FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2039776032> ?p ?o ?g. }

• W2039776032 endingPage "16" @default.
• W2039776032 startingPage "9" @default.
• W2039776032 abstract "Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1+/−) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1+/− mice showed reduced body weight (−25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%, and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1+/− mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation.We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1+/−) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1+/− mice showed reduced body weight (−25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%, and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1+/− mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. The human apolipoprotein C1 (APOC1) gene is predominantly expressed in the liver and adipose tissue (1Lauer S.J. Walker D. Elshourbagy N.A. Reardon C.A. Levy-Wilson B. Taylor J.M. Two copies of the human apolipoprotein C-I gene are linked closely to the apolipoprotein E gene.J. Biol. Chem. 1988; 263: 7277-7286Abstract Full Text PDF PubMed Google Scholar). APOC1 is secreted as a 6.6 kDa protein in plasma, where it resides on chylomicrons, VLDLs, and HDLs (2Shulman R.S. Herbert P.N. Wehrly K. Fredrickson D.S. The complete amino acid sequence of C-I (apoLp-Ser), an apolipoprotein from human very low density lipoproteins.J. Biol. Chem. 1975; 250: 182-190Abstract Full Text PDF PubMed Google Scholar). To elucidate the role of APOC1 in lipid metabolism, we have previously generated transgenic mice overexpressing human APOC1 (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). Overexpression of human APOC1 in these mice is found predominantly in the liver and to a lesser degree in the skin and adipose tissue (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Homozygous overexpressing APOC1 mice have strongly elevated levels of plasma total cholesterol (TC) and triglyceride (TG) due to the inhibitory action of APOC1 on VLDL uptake via hepatic receptors, in particular the LDL receptor-related protein (LRP) (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). In addition, homozygous APOC1 mice exhibit elevated plasma free fatty acid (FFA) concentrations (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Another striking observation was the strong reduction in body weight and adipose tissue mass in these APOC1-overexpressing mice on an obob background, due to diminished net uptake of FFA into adipose tissue (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). Thus, homozygous APOC1 overexpression in mice impairs peripheral FFA metabolism and adipose tissue development, and, as a consequence, APOC1 may be involved in the pathophysiology of insulin resistance. However, these homozygous APOC1 mice are an extreme model, because subcutaneous fat is totally absent and, in addition, they exhibit severe skin abnormalities, e.g., scaly skin and hair loss (4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar). Therefore, to study the effect of APOC1 overexpression on tissue-specific insulin sensitivity in a less-extreme model, we used mildly APOC1-overexpressing (heterozygous) mice on an obob background (obob/APOC1+/−). In obob mice, mild overexpression of human APOC1 results in slightly reduced body weight. Concomitantly with increased hepatic FFA uptake in obob/APOC1+/− mice, we observed hepatic steatosis and severe hepatic insulin resistance. In these mice, rosiglitazone treatment restored hepatic insulin sensitivity, despite a further increase in hepatic FFA uptake and increased steatosis. Rosiglitazone induced a different localization of the hepatic steatosis. We hypothesize that the different hepatic fat accumulation and/or decrease in fatty acid (FA) intermediates has a major effect on the insulin sensitivity of the liver. Transgenic mice with high expression of human APOC1 in the liver (line 11/1) were previously generated in our laboratory (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar, 4Jong M.C. Gijbels M.J. Dahlmans V.E. Gorp P.J. Koopman S.J. Ponec M. Hofker M.H. Havekes L.M. