Central (visceral) obesity is more closely associated with insulin resistance, type 2 diabetes, and cardiovascular disease than is peripheral [subcutaneous (sc)] obesity, but the underlying mechanism for this pathophysiological difference is largely unknown. To understand the molecular basis of this difference, we sequenced 10,437 expressed sequence tags (ESTs) from a human omental fat cDNA library and discovered a novel visceral fat depot-specific secretory protein, which we have named omentin. Omentin ESTs were more abundant than many known adipose genes, such as perilipin, adiponectin, and leptin in the cDNA library. Protein sequence analysis indicated that omentin mRNA encodes a peptide of 313 amino acids, containing a secretory signal sequence and a fibrinogen-related domain. Northern analysis demonstrated that omentin mRNA was predominantly expressed in visceral adipose tissue and was barely detectable in sc fat depots in humans and rhesus monkeys. Quantative real-time PCR showed that omentin mRNA was expressed in stromal vascular cells, but not fat cells, isolated from omental adipose tissue, with >150-fold less in sc cell fractions. Accordingly, omentin protein was secreted into the culture medium of omental, but not sc, fat explants. Omentin was detectable in human serum by Western blot analysis. Addition of recombinant omentin in vitro did not affect basal but enhanced insulin-stimulated glucose uptake in both sc (47%, n = 9, P = 0.003) and omental (∼30%, n = 3, P < 0.05) human adipocytes. Omentin increased Akt phosphorylation in the absence and presence of insulin. In conclusion, omentin is a new adipokine that is expressed in omental adipose tissue in humans and may regulate insulin action.

Central obesity and the accumulation of visceral fat are risk factors for the development of type 2 diabetes and cardiovascular disease. Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in human adipocytes. To determine the impact of obesity-dependent insulin resistance on the regulation of two omentin isoforms, gene expression and plasma levels were measured in lean, overweight, and obese subjects. Omentin 1 was shown to be the major circulating isoform in human plasma. Lean subjects had significantly higher plasma omentin 1 levels than obese and overweight subjects. In addition, higher plasma omentin 1 levels were detected in women compared with men. Plasma omentin 1 levels were inversely correlated with BMI, waist circumference, leptin levels, and insulin resistance as measured by homeostasis model assessment and positively correlated with adiponectin and HDL levels. Both omentin 1 and omentin 2 gene expression were decreased with obesity and were highly correlated with each other in visceral adipose tissue. In summary, decreased omentin levels are associated with increasing obesity and insulin resistance. Therefore, omentin levels may be predictive of the metabolic consequences or co-morbidities associated with obesity.

Apolipoprotein C-III (apoC-III) inhibits triglyceride hydrolysis and has been implicated in coronary artery disease. Through a genome-wide association study, we have found that about 5% of the Lancaster Amish are heterozygous carriers of a null mutation (R19X) in the gene encoding apoC-III (APOC3) and, as a result, express half the amount of apoC-III present in noncarriers. Mutation carriers compared to noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL-cholesterol and lower levels of LDL-cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, suggesting that lifelong deficiency of apoC-III has a cardioprotective effect.Elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are important contributors to premature coronary heart disease (CHD) (1-3), and genetic variants causing low LDL-C are associated with reduced risk of CHD (4). Recently, nonfasting TG was found to be an independent CHD risk factor (5,6), in one study showing higher predictive power than fasting TG (FTG), the traditional measure, likely because of the atherogenic remnant lipoproteins generated during absorption and clearance of dietary fat (5).To identify genetic factors contributing to FTG and post-prandial TG (ppTG) dietary response, we performed a single high fat feeding intervention and genome-wide association study (GWAS) in 809 Old Order Amish individuals as part of the Heredity and Phenotype Intervention (HAPI) Heart Study (7). Characteristics of these participants are shown in Table S1. These individuals were fed a milkshake containing 782 kcal/m 2 body surface area with 77.6% of these calories from fat and had blood drawn for lipid levels 0, 1, 2, 3, 4 and 6 hours after the intervention. The Affymetrix GeneChip® Human Mapping 500K Array Set was used for genotyping leukocyte DNA from these 809 participants. Traits were normalized and * This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/cgi/content/full/322/5908/1702. Their manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. analyses accounting for sex and sex-specific age and age 2 , body mass index (BMI) and relatedness among participants were performed as described in the Methods (8).Results of the GWAS of FTG and ppTG (as estimated by the incremental area under the curve, iAUCTG (8)), transformed by their natural logarithm (ln), are shown in Table S2 and Figure S1. The strongest evidence for association with both ln-FTG (p = 3.8 × 10 −14 ) and ln-iAUCTG (p = 2.8 × 10 −10 ) occurred on chromosome 11q23 at single nucleotide polymorphism (SNP) rs10892151, which had a minor allele frequency (MAF) of 0.028 (A allele; Table S2). SNP rs10892151 is located within an intron of th...