Bromocriptine reduces steatosis in obese rodent models

BACKGROUND/AIMS: Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. METHODS: We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. RESULTS: Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. CONCLUSIONS: Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.     

Pharmacologic action of L-carnitine on hypertriglyceridemia in obese Zucker rats

Administration of pharmacologic amounts of L-carnitine was studied in the hypertriglyceridemic Zucker rat. When administered subcutaneously, doses from 250 to 2,000 mg/kg/d significantly decreased plasma triglycerides in obese rats over eight to 12 weeks, with no effect on plasma triglycerides in lean rats. Oral doses at the same high levels were not effective in decreasing plasma triglycerides. Triglyceride secretion rate was reduced from 367 micrograms/min to 168 micrograms/min in treated obese rats. Concurrently, liver lipid was increased twofold in obese treated rats, and the livers of these rats showed significant fatty infiltration. The mechanism of action of carnitine in decreasing plasma triglycerides appeared to be via decreased secretion of triglycerides by the liver of obese rats. There was no effect of L-carnitine in lean or obese rats on the following variables: carnitine palmitoyltransferase-A kinetics or malonyl CoA inhibition, mitochondrial or peroxisomal oxidative capacity, lipoprotein lipase in heart, muscle, and adipose, or fecal lipids. The effect of pharmacologic L-carnitine thus appears to be an inhibition of triglyceride synthesis and/or secretion by the liver.     

Short-term influences of dichloroacetate on genetically hyperlipemic rats

The effects of short-term (7 days) administration of dichloroacetate (DCA) on carbohydrate and lipid metabolism in the Zucker obese and lean rat were investigated. Metabolic effects of the drug were more pronounced in the obese than in the lean rat. DCA decreased fasting blood glucose concentrations in both lean and obese rats, but more so in the fat animals, probably because of higher initial levels. The hypoglycemic action of DCA is likely attributable to a direct effect on liver and peripheral tissues and not to an indirect action caused by a decrease in the glucagon-to-insulin ratio because the drug induced just the opposite effect. DCA decreased plasma triglycerides (TG) and free fatty acids (FFA) in the hyperlipemic rats but not in lean rats. Intrahepatic triglyceride content diminished after drug treatment in fat rats, suggesting decreased hepatic TG synthesis. Hyperketonemia, induced in both lean and fat rats by DCA treatment, was also greater in the obese animal. This response was probably caused by accelerated hepatic ketone body production due to increased β-oxidation, and not to enhance FFA substrate supply. These data demonstrate that DCA is capable of correcting many of the underlying abnormalities in carbohydrate and fat metabolism in the obese Zucker rat.     

Down-regulation of hepatic stearoyl-CoA desaturase 1 expression by angiotensin II receptor blocker in the obese fa/fa Zucker rat: possible role in amelioration of insulin resistance and hepatic steatosis

Background  It has been reported that angiotensin II type 1 receptor blocker (ARB) can ameliorate hepatic steatosis and insulin resistance. Stearoyl-CoA desaturase 1 (SCD-1), which catalyzes the cellular synthesis of monounsaturated fatty acids, affects lipid metabolism. In this study, we investigated whether SCD-1 gene expression is affected by ARB treatment. Methods  Obese fa/fa Zucker rats fed a high-fat diet were treated with a potent ARB and olmesartan, and the resulting changes in the components of serum and liver were studied. Gene expression of hepatic SCD-1 was assayed using real-time PCR. Results  The serum glucose and insulin levels and hepatic TG content of the obese Zucker rats fed a high-fat diet were reduced after olmesartan administration, while the serum adiponectin level was increased. Real-time PCR revealed an increase of SCD-1 gene expression in the liver of these rats, followed by a reduction after olmesartan administration. The ratio of stearic acid (C18:0) to oleic acid (C18:1) in the liver was increased by olmesartan, indicating a reduction in the in vivo activity of SCD-1. Conclusions  ARB ameliorates hepatic steatosis and insulin resistance in obese fa/fa Zucker rats fed a high-fat diet. Gene expression of SCD-1 is decreased by olmesartan, suggesting that the beneficial effect is due partly to suppression of the key enzyme for hepatic lipid metabolism by ARB.     

Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

Hepatic resection or transplantation in patients with fatty liver is associated with increased morbidity and mortality. The regenerative capacity of fatty livers after major tissue loss is unknown. Interleukin 6 (IL-6) is a potent inducer of hepatic regeneration in normal and ischemic livers. Therefore, we studied hepatic regeneration at day 1, day 2, and day 4 in a model of 70% hepatectomy in obese and lean Zucker rats, and obese Zucker rats pretreated with recombinant interleukin 6 (rIL-6). The mitotic cycle in hepatocytes was investigated by 4 different markers of regeneration representing distinct phases of mitosis (proliferating cell nuclear antigen [PCNA] = G(1) phase, bromodeoxy uridine [BrdU] = S phase, mitotic index, and regenerated liver weight = M phase). Obese Zucker rats had significantly decreased regenerative capacity compared with lean Zucker rats (PCNA, BrdU, mitotic index, regenerated liver weight) at days 1 and 2 after surgery. Four days after resection fatty animals showed an increase in the mitotic index indicating a delay of regeneration in steatotic livers. Animal survival after 70% hepatectomy was significantly decreased in obese rats compared with lean animals. Pretreatment of obese animals with rIL-6 normalized PCNA expression (G(1) phase) in steatotic hepatocytes but failed to increase DNA synthesis (BrdU, S phase), mitosis (mitotic index and regenerated liver weight, M phase), and animal survival. These results indicate major impairment of hepatic regeneration in steatotic livers. Two different blockages of regeneration must be present, one rIL-6 sensitive, at the level of IL-6 or upstream, and a second, rIL-6 resistant, at the level of G(1)/S-phase transition.     

Metabolic consequences of fasting in old lean and obese Zucker rats

The effects of fasting on lipid and carbohydrate metabolism and plasma insulin and glucagon levels were compared in lean and obese Zucker rats. Sixteen-month-old female and male rats were fasted for periods of 2, 4, 6 and 12 days. Fasting produced significant decreases in hepatic rates of lipid, cholesterol, and glycogen synthesis, as well as circulating levels of triglycerides, cholesterol, phospholipids, and insulin. Significant increases in hepatic lipid levels and serum free fatty acids were noted. When compared to lean rats, obese rats had elevated rates of hepatic lipid and glycogen synthesis, hepatic lipid and glycogen stores, serum triglycerides, cholesterol, phospholipids, and plasma insulin. Lean rats had higher plasma glucagon levels. Sex differences in several parameters were observed. Females demonstrated higher levels of lipid and cholesterol synthesis and serum free fatty acids, whereas serum cholesterol levels and hepatic glycogen stores were higher in males. Following a 12-day fast, carcass fat and protein content were decreased in both lean and obese rats, but the obese animals maintained an obese body composition. It is concluded that fasting results in qualitatively similar metabolic and hormonal changes in both lean and obese rats, but that abnormalities in carbohydrate and lipid metabolism persist in obese rats even after a 12-day fast.     

Changes of hepatic fatty acid metabolism produced by chronic thioacetamide administration in rats.

Hepatic mitochondrial functions related to fatty acid metabolism, including the respiratory control ratio, fatty acid oxidative capacity and carnitine palmitoyltransferase I activity, were studied in vitro with mitochondria isolated from rats treated with thioacetamide for up to 12 wk. The levels of ketone bodies, carnitine, carnitine esters and malonyl-coenzyme A were also determined in liver extracts. Polarography of mitochondrial respiration from succinate or glutamate plus malate showed a lower respiratory control ratio in thioacetamide-treated rats, whereas uncoupled oxygen consumption was not altered. This suggests that the mitochondrial respiratory chain capacity remained intact in the thioacetamide-treated rats. The oxygen consumption associated with palmitoyl-coenzyme A and palmitoyl-L-carnitine oxidation by isolated liver mitochondria was increased by thioacetamide treatment on both a per-mitochondrial protein and a per-total liver basis. The carnitine palmitoyl-transferase I activity; the tissue levels of ketone bodies, carnitine and carnitine esters; and the beta-hydroxybutyrate/acetoacetate ratio were all higher in the livers of thioacetamide-treated animals than in control livers, whereas the hepatic malonyl-coenzyme A level was decreased by thioacetamide. These results indicate the increased diversion of cytosolic long-chain acyl-coenzyme As into the mitochondria for beta-oxidation rather than their esterification and use in lipogenesis. These intrahepatic metabolic changes induced by chronic thioacetamide administration may reflect the whole-body catabolic state and can be seen as adaptive for maintaining energy homeostasis under conditions of impaired glucose tolerance.     

