Nutritional and insulin regulation of leptin gene expression

The leptin and lipogenic enzyme genes contain the common DNA sequences of binding sites for Sp1 proteins. These sites appear to be responsible for glucose/insulin stimulation and polyunsaturated fatty acid suppression. In rat adipose tissue leptin and lipogenic gene expression is similarly regulated by nutritional manipulation. Interestingly, leptin has the ability to down-regulate lipogenic enzyme expression.     

Translational regulation of gene expression by omega-3 fatty acids

The incidence of some cancers shows dramatic variations around the world that cannot be explained by ethnic or racial differences. Observational studies point to a negative correlation between consumption of fish and incidence of breast and prostate cancer. In vitro and animal model studies indicate that (omega-3) PUFAs present at high concentrations in marine animals inhibit proliferation of cancer cells and growth of tumors. However, how these fatty acids inhibit cell proliferation and tumor growth is a matter of considerable debate. In this review we summarize our recent work indicating that Ca(++) depletion mediated phosphorylation of the alpha subunit of eIF2 and subsequent inhibition of translation initiation account for the anti-cancer activity of (omega-3) PUFAs.     

Dietary (n-3) polyunsaturated fatty acids up-regulate plasma leptin in insulin-resistant rats

The study was designed to evaluate the chronic regulation of plasma leptin by dietary (n-3) polyunsaturated fatty acids (PUFA) in insulin-resistant, sucrose-fed rats. Male Sprague-Dawley rats were randomly assigned to consume for 3 or 6 wk a diet containing 57.5% (g/100 g) sucrose and 14% lipids as either fish oil (SF) or control oils (SC). After 3 and 6 wk of consuming the SF diet, plasma leptin was 70% (P < 0.001) and 75% (P < 0.05) greater, respectively, than in rats fed the SC diet. The same result was found when plasma leptin was adjusted by total fat mass, as measured by dual-energy X-ray absorptiometry. Despite high leptin levels, food intake of rats fed the SF diet was greater than in SC-fed rats without any difference in body weight or total fat mass. After 3 wk, accumulated leptin in epididymal and retroperitoneal adipose tissue was higher in the SF-fed rats than in the SC-fed rats. However, after 6 wk, tissue leptin in the SF-fed rats did not differ from that of the SC-fed rats. The SF diet increased adipose tissue glucose transporter-4 protein quantity and prevented the sucrose-induced elevations in plasma triglycerides and free fatty acids. When all SC- and SF-fed rats (both diets and feeding durations) were considered, plasma leptin levels were positively correlated with body weight (r = 0.5, P < 0.0001) and with total fat mass (r = 0.5, P < 0.0005). These results suggest that plasma leptin at a given time could be inappropriately high for a given fat mass in insulin-sensitive rats fed (n-3) PUFA.     

Glucose, free fatty acids, and insulin secretion

In obese and normal diabetics, acute increase in blood sugar stimulates insulin release, but prolonged periods of hyperglycemia do not. In dogs, acute increase in plasma frce fatty acids is a potent stimulus for insulin secretion.     

Involvement of plasma leptin,insulin and free tryptophan in cytokine-induced anorexia

BACKGROUND: Hypothalamic serotonin, the synthesis of which parallels plasma free tryptophan, contributes to satiety. Plasma free tryptophan, insulin and leptin, all of which can also decrease food intake partly via the hypothalamic serotonergic system, are modulated by cytokines, which decrease food intake. The mechanisms of anorexia induced by cytokines, as related to plasma tryptophan, leptin and insulin, have not been fully determined. OBJECTIVE: We determined the plasma concentrations of free as well as total tryptophan, leptin and insulin, and correlations to those of food intake and body weight change after cytokines or tryptophan injection. DESIGN: Interleukin-1alpha and/or tumor necrosis factor-alpha, or tryptophan was injected subcutaneously into male rats for 2 days. Daily food intake, body weight, carcass adiposity, plasma total as well as free tryptophan, plasma leptin and insulin were measured. RESULTS:Interleukin-1alpha injection decreased food intake, body weight, carcass adiposity and plasma leptin, but increased plasma free tryptophan and insulin. Tryptophan injection increased both free and total tryptophan, but did not change food intake, body weight, carcass adiposity or leptin. Plasma free tryptophan, but not total tryptophan, was significantly negatively correlated with food intake. There was a negative correlation between plasma insulin and food intake. CONCLUSIONS: Increased plasma free tryptophan may contribute to synthesis of brain serotonin but anorexia may be due to stimulation of its release induced by interleukin-1alpha. Plasma insulin, but not leptin, may partly contribute to anorexia of cytokines.     

