Soluble protein hormones are key regulators of a number of metabolic processes, including food intake and insulin sensitivity. We have used a signal sequence trap to identify genes that encode secreted or membrane-bound proteins in Psammomys obesus, an animal model of obesity and type 2 diabetes (T2D). Using this signal sequence trap, we identified the chemokine chemerin as being a novel adipokine. Gene expression of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), was significantly higher in adipose tissue of obese and type 2 diabetic P. obesus compared with lean, normoglycemic P. obesus. Fractionation of P. obesus adipose tissue confirmed that chemerin was predominantly expressed in adipocytes, whereas CMKLR1 was expressed in both adipocytes and stromal-vascular cells of adipose tissue. In 3T3-L1 adipocytes, chemerin was markedly induced during differentiation, whereas CMKLR1 was down-regulated during differentiation. Serum chemerin levels were measured by ELISA in human plasma samples from 114 subjects with T2D and 142 normal glucose tolerant controls. Plasma chemerin levels were not significantly different between subjects with T2D and normal controls. However, in normal glucose tolerant subjects, plasma chemerin levels were significantly associated with body mass index, circulating triglycerides, and blood pressure. Here we report, for the first time, that chemerin is an adipokine, and circulating levels of chemerin are associated with several key aspects of metabolic syndrome.

Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.

Originally, leptin was described as a product of adipocytes that acts on the hypothalamus to regulate appetite. However, subsequently, it has been shown that leptin receptors are distributed widely and that leptin has diverse functions, including promotion of hemopoietic and osteoblastic differentiation. It has been recognized for some time that both serum leptin and bone mass are correlated positively to body fat mass and, recently, we have shown a direct positive relationship between serum leptin and bone mass in nonobese women. We now report that leptin inhibits osteoclast generation in cultures of human peripheral blood mononuclear cells

The effects of a single bout of exercise and exercise training on the expression of genes necessary for the transport and beta-oxidation of fatty acids (FA), together with the gene expression of transcription factors implicated in the regulation of FA homeostasis were investigated. Seven human subjects (3 male, 4 female, 28.9 +/- 3.1 yr of age, range 20-42 yr, body mass index 22.6 kg/m(2), range 17-26 kg/m(2)) underwent a 9-day exercise training program of 60 min cycling per day at 63% peak oxygen uptake (VO(2 peak); 104 +/- 14 W). On days 1 and 9 of the program, muscle biopsies were sampled from the vastus lateralis muscle at rest, at the completion of exercise, and again 3 h postexercise. Gene expression of key components of FA transport [FA translocase (FAT/CD36), plasma membrane-associated FA-binding protein], beta-oxidation [carntine palmitoyltransferase(CPT) I, beta-hydroxyacyl-CoA dehydrogenase] and transcriptional control [peroxisome proliferator-activated receptor (PPAR)alpha, PPAR gamma, PPAR gamma coactivator 1, sterol regulatory element-binding protein-1c] were unaltered by exercise when measured at the completion and at 3 h postexercise. Training increased total lipid oxidation by 24% (P < 0.05) for the 1-h cycling bout. This increased capacity for lipid oxidation was accompanied by an increased expression of FAT/CD36 and CPT I mRNA. Similarly, FAT/CD36 protein abundance was also upregulated by exercise training. We conclude that enhanced fat oxidation after exercise training is most closely associated with the genes involved in regulating FA uptake across the plasma membrane (FAT/CD36) and across the mitochondrial membrane (CPT I).

The acute (single bout of exercise) and chronic (exercise training) effects of exercise on plasma leptin were investigated in 97 sedentary adult men (n = 51) and women (n = 46) participating in the HERITAGE Family Study. Exercise training consisted of a standardized 20-wk endurance training program performed in the laboratory on a computer-controlled cycle ergometer. Maximal oxygen uptake, body composition assessed by hydrostatic weighing, and fasting insulin level were also measured before and after training. Pre- and posttraining blood samples were obtained before and after completion of a maximal exercise test on the cycle ergometer. Exercise training resulted in significant changes in maximal oxygen uptake (increase in both genders) and body composition (reduction of fat mass in men and increase in fat-free mass in women). There were considerable interindividual differences in the leptin response to acute and chronic effects of exercise, some individuals showing either increase or reduction in leptin, others showing almost no change. On average, leptin levels were not acutely affected by exercise. After endurance training was completed, leptin levels decreased significantly in men (from 4.6 to 3.9 ng/ml; P = 0.004) but not in women. However, after the training-induced changes in body fat mass were accounted for, the effects of exercise training were no longer significant. Most of the variation observed in leptin levels after acute exercise or endurance training appears to be within the confidence intervals of the leptin assay. We conclude that there are no meaningful acute or chronic effects of exercise, independent of the amount of body fat, on leptin levels in humans.