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.J. Clin. Invest. 1998; 101: 145-152Crossref PubMed Scopus (132) Google Scholar) and further bred on a C57BL/6J background. Heterozygous ob/OB mice on a C57BL/6J background, obtained from the Jackson Laboratories, were intercrossed with heterozygous APOC1 transgenic mice (APOC1+/−) to obtain wild-type and APOC1+/− mice on an obob background (obob and obob/APOC1+/−, respectively). Mice were genotyped by PCR procedure and housed in a temperature-controlled room on a 12 h light/dark cycle with free access to water and standard mouse/rat chow [7.2 wt/wt % crude fat (corn oil), 24.4 wt/wt % crude protein, and 41.8% wt/wt carbohydrates (corn starch)] diet. At age 3–4 months, mice were housed individually. Body weight was measured weekly during the study. The study was approved by the institution's animal welfare committee, following Dutch guidelines for using laboratory animals. Three-month-old obob and obob/APOC1+/− mice were subjected to a pair-feeding regime. During the pair-feeding period, mice received 4.0 g of chow diet during the first 4 weeks, followed by 4.5 g for 8 weeks. During the pair-feeding period, body weight was measured weekly. To measure plasma parameters, blood was taken from the mice by tail bleeding after a 4 h fast. The blood was collected in paraoxinized tubes (to prevent hydrolysis of TGs) (6Zambon A. Hashimoto S.I. Brunzell J.D. Analysis of techniques to obtain plasma for measurement of levels of free fatty acids.J. Lipid Res. 1993; 34: 1021-1028Abstract Full Text PDF PubMed Google Scholar) and kept on ice. Subsequently, the samples were spun (13,000 rpm) at 4°C for 3 min, and the separated plasma was immediately assayed for TG, FFAs, ketone bodies, TC, and glucose. The remaining plasma was frozen in liquid nitrogen and stored at −20°C for later measurement of insulin. Levels of TG (corrected for free glycerol) and TC were determined by using commercially available enzymatic kits (#2336691, Boehringer Mannheim GmbH, Mannheim, Germany; and GPO-trinder kit 337-B, Sigma, St. Louis, MO). FFA was measured enzymaticaly with a NEFA-C kit (Wako Chemicals GmbH, Germany). Ketone bodies were determined by measuring β-hydroxybutyrate, using a commercially available enzymatic kit (#310-A, Sigma Diagnostics, Inc., St. Louis, MO). Plasma glucose was determined by a commercially available kit (#315-500, Sigma Diagnostics, Inc.). Insulin levels were measured by using a radioimmunoassay kit (Sensitive Rat Insulin Assay, Linco Research Inc., St. Charles, MO). Whole-body insulin sensitivity was measured by hyperinsulinemic clamp analysis. During the clamp analysis, whole-body glucose uptake and hepatic glucose production (HGP) were determined using [3H]d-glucose, (Amersham, Little Chalfont, UK). The clamp experiments were performed as described earlier (7Voshol P.J. Jong M.C. Dahlmans V.E. Kratky D. Levak-Frank S. Zechner R. Romijn J.A. Havekes L.M. In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake.Diabetes. 2001; 50: 2585-2590Crossref PubMed Scopus (104) Google Scholar). At the end of the hyperinsulinemic clamp analysis period (insulin infusion of 7.0 mU/kg/min), a bolus (100 μl) of [14C]palmitate (3 μCi, Amersham) was given to measure tissue-specific uptake of FA. One minute after administering the [14C]palmitate bolus, blood was collected and the animal was sacrificed. Liver and white adipose tissue (WAT) and reproductive (visceral) and subcutaneous fat pads were rapidly collected, snap frozen in liquid nitrogen, and kept at −20°C for analysis. The collected blood was used to measure plasma insulin, glucose, and FFA. Glucose uptake and HGP were calculated as described by Voshol et al. (7Voshol P.J. Jong M.C. Dahlmans V.E. Kratky D. Levak-Frank S. Zechner R. Romijn J.A. Havekes L.M. In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake.Diabetes. 