetS. Among 376 subjects without the MetS at baseline, 50 had developed it at 5 years. Apart from the homeostasis model assessment index for insulin resistance (Pϭ0.001), baseline A-FABP was the only independent predictor of the development of the MetS during the 5-year follow-up (odds ratio, 4.7; 95% CI, 1.8 to 11.9; highest versus lowest sex-specific tertile, Pϭ0.001, adjusted for the homeostasis model assessment index for insulin resistance and body mass index). A-FABP was predictive of the MetS even after adjustment for each of its individual components. Conclusions-Circulating A-FABP predicts the development of the MetS independently of adiposity and insulin resistance.

Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db͞db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.adipokine ͉ diabetes ͉ fatty liver ͉ metabolism A dipose tissue is now recognized to be an important endocrine organ that secretes a variety of bioactive peptides, known as adipokines (or adipocytokines). Growing evidence suggests that adipokines are critically involved in regulating energy metabolism, systemic insulin sensitivity, cardiovascular tone, and immune response (1, 2). Several adipokines, such as TNF-␣, resistin, and IL6, play causative roles in the pathogenesis of insulin resistance, type 2 diabetes, and thrombotic diseases (1). On the other hand, leptin and adiponectin possess many beneficial functions on energy metabolism and insulin sensitivity. Leptin has long been viewed as an antiobesity hormone (3), whereas adiponectin is an insulin-sensitizing adipokine with direct antidiabetic, antiatherogenic, and antiinflammatory functions (4).Angiopoietin-like protein 4 (ANGPTL4), also known as peroxisome proliferator-activated receptor ␥ (PPAR␥) angiopoietinrelated protein, fasting-induced adipose factor, or hepatic fibrinogen͞angiopoietin-r elated protein, is a recently identified adipokine that is predominantly expressed in adipose tissue and liver (5-7). Mouse ANGPTL4 is composed of an NH 2 -terminal coiled-coil domain and a carboxyl fibronectin-like motif, a structural organization conserved in both angiopoietins and angiopoietin-like proteins (5). ANGPTL4 was originally identified as the target gene of PPAR (5, 6). The agonists of both PPAR␥ and PPAR␣ could enhance ANGPTL4 express...

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OBJECTIVE -Adipocyte fatty acid-binding protein (A-FABP) is abundantly expressed in adipocytes and plays a role in glucose homeostasis in experimental animals. We have previously shown that circulating A-FABP levels are associated with the metabolic syndrome, which confers an increased risk of type 2 diabetes. Here we investigated whether serum A-FABP levels could predict the development of diabetes in a 10-year prospective study. RESEARCH DESIGN AND METHODS-Baseline serum A-FABP levels were measured with an enzyme-linked immunosorbent assay in 544 nondiabetic subjects, recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort, who were followed prospectively to assess the development of type 2 diabetes. The role of A-FABP in predicting the development of type 2 diabetes over 10 years was investigated using Cox regression analysis.RESULTS -At baseline, serum sex-adjusted A-FABP levels were higher in subjects with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) (P Ͻ 0.00001 versus normal glucose tolerance) and correlated positively with adverse cardiometabolic risk factors. Over 10 years, 96 subjects had developed type 2 diabetes. High baseline A-FABP was predictive of type 2 diabetes, independent of obesity, insulin resistance, or glycemic indexes (relative risk [RR] 2.25 [95% CI 1.40 -3.65]; P ϭ 0.001; above versus below sex-specific median). High A-FABP levels remained an independent predictor of type 2 diabetes in the high-risk IGT/IFG subgroup (adjusted RR 1.87 [1.12-3.15]; P ϭ 0.018).CONCLUSIONS -Serum A-FABP was associated with glucose dysregulation and predicted the development of type 2 diabetes in a Chinese cohort. Diabetes Care 30:2667-2672, 2007A dipocyte fatty acid-binding protein (A-FABP), also known as aP2 or FABP4, is one of the most abundant proteins in mature adipocytes (1). It belongs to a family of fatty acid-binding proteins, which are small cytoplasmic proteins expressed in a highly tissuespecific manner, thought to be important in mediating intracellular fatty acid trafficking and energy metabolism (2,3). Recent studies in animal models suggested that A-FABP may be important in glucose homeostasis. Deletion of the A-FABP gene protected mice from insulin resistance and hyperinsulinemia associated with both diet-induced obesity (4) and genetic obesity (5). In humans, a promoter polymorphism, T-87C, of the A-FABP gene that resulted in reduced adipose tissue A-FAPB mRNA expression was found to be associated with reduced risk for type 2 diabetes and cardiovascular disease (6).We have previously demonstrated that A-FABP, although traditionally considered to be an intracellular cytosolic protein, is present in the circulation (7). We have also reported the positive association between serum A-FABP levels and parameters of adiposity, hyperglycemia, insulin resistance, and the metabolic syndrome in cross-sectional (7,8) and longitudinal studies (9). As the metabolic syndrome is known to confer a more than threefold risk of development of type 2 diabetes (10),...

Abstract-Low circulating levels of adiponectin, an adipokine with insulin-sensitizing, antiatherogenic, and antiinflammatory properties, are found in hypertensive patients. Adiponectin replenishment ameliorated hypertension in adiponectin-deficient mice or obese, hypertensive mice with hypoadiponectinemia, suggesting an etiologic role of adiponectin in hypertension. We aimed to determine, in this 5-year prospective study, whether hypoadiponectinemia could predict the development of hypertension in a nondiabetic Chinese cohort. A total of 577 subjects (249 men and 328 women) were recruited from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study and prospectively followed up for 5 years. The relationship of serum adiponectin with the development of hypertension (sitting blood pressure Ն140/90 mm Hg) was investigated in a nested case-control study consisting of 70 subjects who had developed hypertension on follow-up and 140 age-and sex-matched control subjects who were normotensive both at baseline and at year 5. At baseline, serum adiponectin level in the lowest sex-specific tertile was more likely to be associated with hypertension (Pϭ0.003 versus the highest tertile, after adjusting for age, body mass index, fasting insulin, and high-sensitivity C-reactive protein). At year 5, baseline serum adiponectin was a significant independent predictor of incident hypertension in the nested case-control study (Pϭ0.015; age adjusted), together with mean arterial pressure (PϽ0.001), high-sensitivity C-reactive protein (Pϭ0.018), and body mass index (Pϭ0.004). Normotensive subjects with baseline serum adiponectin levels in the lowest sex-specific tertile had an increased risk of becoming hypertensive (adjusted odds ratio: 2.76; 95% CIs: 1.06 to 7.16; Pϭ0.037 versus highest tertile). Our data suggest that hypoadiponectinaemia may be involved in the pathogenesis of hypertension in humans.