毛细管气相色谱法测定人体血液中的游离脂肪酸和总脂肪酸

采用石英毛细管气相色谱法测量人体血液中的游离脂肪酸（FFA）和总脂肪酸（TFA），方法灵敏，可分离血浆中近20种脂肪酸，其中油酸（C18：1）、软脂酸（C16：0），亚油酸（C18：2）、硬脂酸（C18：0）和软脂油酸（C16：1）约占血浆中FFA总量的90％。本方法所需血量少，尤其对采血较困难的婴儿进行脂肪营养研究适用。     

Quantitative role of plasma free fatty acids in the supply of arachidonic acid to extrahepatic tissues in rats

Local desaturation-elongation of linoleic acid, uptake of 2-arachidonyl-lysophosphatidylcholine, and uptake plasma unesterified arachidonic acid (AA) are assumed to be the most important sources of AA for extrahepatic tissues. In this study, we investigated the clearance rate as well as the retention rate of plasma unesterified (14)C-AA in different tissues in fed rats. The initial half-life of (14)C-AA in rat plasma was 3.8 s, and the average pool size of rat plasma unesterified AA was 76 nmol. We calculated that 604 nmol of unesterified AA was cleared from the rat plasma per minute. The retention rate of AA per gram of tissue in the heart (13 nmol/min per g), lungs (12 nmol/min per g), kidney (8 nmol/min per g) and bone marrow (6 nmol/min per g) was higher than that in other tissues but was lower than that in liver (23 nmol/min per g). The total uptake was highest in skeletal muscle (249 +/- 27 nmol/min), in liver (226 +/- 15 nmol/min) and in bone marrow (39 +/- 3 nmol/min). More than 80% of retained (14)C-AA was found in phospholipids in most tissues. The conclusion is that despite the low concentration plasma unesterified, AA is a major source of phospholipid AA in several extrahepatic tissues in rats, due to its rapid turnover and selective acylation into phospholipids.     

Leptin and insulin modulate nutrient partitioning and weight loss in ob/ob mice through regulation of long-chain fatty acid uptake by adipocytes

Leptin treatment of ob/ob mice leads to weight loss appreciably greater than that in pair-fed mice. To test whether this "extra" weight loss is mediated by leptin-induced alterations in nutrient partitioning, the effects in ob/ob mice of subcutaneous leptin infusion (500 ng/h for 0.5 vs. normal C57BL/6J controls). Adipocyte mRNA levels for plasma membrane fatty acid binding protein and fatty acid translocase, putative fatty acid transporters that are up-regulated three- to fourfold in adipocytes from ob/ob mice, had also normalized by d 21. The initial changes in V(max) preceded decreases in food intake and body weight by at least 24 h. In pair-fed mice, insulin levels, V(max) and body weight all declined more slowly than in leptin-treated mice, and all remained significantly elevated compared with normal values at d 21. The data suggest that insulin up-regulates and leptin down-regulates adipocyte fatty acid uptake, leading to alterations in fatty acid partitioning that affect adiposity.     

