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.     

Corn gluten hydrolysate and capsaicin have complimentary actions on body weight reduction and lipid-related genes in diet-induced obese rats

The aim of this study was to test the hypothesis that a combination of corn gluten hydrolysate (CGH) and capsaicin may have an additive or synergistic effect on body weight reduction. For 13 weeks, male Sprague-Dawley rats were provided a diet to induce obesity. Afterward, the rats were randomly divided into 5 dietary groups: the normal control (n = 5), the high-fat control (n = 8), the high-fat diet (HFD) containing 35% CGH (n = 7), the HFD containing 0.02% capsaicin (HF-P) (n = 8), and the HFD containing both CGH and capsaicin (HF-CP) (n = 7) for an additional 4 weeks. Administration of CGH plus capsaicin, along with a HFD, led to significant decreases in body weight, fat mass, lipids in the liver, and plasma leptin as well as increases in plasma adiponectin. The pattern of gene expression was different in each target organ. In the liver, up-regulation of peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1α, and acyl-coenzyme A oxidase was found in the HF-CP group. In contrast, down-regulation of peroxisome proliferator-activated receptor γ was found in both the HFD containing 35% CGH and HF-CP groups. In skeletal muscle, up-regulation of insulin receptor and uncoupling protein 3 was found in the HF-P group only, whereas up-regulation of the glucose transporter 4 gene was observed in both the HF-CP and HF-P groups. In adipose tissue, up-regulation of peroxisome proliferator-activated receptor γ and hormone-sensitive lipase was only found in the HF-CP group. In summary, this study suggests that CGH and capsaicin perform complementary actions on food intake, lipid metabolism, and insulin sensitivity by a coordinated control of energy metabolism in the liver, adipose tissue, and skeletal muscle, thus exerting an additive effect on body weight reduction.     

Comparison of gene expression profiles between white and brown adipose tissues of rat by microarray analysis

To characterize the energy metabolism in brown adipose tissue (BAT), the differences in gene expression profiles between BAT and white adipose tissue (WAT) were analyzed using a high-density cDNA microarray. RNAs isolated from two adipose tissues were hybridized to an Agilent rat cDNA Microarray that contained about 14,500 cDNA probe sets. The expression levels of 499 cDNA/ESTs were found to be at least 5-fold higher or lower in BAT than in WAT. Consistent with our previous findings, high expression levels of genes encoding uncoupling protein 1, muscle-type carnitine palmitoyltransferase and some other proteins involved in energy metabolism in BAT were found. Most of the genes encoding mitochondrial proteins, such as subunits of ATP synthase, cytochrome c oxidase, and NADH dehydrogenase, were highly expressed, reflecting possible differences in the cellular content of mitochondria between BAT and WAT. However, the expression levels of several genes encoding mitochondrial protein, such as liver mitochondrial aldehyde dehydrogenase and dicarboxylate carrier, were remarkably lower in BAT. These results may give important clues to understand the unique energy metabolism in BAT.     

Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine expression is one of the most important targets for the prevention of obesity and improvement of insulin sensitivity. In this study, we have demonstrated that anthocyanin (cyanidin 3-glucoside; C3G) which is a pigment widespread in the plant kingdom, ameliorates hyperglycemia and insulin sensitivity due to the reduction of retinol binding protein 4 (RBP4) expression in type 2 diabetic mice. KK-A(y) mice were fed control or control +0.2% of a C3G diet for 5 weeks. Dietary C3G significantly reduced blood glucose concentration and enhanced insulin sensitivity. The adiponectin and its receptors expression were not responsible for this amelioration. C3G significantly upregulated the glucose transporter 4 (Glut4) and downregulated RBP4 in the white adipose tissue, which is accompanied by downregulation of the inflammatory adipocytokines (monocyte chemoattractant protein-1 and tumor necrosis factor-alpha) in the white adipose tissue of the C3G group. These findings indicate that C3G has significant potency in an anti-diabetic effect through the regulation of Glut4-RBP4 system and the related inflammatory adipocytokines.     

脂肪组织炎症在CYP1B1基因敲除抑制小鼠营养性肥胖及其胰岛素抵抗中的作用

目的 探讨脂肪组织炎症在CYP1B1基因缺失小鼠保护营养性肥胖及其胰岛素抵抗中的作用和可能机制.方法 选择3周龄SPF级CYP1B1基因敲除(KO)和野生型(WT)雄性小鼠各16只,给予低(LFD)、高脂肪(HFD)饲料,每组8只,连续喂养11周.采用实时定量RT-PCR测定脂肪组织中巨噬细胞相关炎症因子、胰岛素通路中...     

Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression

Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor α (TNFα), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon α develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFα; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.     

Serum Irisin levels as a marker in some phenotypes of PCOS

Study objectives

The aim of the study was to assay the serum levels of Irisin in women with PCOS.

Differential inflammatory status in rats susceptible or resistant to diet-induced obesity: effects of EPA ethyl ester treatment

Background  Obesity has been associated with a chronic low degree inflammatory response, characterized by an increase of inflammatory adipocytokines like tumoral necrosis factor-α (TNF-α), interleukin-6 (IL-6) as well as the synthesis of acute phase reactants such as haptoglobin. Aim of the study  To evaluate if impairments in the inflammatory response at the white adipose tissue (WAT) level could be involved in the mechanisms conferring susceptibility or resistance to high-fat diet-induced obesity (DIO). Methods  The expression levels of WAT genes and systemic markers related to inflammation were evaluated in two groups of rats fed with a high-fat diet during 15 days that showed either an early susceptibility (DIO) or resistance (DR) to develop obesity. We also tested the efficacy of the eicosapentaenoic (EPA) ω-3 fatty acid treatment (35 days) to potentially counteract the obesity-associated inflammatory features in DIO rats. Results  This trial showed that high-fat diet induces an increase on mRNA levels on TNF-α and haptoglobin in DIO animals (P < 0.05), while no significant changes were observed on DR rats. Furthermore, a significant increase in IL-6 mRNA (P < 0.05) was found in both DR and DIO rats. EPA-treatment caused a significant decrease in IL-6 mRNA (P < 0.05), without significant changes in haptoglobin mRNA levels in adipose tissue. An unexpected decrease was observed in haptoglobin serum levels (P < 0.05) in DIO rats, which was reverted to control values in EPA-treated animals. Conclusions  Our data suggest that obesity susceptibility or resistance may depend on the genetic make up related to inflammatory features, and support a role for ω-3 fatty acids in the prevention of obesity-associated inflammation in adipose tissue. In addition, our data do not support the hypothesis that serum haptoglobin is an acute phase protein expected to be positively related to increased adiposity in rats, at least in early and medium stages of DIO.