Perinephric and Epididymal Fat Affect Hepatic Metabolism in Rats (original) (raw)
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Differential effects of high-carbohydrate and high-fat diets on hepatic lipogenesis in rats
European Journal of Nutrition, 2013
Purpose Hepatic fatty acid synthesis is influenced by several nutritional and hormonal factors. In this study, we have investigated the effects of distinct experimental diets enriched in carbohydrate or in fat on hepatic lipogenesis. Methods Male Wistar rats were divided into four groups and fed distinct experimental diets enriched in carbohydrates (70 % w/w) or in fat (20 and 35 % w/w). Activity and expression of the mitochondrial citrate carrier and of the cytosolic enzymes acetyl-CoA carboxylase and fatty acid synthetase were analyzed through the study with assessments at 0, 1, 2, 4, and 6 weeks. Liver lipids and plasma levels of lipids, glucose, and insulin were assayed in parallel. Results Whereas the high-carbohydrate diet moderately stimulated hepatic lipogenesis, a strong inhibition of this anabolic pathway was found in animals fed high-fat diets. This inhibition was time-dependent and concentrationdependent. Moreover, whereas the high-carbohydrate diet induced an increase in plasma triglycerides, the high-fat diets determined an accumulation of triglycerides in liver. An increase in the plasmatic levels of glucose and insulin was observed in all cases. Conclusions The excess of sucrose in the diet is converted into fat that is distributed by bloodstream in the organism in the form of circulating triglycerides. On the other hand, a high amount of dietary fat caused a strong inhibition of lipogenesis and a concomitant increase in the level of hepatic lipids, thereby highlighting, in these conditions, the role of liver as a reservoir of exogenous fat.
Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease
Gastroenterology, 2007
Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease.
Hepatology, 2011
Pyruvate dehydrogenase plays a critical role in the regulation of hepatic glucose and fatty acid oxidation, however surprisingly little is known about its regulation in vivo. In this study we examined the individual effects of insulin and substrate availability on the regulation of pyruvate dehydrogenase flux (V PDH ) to tricarboxylic acid flux (V TCA ) in livers of awake rats with lipidinduced hepatic insulin resistance. V PDH /V TCA flux was estimated from the [4-13 C]glutamate/ [3-13 C]alanine enrichments in liver extracts and assessed under conditions of fasting and during a hyperinsulinemic-euglycemic clamp, while the effects of increased plasma glucose concentration on V PDH /V TCA flux was assessed during a hyperinsulinemic-hyperglycemic clamp. The effect of an acute increase of plasma fatty acid concentration on V PDH /V TCA was determined by infusing Liposyn II during a hyperinsulinemic-euglycemic clamp. The effects of chronic lipid-induced hepatic insulin resistance on this flux were also examined by performing these measurements in rats fed a high-fat diet for three weeks. Using this approach we found that fasting V PDH /V TCA was reduced by 95% in rats with hepatic insulin resistance (from 17.2±1.5% to 1.3±0.7%, P<0.00001). Surprisingly neither hyperinsulinemia per se or hyperglycemia per se were sufficient to increase V PDH /V TCA flux. Only under conditions of combined hyperglycemia and hyperinsulinemia did V PDH /V TCA flux increase (44.6±3.2%, P<0.0001 vs. basal) in low-fat fed animals but not in rats with chronic-lipid induced hepatic insulin resistance. In conclusion these studies demonstrate that the combination of both hyperinsulinemia and hyperglycemia are required to increase V PDH /V TCA flux in vivo and that this flux is severely diminished in rats with chronic lipid-induced hepatic insulin resistance.
Hepatic and adipose tissue lipogenic enzyme mRNA levels are suppressed by high fat diets in the rat
Journal of Lipid Research, 1990
Small changes in lipogenic enzyme activity induced by dietary fats of different composition may, over the long term, have significant impact on the development of obesity. We have investigated the effect of high fat diets (45% of calories as fat) on abundance of mRNA encoding fatty acid synthetase (FAS) and glycerophosphate dehydrogenase (GPDH) in male Sprague-Dawley rats. When caloric intake was equal, the relative amount of hepatic FAS mRNA was greater in rats fed a saturated compared to a polyunsaturated fat diet. This difference could not be attributed to diet-induced changes in plasma insulin concentration. However, both fat diets suppressed hepatic FAS mRNA. compared to a sucrose diet. Close correlation between FAS specific activity and the relative amount of mRNA suggested that regulation was mainly at a pre-translational level. Adipose tissue FAS mRNA was suppressed by the two fat diets equally while G P D H mRNA was unaffected by dietary composition. Retroperitoneal fat pads were significantly larger in rats fed saturated compared to those fed polyunsaturated fat for 26 weeks. We concluded that dietary saturated fats fail to suppress hepatic de novo lipogenesis as effectively as polyunsaturated fats, which may have implications for the prevention of obesity in humans.-Shillabeer, G., J.
