Antiobesity Effect of Eicosapentaenoic Acid in High-Fat/High-Sucrose Diet�CInduced Obesity: Importance of Hepatic Lipogenesis

OBJECTIVE

Given the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity.

RESEARCH DESIGN AND METHODS

Male C57BL/6J mice were fed a high-fat/high-sucrose diet (25.0% [w/w] fat, 32.5% [w/w] sucrose) (HF/HS group) or a high-fat diet (38.1% [w/w] fat, 8.5% [w/w] sucrose) (HF group) for 4–20 weeks. A total of 5% EPA was administered by partially substituting EPA for fat in the HF/HS + EPA and HF + EPA groups.

RESULTS

Both the HF/HS and HF groups similarly developed obesity. EPA treatment strongly suppresses body weight gain and obesity-related hyperglycemia and hyperinsulinemia in HF/HS-fed mice (HF/HS + EPA group), where hepatic triglyceride content and lipogenic enzymes are increased. There is no appreciable effect of EPA on body weight in HF-fed mice (HF + EPA group) without enhanced expression of hepatic lipogenic enzymes. Moreover, EPA is capable of reducing hepatic triglyceride secretion and changing VLDL fatty acid composition in the HF/HS group. By indirect calorimetry analysis, we also found that EPA is capable of increasing energy consumption in the HF/HS + EPA group.

CONCLUSIONS

This study is the first demonstration that the anti-obesity effect of EPA in HF/HS-induced obesity is associated with the suppression of hepatic lipogenesis and steatosis. Because the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data suggest that EPA is suited for treatment of the metabolic syndrome.The metabolic syndrome has been defined as a cluster of visceral fat obesity, impaired glucose metabolism, atherogenic dyslipidemia (high plasma triglyceride and low HDL cholesterol), and hypertension (1). There is considerable evidence that visceral fat obesity is a key etiological factor in the metabolic syndrome (2). Enhanced hepatic lipogenesis and hepatic steatosis also appear to play an important role in the pathogenesis of the metabolic syndrome (3). Indeed, nonalcoholic fatty liver disease may constitute the common features of the metabolic syndrome.Numerous epidemiological studies and clinical trials have revealed that fish oil and n-3 polyunsaturated fatty acids (PUFAs) reduce the risk of coronary heart disease (4). Eicosapentaenoic acid (EPA), one of the major n-3 PUFAs contained in fish oil, has a variety of pharmacological effects such as lipid-lowering (5), anti-platelet (6), anti-inflammatory (7), and anti-atherogenic effects (8,9). Recently, the Japan EPA Lipid Intervention Study (JELIS), a large-scale prospective randomized clinical trial, demonstrated that EPA delays the onset of cardiovascular events via cholesterol-independent mechanisms (10,11), but the molecular mechanisms remain to be elucidated. In a recent sub-analysis of the JELIS, EPA had a great risk reduction of coronary artery events of 53% in patients with high triglycerides and low HDL cholesterol (11), suggesting that EPA may be effective to reduce the incidence of atherosclerosis in the metabolic syndrome. These findings are supported by our recent observations that EPA administration results in decreases in remnant-like particle-triglyceride, small dense LDL, and C-reactive protein and an increase in adiponectin in patients with the metabolic syndrome (12,13).Given the pleiotropic effect of EPA, it is interesting to know whether highly purified EPA is capable of improving obesity. There is currently a controversy as to the anti-obesity effect of EPA; it has been effective (13,14), has been ineffective (15), or has even increased visceral fat accumulation (16). On the other hand, it is noteworthy that EPA suppresses hepatic lipogenesis and steatosis by reducing mRNA and active protein of sterol regulatory element binding protein-1c (SREBP-1c) (17–19). We, therefore, examined the impact of hepatic lipogenesis on the anti-obesity effect of highly purified EPA.Here, we demonstrate that EPA strongly suppresses body weight gain and obesity-related hyperglycemia and hyperinsulinemia in high-fat (HF)/high-sucrose (HS)-induced obese mice with enhanced hepatic lipogenesis but not in HF-induced obese mice without enhanced hepatic lipogenesis. This study is the first demonstration that the anti-obesity effect of EPA is related to the suppression of hepatic lipogenesis. Given that the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data of this study suggest that EPA is suited for the treatment of the metabolic syndrome.     