The messenger RNA profiles in liver, hypothalamus, white adipose tissue, and skeletal muscle of female Zucker diabetic fatty rats after topiramate treatment

Topiramate (TPM) is a novel neurotherapeutic agent approved for the treatment of epilepsy and for migraine prophylaxis. It has been observed that in obese-associated, type 2 diabetic rodent models, TPM treatment reduced the body weight gain, improved insulin sensitivity, and enhanced glucose-regulated insulin release. A long-term treatment with TPM thus ameliorated obesity and diabetic syndromes in female Zucker diabetic fatty rats and db/db mice. The molecular mechanisms of TPM antiobesity and antidiabetic effects remain unknown. We have applied DNA microarray technology to explore genes that might be involved in the mechanisms by which TPM improves insulin sensitivity and blood glucose handling, as well as body weight control. In female Zucker diabetic fatty rats, 7-day TPM treatment significantly reduced the plasma levels of glucose and triglyceride in a dose-dependent manner. The DNA microarray data revealed that TPM treatment altered messenger RNA profiles in liver, hypothalamus, white adipose tissue, and skeletal muscle. The most marked effect of TPM on gene expression occurred in liver with those genes related with metabolic enzymes and signaling regulatory proteins involved in energy metabolism. TPM treatment decreased messenger RNA amounts for sterol regulatory element binding protein-1c, stearoyl-coenzyme A (CoA) desaturase-1, choline kinase, and fatty acid CoA ligase, long chain 4. TPM also up-regulated 3 cholesterol synthesis genes. In addition, the short-term effect of TPM on gene expression was examined at 16 hours after a single administration. TPM markedly reduced hepatic expression of genes related with fatty acid synthesis, eg, stearoyl-CoA desaturase and acetyl-CoA carboxylase. TPM also changed genes related with fatty acid beta-oxidation, increased 3-2-trans-enoyl-CoA isomerase and mitochondrial acyl-CoA thioesterase, and decreased fatty acid CoA ligase (long chain 2 and long chain 5). These gene expression changes were independent of food intake as shown by pair feeding. Our results suggest that TPM regulates hepatic expression of genes involved in lipid metabolism, which could be part of the mechanisms by which TPM reduces plasma triglyceride levels in obese diabetic rodents.     

Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload

Peroxidative decomposition of mitochondrial membrane phospholipids with subsequent mitochondrial dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. Malondialdehyde is formed when polyunsaturated fatty acids of membrane phospholipids undergo peroxidative decomposition, and it is metabolized by aldehyde dehydrogenase. We studied mitochondrial metabolism of malondialdehyde in rats with chronic dietary iron overload. Hepatic malondialdehyde concentrations were significantly increased in iron-loaded livers, and mitochondrial respiratory control ratios using glutamate as a substrate were decreased by 47% largely owing to reductions in state 3 respiration. When exogenous malondialdehyde was added to mitochondrial fractions, there was significantly less metabolism of malondialdehyde in mitochondria of iron-loaded livers as compared with controls. In addition, there was a 28% decrease in mitochondrial aldehyde dehydrogenase in iron-loaded livers but no change in cytosolic aldehyde dehydrogenase. Increased hepatic malondialdehyde in chronic iron overload may result from a combination of increased production and decreased metabolism of malondialdehyde, both of which may be due to iron-induced mitochondrial lipid peroxidation.     

Metabolic effects of high-protein diets in Zucker rats

The effects of dietary protein on the metabolism of proteins, carbohydrates, and especially, lipids were investigated in genetically obese Zucker rats and their lean siblings. For 40 days the rats received diets containing 15%, 64%, or 82% protein, included at the expense of cornstarch. In the obese animals, the high-protein diets led to decreased food intake and weight gain. While these diets decreased the activities of lipogenic enzymes along with the lipid gain, they did not decrease the final body-fat content. The increase protein intake stimulated hepatic ureogenesis and gluconeogenesis. Lipolysis was stimulated, as demonstrated by an accumulation of ketone bodies in the liver. Blood levels of triacylglycerols, free glycerol, and nonesterified fatty acids were concomitantly decreased, which suggests an accelerated turnover of lipids. Whatever the composition of the diet, total energy retention of the lean rats was always less than that of the obese rats. The changes observed on high-protein diets were essentially the same for the two groups, except that the final body-content of lipids in the lean rats was significantly lower. In the absence of exogenous carbohydrate, the lean rats were barely able to retain nitrogen and to maintain hepatic lipogenesis. Unlike the rats from other strains, the lean Zucker rats could not adapt to a low-carbohydrate diet; this failure may be due to a metabolic disorder.     

Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats

Background and ObjectiveRecent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome.Materials and MethodsFour groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed.ResultsDaily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers.ConclusionOur results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.     

Growth hormone treatment reduces total body fat accumulation in Zucker obese rats

Lean and obese Zucker rats were injected daily intraperitoneally with high doses (5-10 mg/kg) of human growth hormone (GH) for 3 weeks. In the obese rats after GH treatment, carcass lipid was decreased by 50 percent, and bone weight increased to levels of lean controls. During the last two weeks of GH treatment, food intake was increased in lean rats and not significantly affected in obese rats. Loss of body weight in obese animals was masked by water retention. Serum insulin concentrations were doubled in obese animals but unchanged in lean phenotypes after GH treatment. Hepatic fatty acid oxidation in obese animals was stimulated 5-fold by treatment, while hepatic lipid synthesis was stimulated 2-fold and adipose lipid synthesis was reduced 3-fold. These results suggest that growth hormone induces a partitioning of nutrients in obese rats which results in less lipid accumulation.     

The postprandial rates of glycogen and lipid synthesis of lean and obese female Zucker rats

OBJECTIVE: To determine the relative rates of glycogenesis and lipogenesis following administration of a test meal in lean and obese Zucker rats. PROTOCOL: Nine-week-old lean and obese Zucker rats were fasted overnight, then tube-fed a test meal of balanced composition amounting to 16kJ (lean rats and one group of obese rats) or 24kJ (one group of obese rats) and containing 200 mg 1-(13)C glucose. Immediately after the meal the rats were injected intraperitoneally with 5 mCi of 3H2O and killed 1 h later. METHODS: Glycogenesis was calculated from the incorporation of 3H into liver glycogen divided by the specific activity of plasma water. Lipogenesis was calculated similarly from the incorporation of 3H into saponifiable lipids in liver and perirenal adipose tissue. The proportion of glycogen synthesized by the indirect pathway via pyruvate was determined from the ratio of 3H labelling at positions C6 and C2 in the glycogen glucose residues. Glycogen synthesis from glucose was determined from the ratio of 13C enrichment in liver glycogen to that in plasma glucose. RESULTS: The rate of synthesis of glycogen was considerably lower in the livers of obese rats than those of lean controls, with the larger meal causing a small but significant increase in glycogenesis. The proportion of glycogen synthesized via pyruvate showed a non-significant increase in the obese rats, while the amount of glycogen synthesized from glucose was significantly decreased. Hepatic lipogenic rates were about five times higher in both groups of obese rats than the lean controls. In adipose tissue, lipogenesis per g tissue was slightly reduced in the obese rats, although there was clearly an increase in adipose tissue lipogenic activity per whole animal. The larger meal caused a greater rise in plasma glucose and insulin concentrations but did not affect lipogenic rates, although it did cause a greater suppression of lipolysis, as indicated by a lower plasma glycerol concentration. CONCLUSION: Ingested carbohydrate is partitioned predominantly into hepatic fatty acid synthesis in obese Zucker rats. Hepatic glycogen synthesis is suppressed and comes mainly from precursors other than glucose. The suppression of hepatic glycogen synthesis may contribute to the increased energetic efficiency of obese Zucker rats.     