2001; 50: 2585-2590Crossref PubMed Scopus (104) Google Scholar). In short, under steady-state conditions, the rate of glucose disappearance equals the rate of glucose appearance. The latter was calculated as the ratio of the infusion rate of [3H]glucose (dpm) to the steady-state plasma [3H]glucose-specific activity (dpm/μmol glucose). The HGP (μmol/kg/min) was calculated as the difference between the rate of glucose disappearance and the rate of glucose infusion. The whole-body insulin sensitivity index was calculated as the ratio of the change in whole-body glucose uptake to the change in plasma insulin levels from basal to hyperinsulinemic conditions. The hepatic insulin sensitivity index was calculated as the ratio of the suppression of HGP during the hyperinsulinemic condition to the change in plasma insulin levels. To determine the uptake of palmitate by the various tissues, tissue samples (±250 mg) were homogenized in 1 ml demineralized water (demi-water). Tissue protein was measured according to the method of Lowry et al. (8Lowry O.H. Rosenbrough N.J. Farr A.L. Randall R.J. Protein measurement with Folin reagent.J. Biol. Chem. 1951; 193: 265-275Abstract Full Text PDF PubMed Google Scholar), using BSA (Sigma, Deisenhofen, Germany) as standard. To determine the uptake of [14C]palmitate in liver, muscle, and WAT, lipids were extracted by a modification of the method of Bligh and Dyer (9Bligh E.G. Dyer W.J. A rapid method of total lipid extraction and purification.Can. J. Med. Sci. 1959; 37: 911-917Google Scholar). TLC analyses revealed that 90% of the label was in the FFA fraction. Uptake of palmitate was calculated as percent uptake by the tissue of total administered 14C activity per gram tissue protein and subsequently corrected for plasma FFA levels by multiplying the uptake of palmitate by the plasma FFA levels measured during the clamp experiment. Total TG and diacylglycerol (DAG) content was determined in homogenates of liver, muscle, and WAT retrieved from the mice. Lipids were extracted and separated by high-performance TLC as described previously (10Havekes L.M. de Wit E.C. Princen H.M. Cellular free cholesterol in Hep G2 cells is only partially available for down-regulation of low-density-lipoprotein receptor activity.Biochem. J. 1987; 247: 739-746Crossref PubMed Scopus (84) Google Scholar). Quantification of the amounts was performed by scanning the plates and integrating the density areas using TINA® version 2.09 software (Raytest, Straubenhardt, Germany). To confirm hepatic steatosis, frozen sections (7 μm) were made and hepatic morphology was visualized by Oil Red O staining. Obob/APOC1+/− littermates were divided into two groups that were matched for body weight. One group received normal chow, the other chow containing rosiglitazone maleate (Avandia; SmithKline Beecham plc, Brentford, UK), achieving a daily dose of ∼3 mg/kg per mouse. During treatment, body weight was measured every week. Plasma levels of glucose, insulin, TG, TC, FFA, and ketone bodies were measured after 5 weeks of treatment. Furthermore, whole-body glucose uptake, HGP, and tissue-specific uptake of FA were measured under hyperinsulinemic clamp conditions in mice that were treated for 5 weeks. All analytical procedures were performed as mentioned above. For statistical analysis, SPSS version 11 was used. The Mann-Whitney nonparametric test for two independent samples was used to define differences between the groups of mice. The criterion for significance was set at P < 0.05. Obob/APOC1+/− mice were hyperlipidemic (Table 1), showing significantly increased plasma TG, TC, and FFA levels, compared with their obob littermates. In addition, plasma levels of glucose and insulin were significantly elevated in obob/APOC1+/− mice, suggesting, indeed, alterations in insulin sensitivity. As expected, rosiglitazone treatment in obob/APOC1+/− mice resulted in significantly decreased plasma TG levels. Rosiglitazone treatment in obob/APOC1+/− mice showed a dramatic normalization of the hyperglycemia, concomitant with decreased plasma insulin levels, compared with untreated littermates.TABLE 1Plasma levels of TG, TC, FFA, glucose, and insulin of obob mice, untreated obob/APOC1+/− mice, and ROSI-treated obob/APOC1+/− miceobobobob/APOC1obob/APOC1 + ROSITG (mM)0.28 ± 0.117.6 ± 2.6aP < 0.05 obob/APOC1 mice versus obob mice. 3.1 ± 2.0bP < 0.05 obob/APOC1 mice versus obob/APOC1 + ROSI mice.TC (mM)4.1 ± 1.09.6 ± 2.9aP < 0.05 obob/APOC1 mice versus obob mice.10.7 ± 2.5FFA (mM)0.85 ± 