Effects of capsaicin on biliary free fatty acids in rats

The effects of capsaicin, a major pungent agent of capsicum fruits, on biliary free fatty acids (FFAs) were studied in male rats. Animals were dosed 100 mg/kg capsaicin after the administration of olive oil, and the bile was obtained for 6 hours continuously after dosing with capsaicin for analysis of FFAs using HPLC methods. Capsaicin significantly decreased the total biliary FFA concentration in the animals which had been previously increased by the administration of olive oil. The main FFAs in the bile of control rats are lauric and palmitic acids, followed by linoleic, oleic, stearic and palmitoleic acids. Capsaicin alone decreased the values of these main FFAs. While lauric, palmitic, linoleic, stearic and arachidonic acids were increased significantly by the treatment with olive oil, elevation of these FFAs was inhibited by the treatment with capsaicin.     

Effect of dietary cholesterol on hepatic lipogenesis and plasma insulin and free fatty acid levels in rats.

In order to further investigate the metabolic alterations in the liver of cholesterol-fed rats, the following parameters were determined: (a) the activities of hepatic glucose-6-phosphate dehydrogenase, NADP-malate dehydrogenase, citrate cleavage enzyme, acetyl CoC carboxylase, and fatty acid synthetase; (b) the rate of hepatic fatty acids synthesis in vivo or in vitro; and (c) the concentration of immunoreactive insulin, free fatty acids, and glucose in the plasma. The experimental diets usually contained 1.5% cholesterol and 0.5% cholic acid. Cholesterol feeding resulted in a three- to fourfold decrease in the activities of hepatic glucose-6-phosphate dehydrogenase, NADP-malate dehydrogenase, and citrate cleavage enzyme and up to a two-fold decrease in the activities of acetyl CoA carboxylase and fatty acid synthetase. The rate of fatty acid synthesis was not sifnigicantly decreased when rats were fed the cholesterol-supplemented diets for only 2 to 4 weeks, despite marked decreases in the activities of the lipogenic enzymes. But when cholesterol feeding was continued for periods longer than 5 weeks, there was a significant decrease in the rate of fatty acid synthesis in the liver. Cholesterol feeding decreased the levels of circulating insulin and elevated plasma free fatty acid levels. Plasma glucose levels were not significantly changed. Cholesterol feeding can result in a wide range of metabolic alterations. These metabolic alterations may have some impact on the development of hypercholesterolemic-related metabolic disorders.     

Plasma leptin,fatty acids,and tumor necrosis factor-receptor and insulin resistance in children

OBJECTIVE: To evaluate the effect of plasma leptin, nonsterified fatty acids (NEFAs), and tumor necrosis factor-receptor 1 (TNFR1) on plasma insulin and insulin-resistance status in children. RESEARCH METHODS AND PROCEDURES: One thousand thirty-two children (521 boys and 511 girls) were included in this study. We measured plasma insulin and leptin levels by radioimmunoassay, plasma NEFA levels by enzymatic acyl-coenzyme A synthase-acyl-coenzyme A oxidase spectrophotometric methods, and TNFR1 levels by enzyme-linked immunosorbent assay. We calculated insulin resistance index (IRI) using homeostasis model assessment and calculated insulin-resistance syndrome summary score (IRS) by adding the quartile ranks from the distribution of systolic blood pressure (BP), serum triglyceride, high-density lipoprotein-cholesterol (inverse), and insulin levels. RESULTS: Overweight children had higher BP, plasma leptin, and insulin levels and higher IRI and IRS than normal-weight children. Plasma leptin and TNFR1 were positively correlated with insulin levels, IRI, and IRS. The correlation coefficients of leptin and TNFR1 in IRI were 0.53 and 0.12, respectively, for boys and 0.25 and 0.18, respectively, for girls. In multivariate regression analyses, TNFR1 was positively associated with insulin level and IRI in girls; NEFA was positively associated only with IRS. Plasma leptin levels were significantly positively associated with insulin levels, IRI, and IRS, even after adjusting for BMI and other potential confounders. DISCUSSION: Overweight children had higher BP, plasma insulin, and leptin levels and adverse insulin-resistance status than normal-weight children. Plasma leptin levels, rather than NEFA and TNFR1, may play a significant role in the development of hyperinsulinemia and insulin resistance in children.