World Journal of Gastroenterology, 2007
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver-related morbidity and mortality. It can develop secondary to numerous causes but a great majority of NAFLD cases occur in patients who are obese or present with other components of metabolic syndrome (hypertension, dyslipidemia, diabetes). This is called primary NAFLD and insulin resistance plays a key role in its pathogenesis. Obesity is characterized by expanded adipose tissue, which is under a state of chronic inflammation. This disturbs the normal storage and endocrine functions of adipose tissue. In obesity, the secretome (adipokines, cytokines, free fatty acids and other lipid moieties) of fatty tissue is amplified, which through its autocrine, paracrine actions in fat tissue and systemic effects especially in the liver leads to an altered metabolic state with insulin resistance (IR). IR leads to hyperglycemia and reactive hyperinsulinemia, which stimulates lipid-accumulating processes and impairs hepatic lipid metabolism. IR enhances free fatty acid delivery to liver from the adipose tissue storage due to uninhibited lipolysis. These changes result in hepatic abnormal fat accumulation, which may initiate the hepatic IR and further aggravate the altered metabolic state of whole body. Hepatic steatosis can also be explained by the fact that there is enhanced dietary fat delivery and physical inactivity. IR and NAFLD are also seen in various lipodystrophic states in contrary to popular belief that these problems only occur due to excessive adiposity in obesity. Hence, altered physiology of adipose tissue is central to development of IR, metabolic syndrome and NAFLD.
Surgical removal of visceral fat reverses hepatic insulin resistance
Diabetes, 1999
We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt ~400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads ( V F -; n = 9) or a sham operation (VF + ; n = 11). Three weeks later, total VF was fourfold increased (8.5 ± 1.2 vs. 2.1 ± 0.3 g, P < 0.001) in the VF + compared with the V Fgroup, but whole-body fat mass (determined using 3 H 2 O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VFcompared with VF + rats (0.57 ± 0.02 vs. 1.22 ± 0.19 mU · kg -1 · min -1 , P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF + group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in V Fbut not V F + rats. The improvement in hepatic insulin sensitivity in V Fr a t s was also supported by a ~70% decrease in the plasma levels of insulin-like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver.
2010
Rats were trained to eat a fat-free high carbohydrate diet from 800 to 1100 hours each day. After adaptation to meal-eating, the fatfree diet was supplemented with 8% methyl stéarate(Ci8;o) or 3% methyl linoleate (Ci8:2) for 7 days. Relative to the fat-free group, hepatic utiliza tion of acetate unit equivalents (C2 units) for fatty acid synthesis per mg soluble protein by the Ci8:o group was not significantly altered, whereas Ci8:2 supplementation significantly depressed hepatic fatty acid synthesis. Supplemental Ci8:2 also caused a significant decline in liver fatty acid synthetase and acetyl CoA carboxylase while fat-free and Ci8:o groups dis played similar enzyme activities. Within a treatment, C2 unit utilization tor in vivo fatty acid synthesis was identical to that of acetyl CoA car boxylase and fatty acid synthetase activities in vitro. Therefore, shortly after a meal, the hepatic activities of these two enzymes appear to be functioning at near capacity. Ci8:2 supplementation to the fat-free diet for 7 days caused a 25% decline in glucokinase and pyruvate kinase activ ities, but only pyruvate kinase was significantly depressed. In contrast, citrate cleavage enzyme and fatty acid synthetase were both significantly reduced in activity by 50%. Plasma unesterified fatty acid levels in rats fed Ci8:2 for 5 days were not significantly elevated prior to a meal, al though dietary Ci8:2 did cause a fourfold rise in plasma free linoleate. Quantitation of long chain acyl CoA esters in freeze-clamped liver tissue of rats fed fat-free or fat-free plus 3% Ci8:2 or Ci8:3 diets revealed no con centration differences between treatments either before or after a meal. Similarly, lactate and pyruvate concentrations as well as the lactate: pyru vate ratios were not significantly changed by dietary Ci8:2 or Ci8:3. The inhibitory effects of C18:2 or Ci8;3 appear not to be mediated through changes in total plasma free fatty acid levels, in total hepatic long chain acyl CoA concentration or in hepatic cytosolic redox state.