0.131.4 ± 0.2aP < 0.05 obob/APOC1 mice versus obob mice. 1.1 ± 0.1Glucose (mM)10.2 ± 2.817.6 ± 5.4aP < 0.05 obob/APOC1 mice versus obob mice. 8.4 ± 1.0bP < 0.05 obob/APOC1 mice versus obob/APOC1 + ROSI mice.Insulin (ng/ml)19.9 ± 5.729.6 ± 14.9aP < 0.05 obob/APOC1 mice versus obob mice. 5.8 ± 0.3bP < 0.05 obob/APOC1 mice versus obob/APOC1 + ROSI mice.TG, triglyceride; TC, total cholesterol; FFA, free fatty acid; ROSI, rosiglitazone. Values represent mean ± SD.a P < 0.05 obob/APOC1 mice versus obob mice.b P < 0.05 obob/APOC1 mice versus obob/APOC1 + ROSI mice. Open table in a new tab TG, triglyceride; TC, total cholesterol; FFA, free fatty acid; ROSI, rosiglitazone. Values represent mean ± SD. At 4 to 5 months of age, obob/APOC1+/− mice showed significantly lower body weight and visceral adipose tissue content compared with their obob littermates (Table 2). No differences were observed in subcutaneous fat pad weight between obob/APC1+/− mice and their obob littermates. The difference in body weight between obob and obob/APOC1+/− mice was not due to altered food intake, because forced food restriction (daily intake of 4.5 g chow per day for a period of 12 weeks) resulted in the same absolute difference in body weight between obob and obob/APOC1+/− mice (Fig. 1). Rosiglitazone treatment in obob/APOC1+/− mice resulted in significantly increased body weights (+ 18.6 ± 2.0 g, Table 2) in 5-month-old mice.TABLE 2Body weight and subcutaneous and visceral adipose tissue content of obob mice, untreated obob/APOC1+/− mice, and ROSI-treated obob/APOC1+/− miceobobobob/APOC1obob/APOC1 + ROSIBody weight (g)61.6 ± 6.046.0 ± 5.4aP < 0.05 obob/APOC1 mice versus obob mice.64.6 ± 5.5bP < 0.05 obob/APOC1 + ROSI mice versus obob/APOC1 mice.Subcutaneous adipose tissue content(% of body weight)11.3 ± 1.811.6 ± 0.9NDVisceral adipose tissue content (% of body weight)12.0 ± 3.98.6 ± 0.9aP < 0.05 obob/APOC1 mice versus obob mice.NDND, not determined. Values represent mean ± SD.a P < 0.05 obob/APOC1 mice versus obob mice.b P < 0.05 obob/APOC1 + ROSI mice versus obob/APOC1 mice. Open table in a new tab ND, not determined. Values represent mean ± SD. To investigate whether the severe hyperglycemia and hyperinsulinemia were due to insulin resistance, a hyperinsulinemic clamp analysis was performed. Table 3 shows plasma glucose, insulin, and FA levels determined at the end of the clamp period. Plasma glucose and insulin levels were not different between obob/APOC1+/− and obob mice during the clamp period. Rosiglitazone-treated obob/APOC1+/− mice showed significantly lower plasma glucose and insulin levels during the clamp period compared with untreated obob/APOC1+/− and obob control mice (Table 3). Plasma FFA concentration remained increased in untreated and rosiglitazone-treated obob/APOC1+/− mice compared with obob littermates. Obob/APOC1+/− mice showed severe whole-body insulin resistance, as indicated by the insulin sensitivity index (Fig. 2A), compared with obob littermates. The results of wild-type mice shown are given to confirm that obob and obob/APOC1+/− mice are insulin resistant in our hands using a similar insulin infusion protocol. Whole-body glucose uptake did not increase during hyperinsulinemia in obob/APOC1+/− mice compared with a 30% increase in obob littermates. Furthermore, obob/APOC1+/− mice showed complete hepatic insulin resistance, because there was no suppression of the HGP during the clamp conditions (Fig. 2B). The insulin-sensitizer rosiglitazone improved both whole-body (Fig. 2A) as well as hepatic insulin sensitivity (Fig. 2B) in obob/APOC1+/− mice, compared with untreated littermates.TABLE 3Plasma insulin, glucose, and FFA levels measured at the end of the clamp periodobobobob/APOC1ChowChowROSIInsulin (ng/ml)41.8 ± 10.735.7 ± 4.217.5 ± 3.5bP < 0.05 ROSI versus chow.Glucose (mM)9.0 ± 2.617.7 ± 1.9aP < 0.05 obob/APOC1 mice versus obob mice.9.6 ± 1.4bP < 0.05 ROSI versus chow.FFA (mM)0.78 ± 0.242.0 ± 1.1aP < 0.05 obob/APOC1 mice versus obob mice.2.2 ± 0.16aP < 0.05 obob/APOC1 mice versus obob mice.Values represent mean ± SD.a P < 0.05 obob/APOC1 mice versus obob mice.b P < 0.05 ROSI versus chow. Open table in a new tab Values represent