The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance

Flavin-containing monooxygenases (FMOs) of mammals are thought to be involved exclusively in the metabolism of foreign chemicals. Here, we report the unexpected finding that mice lacking Fmos 1, 2 and 4 exhibit a lean phenotype and, despite similar food intake, weigh less and store less triglyceride in white adipose tissue (WAT) than wild-type mice. This is a consequence of enhanced whole-body energy expenditure, due mostly to increased resting energy expenditure (REE). This is fuelled, in part, by increased fatty acid β-oxidation in skeletal muscle, which would contribute to depletion of lipid stores in WAT. The enhanced energy expenditure is attributed, in part, to an increased capacity for exercise. There is no evidence that the enhanced REE is due to increased adaptive thermogenesis; instead, our results are consistent with the operation in WAT of a futile energy cycle. In contrast to FMO2 and FMO4, FMO1 is highly expressed in metabolic tissues, including liver, kidney, WAT and BAT. This and other evidence implicates FMO1 as underlying the phenotype. The identification of a novel, previously unsuspected, role for FMO1 as a regulator of energy homeostasis establishes, for the first time, a role for a mammalian FMO in endogenous metabolism. Thus, FMO1 can no longer be considered to function exclusively as a xenobiotic-metabolizing enzyme. Consequently, chronic administration of drugs that are substrates for FMO1 would be expected to affect energy homeostasis, via competition for endogenous substrates, and, thus, have important implications for the general health of patients and their response to drug therapy.     

Elevated lipoprotein (a) levels are associated with the presence and severity of coronary artery disease in patients with type 2 diabetes mellitus

Background and aims

The role of lipoprotein (a) [Lp(a)] in coronary artery diseases (CAD) with special clinical background such as type 2 diabetes mellitus (T2DM) has not been fully determined. The aim of the present study was to investigate the relation of Lp(a) to type 2 diabetic patients with or without CAD.

Influence of the Mediterranean diet on carotid intima–media thickness in hypercholesterolaemic children: A 12-month intervention study

Background and aimsThe Mediterranean diet has been recognised as having a protective role on the cardiovascular system due to its low lipid and high antioxidant content. Lipid profile and oxidant status represent two important risk factors related to endothelial dysfunction, even at early stages of cardiovascular diseases. The aim of the study was to evaluate the influence of a 12-month Mediterranean diet on the variation of lipid profile and carotid intima–media thickness (cIMT) in pre-pubertal hypercholesterolaemic children.Methods and resultsWe performed a cross-sectional study comparing lipid profile and cIMT in a group of 68 pre-pubertal children (36 with hypercholesterolaemia and 32 controls). In addition, in the hypercholesterolaemic children a 12-month intervention programme with a Mediterranean diet was started to evaluate the variation of lipid profile and cIMT. At baseline, hypercholesterolaemic children showed a significantly higher cIMT (both right and left carotid artery) compared to controls (both p < 0.05). After 12 months of diet intervention, a significant reduction of total cholesterol, LDL-cholesterol and cIMT was documented (all p < 0.05). Furthermore, at the end of follow-up, delta body mass index-Standard Deviation score and delta LDL-cholesterol were significantly and independently related to the changes of cIMT (both p < 0.05).ConclusionThe Mediterranean diet represents a valid approach in the treatment of hypercholesterolaemia even during childhood.     

Inflammatory status modulates plasma lipid and inflammatory marker responses to kiwifruit consumption in hypercholesterolaemic men