1H and 31P NMR Lipidome of Ethanol‐Induced Fatty Liver

Background: Hepatic steatosis (fatty liver), an early and reversible stage of alcoholic liver disease, is characterized by triglyceride deposition in hepatocytes, which can advance to steatohepatitis, fibrosis, cirrhosis, and ultimately to hepatocellular carcinoma. In the present work, we studied altered plasma and hepatic lipid metabolome (lipidome) to understand the mechanisms and lipid pattern of early‐stage alcohol‐induced‐fatty liver. Methods: Male Fischer 344 rats were fed 5% alcohol in a Lieber‐DeCarli diet. Control rats were pair‐fed an equivalent amount of maltose‐dextrin. After 1 month, animals were killed and plasma collected. Livers were excised for morphological, immunohistochemical, and biochemical studies. The lipids from plasma and livers were extracted with methyl‐tert‐butyl ether and analyzed by 750/800 MHz proton nuclear magnetic resonance (¹H NMR) and phosphorus (³¹P) NMR spectroscopy on a 600 MHz spectrometer. The NMR data were then subjected to multivariate statistical analysis. Results: Hematoxylin and Eosin and Oil Red O stained liver sections showed significant fatty infiltration. Immunohistochemical analysis of liver sections from ethanol‐fed rats showed no inflammation (absence of CD3 positive cells) or oxidative stress (absence of malondialdehyde reactivity or 4‐hydroxynonenal positive staining). Cluster analysis and principal component analysis of ¹H NMR data of lipid extracts of both plasma and livers showed a significant difference in the lipid metabolome of ethanol‐fed versus control rats. ³¹P NMR data of liver lipid extracts showed significant changes in phospholipids similar to ¹H NMR data. ¹H NMR data of plasma and liver reflected several changes, while comparison of ¹H NMR and ³¹P NMR data offered a correlation among the phospholipids. Conclusions: Our results show that alcohol consumption alters metabolism of cholesterol, triglycerides, and phospholipids that could contribute to the development of fatty liver. These studies also indicate that fatty liver precedes oxidative stress and inflammation. The similarities observed in plasma and liver lipid profiles offer a potential methodology for detecting early‐stage alcohol‐induced fatty liver disease by analyzing the plasma lipid profile.     

The effect of vigorous treadmill exercise on plasma lipoproteins and hepatic lipoprotein production in Zucker rats

Chronic exercise has been shown to alter plasma lipids in man and animals, but the mechanism(s) responsible for this phenomenon have not been clarified. In the present study we have examined the role of the liver in the production of lipoproteins following an intensive exercise regimen in lean and obese Zucker rats. Four-week-old lean and obese male Zucker rats were subjected to a vigorous exercise regimen of running on a motor-driven treadmill for 10 weeks. Hepatic lipoprotein cholesterol production was then assessed using liver perfusion techniques. Plasma cholesterol concentration was significantly lower in both lean and obese runners versus appropriate non-exercised controls. This decrease was due to a decline in both chylomicron and HDL cholesterol. Exercise had no affect on plasma VLDL and LDL cholesterol concentrations. Hepatic VLDL cholesterol production was elevated in obese rats versus lean rats and was not affected by exercise in runners of either phenotype. Hepatic HDL cholesterol production was higher in lean runners but was unchanged in obese runners. Plasma triglyceride was reduced by 50% in exercised obese rats. In summary, intense exercise decreased plasma triglyceride, cholesterol, and HDL cholesterol concentrations in lean and obese Zucker rats. Since hepatic HDL cholesterol production was increased and hepatic VLDL cholesterol production was unaffected by exercise, the changes in plasma lipid levels observed following exercise appear to be mediated by extrahepatic mechanisms.     

Stereological and functional analysis of liver mitochondria from rats with secondary biliary cirrhosis: impaired mitochondrial metabolism and increased mitochondrial content per hepatocyte.

Mitochondrial and cytosolic functions were studied in vivo and in perfused livers from rats with secondary biliary cirrhosis induced by bile duct ligation for 5 wk and in sham-operated controls. The livers were stereologically analyzed, and mitochondrial and cytosolic functions were related to liver structure. Oxygen consumption by perfused livers expressed per stereologically determined mitochondrial volume was decreased by 49% in bile duct-ligated rats compared with control rats. Glucose production (expressed per mitochondrial volume) was reduced by more than 90% in bile duct ligation, whereas urea production was not affected. Lactate production, a cytosolic function, was increased fivefold in bile duct ligation, and both the lactate/pyruvate and the beta-hydroxybutyrate/aceto-acetate ratios were increased in the liver perfusate of bile duct-ligated rats. In comparison with control rats, the stereologically determined mitochondrial volume fraction per hepatocyte was increased by 28% in bile duct-ligated rats. Activities of mitochondrial enzymes expressed per area of mitochondrial membrane or per mitochondrial volume were either unchanged (ATPase, cytochrome c oxidase and glutamate dehydrogenase) or decreased (monoamine oxidase) in bile duct ligation. Thus in comparison with control rats, mitochondrial metabolism is impaired in perfused livers from bile duct-ligated rats; increased mitochondrial volume per hepatocyte may represent a strategy to maintain hepatic energy metabolism in rats with secondary biliary cirrhosis.     

Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action. METHODS: Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined. RESULTS: ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice. CONCLUSIONS: This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.