mean ± SD. To obtain more insight into a possible cause of the severe hepatic insulin resistance in obob/APOC1+/− mice, we measured hepatic FA uptake during the hyperinsulinemic clamp and determined hepatic TG content (Fig. 3). Obob/APOC1+/− mice showed a 3-fold increased hepatic FA uptake (Fig. 3A) compared with obob controls. This increased hepatic FA flux in obob/APOC1+/− mice was associated with an increased hepatic TG accumulation (Fig. 3B), compared with obob littermates. DAG levels were also significantly increased in obob/APOC1+/− mice compared with obob controls (0.7 ± 0.1 μg/mg cell protein vs. 0.5 ± 0.1 μg/mg cell protein, respectively; P < 0.05). Surprisingly, although rosiglitazone treatment increased hepatic insulin sensitivity in obob/APOC1+/− mice, hepatic FA uptake and hepatic TG content were significantly increased, compared with untreated littermates. Hepatic DAG content did not significantly decrease with rosiglitazone treatment in obob/APOC1+/− mice (0.9 ± 0.3 μg/mg cell protein vs. 0.7 ± 0.1 μg/mg cell protein). In addition, we found that plasma ketone bodies were significantly increased in obob/APOC1+/− mice receiving rosiglitazone treatment (0.65 ± 0.17 vs. 0.39 ± 0.16 mM, respectively; P < 0.05), compared with untreated littermates, concomitant with the increased hepatic FA flux. FFA and TG are involved in the pathophysiology of insulin resistance in nonadipose tissues. Overexpression of human APOC1 considerably affects whole-body FA and TG metabolism and adipose tissue formation. Strong APOC1 overexpression, as in homozygous APOC1 mice, however, is an extreme model with complete loss of subcutaneous adipose tissue mass and severe skin complications. Thus, to study the effect of APOC1 on the pathophysiology of insulin resistance under more physiological circumstances, we studied the effects of mild, (heterozygous) overexpression of human APOC1 in obob mice (obob/APOC1+/− mice). Compared with obob mice, obob/APOC1+/− mice show strongly elevated levels of plasma TG, cholesterol, and FFA. These observations are in line with those reported previously for homozygous APOC1-overexpressing mice on an obob background (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). The observed hypertriglyceridemia can be explained by APOC1-mediated inhibition of the uptake of TG-rich particles by the liver via the LDL and LRP receptors (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). In addition, Jong et al. (3Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar) have postulated that strong APOC1 overexpression completely blocks binding of VLDL particles to the VLDL receptor, which is thought to function as a docking protein for efficient TG-rich lipoprotein lipolysis (11Yamamoto T. Hoshino A. Takahashi S. Kawarabayasi Y. Iijima H. Sakai J. The role of the very low density lipoprotein receptor in the metabolism of plasma lipoproteins containing ApoE.Ann. N.Y. Acad. Sci. 1995; 748: 217-224Crossref PubMed Scopus (8) Google Scholar) and subsequent delivery of FFA to underlying tissue, such as adipose tissue, thus leading to less adipose tissue mass. The molecular mechanisms underlying the impaired FFA uptake in APOC1-overexpressing mice remains unknown at the present time. In addition to the VLDL receptor, the action of FA transporters (such as CD36 and FATP) may also be affected by APOC1. Our data indicate that APOC1 is not likely to inhibit FFA tissue uptake through interference with the FA transporter CD36. Recent studies with CD36 knockout mice showed reduced uptake of FA in heart, skeletal muscle, and adipose tissue, whereas APOC1 appears to inhibit FA uptake in WAT only (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). In addition, it is possible that APOC1, either bound to VLDL or present in a free form in plasma, is able to bind FAs, thereby preventing rapid uptake by peripheral tissues. In the current study, we show that mild overexpression of APOC1 (obob/APOC1+/− mice) leads to mildly reduced body weights compared with their obob littermates, which is also in line with our previous study (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). In accordance with this previous study, the lower