Restorative proctocolectomy with ileal reservoir

International Journal of Colorectal Disease -     

Gonadotropin-inhibitory hormone neurons interact directly with gonadotropin-releasing hormone-I and -II neurons in European starling brain

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic dodecapeptide (SIKPSAYLPLRF-NH(2)) that directly inhibits gonadotropin synthesis and release from quail pituitary. The action of GnIH is mediated by a novel G-protein coupled receptor. This gonadotropin-inhibitory system may be widespread in vertebrates, at least birds and mammals. In these higher vertebrates, histological evidence suggests contact of GnIH immunoreactive axon terminals with GnRH neurons, thus indicating direct regulation of GnRH neuronal activity by GnIH. In this study we investigated the interaction of GnIH and GnRH-I and -II neurons in European starling (Sturnus vulgaris) brain. Cloned starling GnIH precursor cDNA encoded three peptides that possess characteristic LPXRF-amide (X = L or Q) motifs at the C termini. Starling GnIH was further identified as SIKPFANLPLRF-NH(2) by mass spectrometry combined with immunoaffinity purification. GnIH neurons, identified by in situ hybridization and immunocytochemistry (ICC), were clustered in the hypothalamic paraventricular nucleus. GnIH immunoreactive fiber terminals were present in the external layer of the median eminence in addition to the preoptic area and midbrain, where GnRH-I and GnRH-II neuronal cell bodies exist, respectively. GnIH axon terminals on GnRH-I and -II neurons were shown by GnIH and GnRH double-label ICC. Furthermore, the expression of starling GnIH receptor mRNA was identified in both GnRH-I and GnRH-II neurons by in situ hybridization combined with GnRH ICC. The cellular localization of GnIH receptor has not previously been identified in any vertebrate brain. Thus, GnIH may regulate reproduction of vertebrates by directly modulating GnRH-I and GnRH-II neuronal activity, in addition to influencing the pituitary gland.     

Effects of gastric inhibitory polypeptide and glucagon on portal venous and hepatic arterial flow in conscious dogs

Gastric inhibitory polypeptide (GIP) has considerable structural homology with glucagon, which is known to increase liver blood flow. We compared the effects of GIP on portal venous and hepatic arterial flow with those of glucagon in conscious dogs. Injection of GIP significantly increased portal venous flow in a dose-related manner (by 7%, 15%, and 46% at doses of 1, 100, and 500 pmol/kg, respectively). The increase in portal venous flow induced by GIP and glucagon was comparable; however, the increase in portal venous flow after GIP injection reached its peak significantly earlier than that after glucagon injection. Hepatic arterial flow decreased after GIP injection (by 17%, 21%, and 35% at doses of 1, 100, and 500 pmol/kg, respectively), whereas it was not altered by glucagon. Thus, GIP causes significant changes in both portal venous and hepatic arterial flow in conscious dogs. Although structurally related, GIP and glucagon may influence liver blood flow through different mechanisms.Supported by a grant from the Ministry of Education, Japan (No. A-02404052)     

An application of a patient-specific cardiac simulator for the prediction of outcomes after mitral valve replacement: a pilot study

Journal of Artificial Organs - Despite advancements in preoperative prediction of patient outcomes, determination of the most appropriate surgical treatments for patients with severely impaired...     

External compression due to seroma of ventricular assist device outflow graft

Journal of Artificial Organs - A 45-year-old woman with repaired complex congenital heart disease, who underwent placement of Jarvik 2000, a ventricular assist device (VAD) for 4 years,...