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Background/objectives:Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects.Subjects/methods:Hemopexin (HPX) was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both the reproductive fat pads and livers of mice representing three strains, LG/J (n=25), SM/J (n=27) and C57Bl/6J (n=19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n=18) and of metabolically normal (n=24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n=18).Results:HPX expression in mouse adipose tissue, but not in liver, was regulated by dietary fat regardless of genetic background. HPX increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of HPX based on metabolic disease status (P<0.05), and circulating HPX levels were correlated with serum triglycerides in these subjects (r=0.33; P=0.03). HPX was also found in an unbiased proteomic screen of human atherosclerotic plaques and shown to display differential abundance based on the extent of disease and triglyceride content (P<0.05).Conclusions:Our findings suggest that HPX is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

Excess upper-body (android) fat is considered an health hazard. Exercise training is known to have the potential to modify body composition and to induce a preferential loss of abdominal fat. We studied and compared the composition of whole body and major body regions using dual-energy X-ray absorptiometry (DEXA) in 21 exercising (3–4 hours of intense physical activity/day) and 21 sedentary eumen-orrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio (WHR) and age of menar-che. In a small number of women in each group (6 out of 21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol excretion was evaluated. Exercising women had 10% higher total and leg lean mass (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women. Furthermore, the proportion of android fat was 22% lower in exercising than sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was unchanged. BMI and WHR were not different between the two groups, while the android/gynoid fat ratios were 16% lower in exercising than in sedentary women (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in the sedentary women studied. In these subjects, a direct relationship between the peak ? percentage increases of ACTH and cortisol after the CRH test and the proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02, respectively). These results demonstrate that in women who practise intense exercise there are significant differences in body fat distribution in comparison to sedentary women, with a marked less amount of android fat, and suggest that this difference may be related to a reduced response of the pituitary-adrenal axis to CRH.