body weight observed in obob/APOC1+/− mice was due mainly to reduced fat pad weight. To exclude a possible interfering role of food intake in body weight control in these obob/APOC1+/− mice, we applied feeding restrictions to our obob/APOC1+/− mice and their obob littermates (4.5 g of chow diet per day). During the 12 weeks of feeding restrictions, the absolute body weight differences between the two genotypes remained unchanged, indicating that human APOC1 overexpression has direct effects on adipose tissue formation, independent of food intake, most probably by blocking the VLDL receptor. This hypothesis is sustained by two previous studies: i) Goudriaan et al. (12Goudriaan J.R. Tacken P.J. Dahlmans V.E. Gijbels M.J. van Dijk K.W. Havekes L.M. Jong M.C. Protection from obesity in mice lacking the VLDL receptor.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1488-1493Crossref PubMed Scopus (110) Google Scholar) showed less adipose tissue formation with high-fat feeding in VLDL receptor-deficient mice, resulting in decreased body weight compared with wild-type mice; and ii) net FFA uptake in adipose tissue was decreased in APOC1-overexpressing mice (5Jong M.C. Voshol P.J. Muurling M. Dahlmans V.E. Romijn J.A. Pijl H. Havekes L.M. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.Diabetes. 2001; 50: 2779-2785Crossref PubMed Scopus (80) Google Scholar). Interestingly, obob/APOC1+/− mice revealed severe hyperglycemia concomitant with hyperinsulinemia, two phenotypic features of severe insulin resistance and type 2 diabetes mellitus. Hyperinsulinemic clamp studies using [3H]glucose as a tracer showed indeed severe whole-body and hepatic insulin resistance in obob/APOC1+/− mice compared with obob controls. After an overnight fast, HGP was ∼45% increased in obob/APOC1+/− mice, compared with their obob littermates. Thus, both the increased HGP and the inability of insulin to suppress this HGP, in combination with the whole-body insulin resistance, fully explain the observed severe hyperglycemia in the obob/APOC1+/− mice. Several studies have shown that HGP is the main regulator of plasma glucose concentrations during fasting (13Owen O.E. Reichard G.A.J. Patel M.S. Boden G. Energy metabolism in feasting and fasting.Adv. Exp. Med. Biol. 1979; 111: 169-188Crossref PubMed Scopus (87) Google Scholar, 14Tayek J.A. Low-dose oral glyburide reduces fasting blood glucose by decreasing hepatic glucose production in healthy volunteers without increasing carbohydrate oxidation.Am. J. Med. Sci. 1995; 309: 134-139Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 15Moore M.C. Connolly C.C. Cherrington A.D. Autoregulation of hepatic glucose production.Eur. J. Endocrinol. 1998; 138: 240-248Crossref PubMed Scopus (100) Google Scholar). We can only speculate on a possible mechanism underlying the link between decreased peripheral FA uptake and whole-body insulin resistance. The mild overexpression of APOC1 may have effects only on adipose tissue FA uptake (4 ± 2% doses vs. 8 ± 3% doses, in obob/APOC1+/− mice and obob litttermates, res" @default.
• W2039776032 created "2016-06-24" @default.
• W2039776032 creator A5006945105 @default.
• W2039776032 creator A5019829980 @default.
• W2039776032 creator A5025131217 @default.
• W2039776032 creator A5030928999 @default.
• W2039776032 creator A5042579611 @default.
• W2039776032 creator A5047067871 @default.
• W2039776032 creator A5087117156 @default.
• W2039776032 date "2004-01-01" @default.
• W2039776032 modified "2023-10-18" @default.
• W2039776032 title "Overexpression of APOC1 in obob mice leads to hepatic steatosis and severe hepatic insulin resistance" @default.
• W2039776032 cites W147957900 @default.
• W2039776032 cites W1552597422 @default.
• W2039776032 cites W1567050319 @default.
• W2039776032 cites W1775749144 @default.
• W2039776032 cites W1961174746 @default.
• W2039776032 cites W1970717117 @default.
• W2039776032 cites W1972220181 @default.
• W2039776032 cites W1978677356 @default.
• W2039776032 cites W1986219421 @default.
• W2039776032 cites W2003323316 @default.
• W2039776032 cites W2011246715 @default.
• W2039776032 cites W2035256114 @default.
• W2039776032 cites W2041197131 @default.
