l-Arginine supplementation regulates energy-substrate metabolism in skeletal muscle and adipose tissue of diet-induced obese rats.

Dietary supplementation with l-arginine has been reported to reduce white fat mass in diet-induced obese rats and in obese humans. This study was conducted to test the hypothesis that the arginine treatment regulates glucose and fatty acid metabolism in insulin-sensitive tissues. Male Sprague-Dawley rats (4-week-old) were fed either low- or high-fat diets for 15 weeks (n = 16/diet). Thereafter, lean or obese rats were fed their respective diets and received drinking water containing either 1.51% l-arginine-HCl or 2.55% alanine (isonitrogenous control) (n = 8/treatment group). After 12 weeks of treatment, rats were euthanized and tissue samples were collected for biochemical assays. High-fat feeding increased the size of adipocytes isolated from retroperitoneal (RP) adipose tissue, while arginine treatment reduced their size. The total number of adipocytes in the adipose tissue did not differ among the four groups of rats. Glucose oxidation in extensor digitorum longus (EDL) muscle, soleus muscle, and RP adipose tissue were reduced in response to high-fat feeding. On the contrary, oleic acid oxidation in RP adipose tissue was enhanced in rats fed the high-fat diet. Arginine treatment stimulated both glucose and oleic acid oxidation in EDL and soleus muscles, while having no effect on glucose oxidation, oleic acid oxidation, or basal lipolysis per 106 adipocytes in RP adipose tissue. Collectively, these results indicate that oral supplementation with arginine to diet-induced obese rats promoted the oxidation of energy substrates in skeletal muscle, thereby reducing white fat in the body.

Remodeling of Adipose Tissues by Fatty Acids: Mechanistic Update on Browning and Thermogenesis by n-3 Polyunsaturated Fatty Acids.

Enhancing thermogenesis by increasing the amount and activity of brown and brite adipocytes is a potential therapeutic target for obesity and its associated diseases. Diet plays important roles in energy metabolism and a myriad of dietary components including lipids are known to regulate thermogenesis through recruitment and activation of brown and brite adipocytes. Depending on types of fatty acids (FAs), the major constituent in lipids, their health benefits differ. Long-chain polyunsaturated FAs (PUFAs), especially n-3 PUFAs remodel adipose tissues in a healthier manner with reduced inflammation and enhanced thermogenesis, while saturated FAs exhibit contrasting effects. Lipid mediators derived from FAs act as autocrine/paracrine as well as endocrine factors to regulate thermogenesis. We discuss lipid mediators that may contribute to the differential effects of FAs on adipose tissue remodeling and hence, cardiometabolic diseases. We also discuss current understanding of molecular and cellular mechanisms through which n-3 PUFAs enhance thermogenesis. Elucidating molecular details of beneficial effects of n-3 PUFAs on thermogenesis is expected to provide information that can be used for development of novel therapeutics for obesity and its associated diseases.

Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice.

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (-38%, p < 0.05), visceral adipose tissue mass (-46%, p < 0.05), and visceral adipocyte size (-20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (-69%, p < 0.05) and infiltration of macrophages (-72%, p < 0.05), while concomitantly upregulating the expression of fatty acid ß-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

The herbal extract ALS-L1023 from Melissa officinalis reduces weight gain, elevated glucose levels and ß-cell loss in Otsuka Long-Evans Tokushima fatty rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Labiatae; lemon balm) is a traditional medicinal plant with hypoglycemic and hypolipidemic effects; however, how it imparts its beneficial effects remains unclear. We thus hypothesized that the herbal extract ALS-L1023, isolated from Melissa officinalis, inhibits obesity and diabetes, and tested our hypothesis using Otsuka Long-Evans Tokushima fatty (OLETF) rats, which are an established animal model of type 2 diabetes. MATERIALS AND METHODS: In this study, 28-week-old OLETF rats were fed a high-fat diet for 4 weeks to induce a marked impairment of the insulin response and were treated with or without ALS-L1023. Subsequently, the variables and determinants of glucose metabolism and pancreatic function were assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: The administration of ALS-L1023 resulted in a weight reduction without changes in food intake. It also markedly inhibited hyperglycemia and hypoinsulinemia, and restored ß-cell mass that was severely impaired in OLETF rats. There was a decrease in lipid accumulation in the liver and skeletal muscle of the obese rats after treatment with ALS-L1023. Concomitantly, there was an increase in the expression levels of fatty acid-oxidizing enzymes (AMPKα2, ACOX, MCAD, and VLCAD) in the liver and skeletal muscle after ALS-L1023 treatment. Furthermore, ALS-L1023 attenuated the pancreatic inflammation including the infiltration of CD68-positive macrophages and mast cells, in addition to attenuating the expression of inflammatory factors (IL-6 and CD68). CONCLUSIONS: These results suggest that treatment with ALS-L1023 may reduce weight gain, elevated glucose levels, and ß-cell loss, by changing the expression of fatty acid-oxidizing enzymes in the liver and skeletal muscle, including inflammatory factors in the pancreas. These findings indicate that ALS-L1023 may be an effective therapeutic strategy to treat human obesity and type 2 diabetes.

Vitamin D regulation of adipogenesis and adipose tissue functions.

Vitamin D insufficiency is associated with obesity and its related metabolic diseases. Adipose tissues store and metabolize vitamin D and expression levels of vitamin D metabolizing enzymes are known to be altered in obesity. Sequestration of vitamin D in large amount of adipose tissues and low vitamin D metabolism may contribute to the vitamin D inadequacy in obesity. Vitamin D receptor is expressed in adipose tissues and vitamin D regulates multiple aspects of adipose biology including adipogenesis as well as metabolic and endocrine function of adipose tissues that can contribute to the high risk of metabolic diseases in vitamin D insufficiency. We will review current understanding of vitamin D regulation of adipose biology focusing on vitamin D modulation of adiposity and adipose tissue functions as well as the molecular mechanisms through which vitamin D regulates adipose biology. The effects of supplementation or maintenance of vitamin D on obesity and metabolic diseases are also discussed.

Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) ß up-regulation.

AIM OF THE STUDY: Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. MATERIALS AND METHODS: For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60 min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTT assay, and gene expression by Western blot, ELISA, or qPCR. RESULTS: Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated >40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up-regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-ß expression but not ERα. However, RG treatment increased ERß expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that TNF-α plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced TNF-α and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ERß inhibited the PADI4 expression. CONCLUSION: PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ERß expression in the brain thus protecting brain cells from apoptosis.

Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.

Previous studies showed that dietary L-arginine supplementation decreased white fat mass in genetically obese rats. This study tested the effectiveness of L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of age, resulting in 18% higher body weight gains and 74% higher weights of major white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and arginine groups were individually pair-fed to alanine controls. Despite similar energy intake, absolute weights of white fat pads increased by 98% in control rats over a 12-wk period but only by 35% in arginine-supplemented rats. The arginine treatment reduced the relative weights of white fat pads by 30% and enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%, and brown fat by 34% compared with control rats. Serum concentrations of insulin, adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did not differ between control and arginine-supplemented rats. However, arginine treatment resulted in lower serum concentrations of leptin, glucose, triglycerides, urea, glutamine, and branched-chain amino acids, higher serum concentrations of nitric-oxide metabolites, and improvement in glucose tolerance. Thus, dietary arginine supplementation shifts nutrient partitioning to promote muscle over fat gain and may provide a useful treatment for improving the metabolic profile and reducing body white fat in diet-induced obese rats.