Background and aimsKiwifruit has the potential to improve markers of metabolic dysfunction, but the response may be influenced by inflammatory state. We aimed to investigate whether inflammatory state would modulate the effect of consuming two green kiwifruit daily on plasma lipids and markers of inflammation.Methods and resultsEighty-five hypercholesterolaemic men completed a 4-week healthy diet run-in, before randomisation to a controlled cross-over study of two 4-week interventions of two green kiwifruit/day plus healthy diet (intervention) or healthy diet alone (control). Anthropometric measures and fasting blood samples (plasma lipids, serum apolipoproteins A1 and B, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6, tumour necrosis factor-alpha (TNF-α) and IL-10) were taken at baseline, 4 and 8 weeks. Subjects were divided into low and medium inflammatory groups, using pre-intervention hs-CRP concentrations (hs-CRP <1 and 1–3 mg/L, respectively).In the medium inflammatory group the kiwifruit intervention resulted in significant improvements in plasma high-density lipoprotein cholesterol (HDL-C) (mean difference 0.08 [95% CI: 0.03, 0.12] mmol/L [P < 0.001]), total cholesterol (TC)/HDL-C ratio (−0.29 [−0.45, −0.14] mmol/L [P = 0.001]), plasma hs-CRP (−22.1 [−33.6, −4.97]% [P = 0.01]) and IL-6 (−43.7 [−63.0, −14.1]% [P = 0.01]) compared to control treatment. No effects were seen in the low inflammatory group. There were significant between inflammation group differences for TC/HDL-C (P = 0.02), triglyceride (TG)/HDL-C (P = 0.05), and plasma IL-6 (P = 0.04).ConclusionsInflammatory state modulated responses to the kiwifruit intervention by improving inflammatory markers and lipid profiles in subjects with modestly elevated CRP, suggesting this group may particularly benefit from the regular consumption of green kiwifruit.Registered 16th March 2010, Australian New Zealand Clinical Trials Registry (no. ACTRN12610000213044), www.ANZCTR.org.au.     

Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes

Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized.     

Bariatric surgery in severely obese adolescents improves major comorbidities including hyperuricemia

Objective

Serum uric acid (sUA) is believed to contribute to the pathogenesis of metabolic comorbidities like hypertension, insulin-resistance (IR) and endothelial dysfunction (EDF) in obese children. The present pilot study investigated the association between sUA concentrations and loss of body weight following laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y-gastric bypass (RYGB) in severely obese adolescents.

Materials/Methods

10 severely obese adolescents underwent either LSG (n = 5) or RYGB (n = 5). 17 normal weight, healthy, age- and gender-matched adolescents served as a normal weight peer group (NWPG). Pre- and 12 months postoperatively, sUA and relevant metabolic parameters (glucose homeostasis, transaminases, lipids) were compared.

Results

Preoperatively, sUA was significantly elevated in patients with severe obesity compared to NWPG. Twelve months after LSG and RYGB, a significant decrease in sUA, BMI, CVD risk factors, hepatic transaminases, and HOMA-IR was observed. Reduction in SDS-BMI significantly correlated with changes in sUA.

Conclusions

sUA levels and metabolic comorbidities improved following bariatric surgery in severely obese adolescents. The impact of changes in sUA on long-term clinical complications of childhood obesity deserves further study.     

Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels

The aim of the study was to explore the effects of 12 weeks daily krill oil supplementation on fasting serum triglyceride (TG) and lipoprotein particle levels in subjects whose habitual fish intake is low and who have borderline high or high fasting serum TG levels (150–499 mg/dL). We hypothesized that Krill oil lowers serum TG levels in subjects with borderline high or high fasting TG levels. To test our hypothesis 300 male and female subjects were included in a double-blind, randomized, multi-center, placebo-controlled study with five treatment groups: placebo (olive oil) or 0.5, 1, 2, or 4 g/day of krill oil. Serum lipids were measured after an overnight fast at baseline, 6 and 12 weeks. Due to a high intra-individual variability in TG levels, data from all subjects in the four krill oil groups were pooled to increase statistical power, and a general time- and dose-independent one-way analysis of variance was performed to assess efficacy. Relative to subjects in the placebo group, those administered krill oil had a statistically significant calculated reduction in serum TG levels of 10.2%. Moreover, LDL-C levels were not increased in the krill oil groups relative to the placebo group. The outcome of the pooled analysis suggests that krill oil is effective in reducing a cardiovascular risk factor. However, owing to the individual fluctuations of TG concentrations measured, a study with more individual measurements per treatment group is needed to increase the confidence of these findings.