• W2039776032 cites W2042144976 @default.
• W2039776032 cites W2058166721 @default.
• W2039776032 cites W2077828459 @default.
• W2039776032 cites W2092621119 @default.
• W2039776032 cites W2097505907 @default.
• W2039776032 cites W2104785728 @default.
• W2039776032 cites W2108916652 @default.
• W2039776032 cites W2111938066 @default.
• W2039776032 cites W2112327050 @default.
• W2039776032 cites W2120413507 @default.
• W2039776032 cites W2122252892 @default.
• W2039776032 cites W2126521413 @default.
• W2039776032 cites W2129722153 @default.
• W2039776032 cites W2131702141 @default.
• W2039776032 cites W2133935188 @default.
• W2039776032 cites W2148877387 @default.
• W2039776032 cites W2152874974 @default.
• W2039776032 cites W2164061949 @default.
• W2039776032 cites W2164849270 @default.
• W2039776032 doi "https://doi.org/10.1194/jlr.m300240-jlr200" @default.
• W2039776032 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/14523051" @default.
• W2039776032 hasPublicationYear "2004" @default.
• W2039776032 type Work @default.
• W2039776032 sameAs 2039776032 @default.
• W2039776032 citedByCount "45" @default.
• W2039776032 countsByYear W20397760322012 @default.
• W2039776032 countsByYear W20397760322013 @default.
• W2039776032 countsByYear W20397760322014 @default.
• W2039776032 countsByYear W20397760322015 @default.
• W2039776032 countsByYear W20397760322016 @default.
• W2039776032 countsByYear W20397760322017 @default.
• W2039776032 countsByYear W20397760322018 @default.
• W2039776032 countsByYear W20397760322021 @default.
• W2039776032 countsByYear W20397760322022 @default.
• W2039776032 countsByYear W20397760322023 @default.
• W2039776032 crossrefType "journal-article" @default.
• W2039776032 hasAuthorship W2039776032A5006945105 @default.
• W2039776032 hasAuthorship W2039776032A5019829980 @default.
• W2039776032 hasAuthorship W2039776032A5025131217 @default.
• W2039776032 hasAuthorship W2039776032A5030928999 @default.
• W2039776032 hasAuthorship W2039776032A5042579611 @default.
• W2039776032 hasAuthorship W2039776032A5047067871 @default.
• W2039776032 hasAuthorship W2039776032A5087117156 @default.
• W2039776032 hasBestOaLocation W20397760321 @default.
• W2039776032 hasConcept C126322002 @default.
• W2039776032 hasConcept C134018914 @default.
• W2039776032 hasConcept C185592680 @default.
• W2039776032 hasConcept C2776175330 @default.
• W2039776032 hasConcept C2777391703 @default.
• W2039776032 hasConcept C2778772119 @default.
• W2039776032 hasConcept C2779134260 @default.
• W2039776032 hasConcept C2779306644 @default.
• W2039776032 hasConcept C71924100 @default.
• W2039776032 hasConcept C86803240 @default.
• W2039776032 hasConceptScore W2039776032C126322002 @default.
• W2039776032 hasConceptScore W2039776032C134018914 @default.
• W2039776032 hasConceptScore W2039776032C185592680 @default.
• W2039776032 hasConceptScore W2039776032C2776175330 @default.
• W2039776032 hasConceptScore W2039776032C2777391703 @default.
• W2039776032 hasConceptScore W2039776032C2778772119 @default.
• W2039776032 hasConceptScore W2039776032C2779134260 @default.
• W2039776032 hasConceptScore W2039776032C2779306644 @default.
• W2039776032 hasConceptScore W2039776032C71924100 @default.
• W2039776032 hasConceptScore W2039776032C86803240 @default.
• W2039776032 hasIssue "1" @default.
• W2039776032 hasLocation W20397760321 @default.
• W2039776032 hasLocation W20397760322 @default.
• W2039776032 hasOpenAccess W2039776032 @default.
• W2039776032 hasPrimaryLocation W20397760321 @default.
• W2039776032 hasRelatedWork W2103615167 @default.
• W2039776032 hasRelatedWork W2109444927 @default.
• W2039776032 hasRelatedWork W2151429631 @default.
• W2039776032 hasRelatedWork W2363489163 @default.

• next