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Diabetes Branch (M.H., C.C., O.G., B.S., K.R.D., D.L.R., M.L.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Third Department of Medicine (M.H.), First Faculty of Medicine, Charles University, 12808 Prague-2, Czech Republic; Division of Molecular Genetics and New York Obesity Research Center (S.C.), Department of Pediatrics, Columbia University, New York, New York 10032; and Metabolic Diseases Branch (N.W., M.C.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Martin Haluzik, Third Department of Medicine, First Faculty of Medicine, Charles University, U nemocnice 1, 12808, Prague-2, Czech Republic. E-mail: mhalu{at}lf1.cuni.cz.
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Introduction |
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We have recently demonstrated the importance of the genetic background on the phenotype of A-ZIP/F-1 mice, which lack adipose tissue (12). The lipoatrophic A-ZIP/F-1 mouse is an extreme example of insulin resistance with hepatic steatosis and severe hyperinsulinemia (13). A-ZIP/F-1 mice on the FVB background have severe hyperglycemia and high circulating triglyceride and free fatty acid levels. A-ZIP/F-1 mice on B6 background, with similarly severe hyperinsulinemia, have milder hyperglycemia but worse hepatic steatosis (12). It appears that the increased capacity of the liver of B6 A-ZIP/F-1 mice to store triglycerides leads to lower circulating lipid levels, less lipid deposition in muscle tissue, and thus milder muscle, but worse liver insulin resistance.
Here, we test the hypothesis that the effects of B6 vs. FVB genetic background on glucose and lipid phenotypes are manifest in the ob/ob mouse, a diabetes model in which adipose tissue is in excess, rather than missing. We demonstrate that, like A-ZIP/F-1 mice, B6 ob/ob mice are less hyperglycemic and have less muscle insulin resistance than FVB ob/ob mice. Additionally, differences between B6 ob/ob and FVB ob/ob mice were observed in acute lipid clearance and circulating adiponectin levels.
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Materials and Methods |
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Hyperinsulinemic-euglycemic clamp
Catheters were implanted under ketamine and xylazine anesthesia. The SILASTIC catheter (inside diameter, 0.30 mm; outside diameter, 0.64 mm; no. 508–001; Dow Corning Corp., Midland, MI), filled with heparin solution (100 USP U/ml in 0.9% NaCl), was inserted via a right lateral neck incision, advanced into the superior vena cava via the right internal jugular vein, and sutured in place [procedure adapted from MacLeod and Shapiro (14)]. The distal end of the catheter was knotted, tunneled sc, exteriorized first at the dorsal cervical midline, and then further tunneled sc and exteriorized in the dorsal midline, 2 cm above the tail. A silk suture was fastened around the catheter at the neck site. The clamps were then performed 4–5 d later, after complete recovery of the animals from the operation. On the day of the clamp, the catheter was externalized by pulling the suture through the dorsal cervical incision site. The clamps were performed after 16 h of fasting in conscious mice, as described in detail previously (15, 16), using [3-3H]glucose and 2-deoxy-D-[1-14C] glucose (both from NEN Life Science Products, Boston, MA) for the estimation of whole-body glucose fluxes and tissue glucose uptake, respectively.
In vivo glucose flux analysis
The determination of plasma [3-3H]glucose and 2-deoxy-D-[1-14C] glucose concentrations and tissue 2-deoxy-D-[1-14C] glucose-6-phosphate were performed as described previously (17).
Calculations
Basal endogenous glucose production was calculated as the ratio of the preclamp [3-3H]glucose infusion rate (dpm/min) to the specific activity of the plasma glucose (mean of the values in the 90 and 120 min of basal preclamp period, in dpm/µmol). Clamp whole-body glucose uptake was calculated as the ratio of the [3-3H]glucose infusion rate (dpm/min) to the specific activity of plasma glucose (dpm/µmol) during the last 30 min of the clamp (mean of the 90–120 min samples). Whole-body glycolysis was determined from the rate of increase in plasma 3H2O determined by linear regression using the 80–120 min points. Plasma 3H2O concentrations were measured from the difference between nondried vs. dried plasma 3H counts. Clamp endogenous glucose production was determined by subtracting the average glucose infusion rate in the last 30 min of clamp from the whole-body glucose uptake. Whole-body glycogen and lipid synthesis were estimated by subtracting the whole-body glycolysis from the whole-body glucose uptake, which assumes that glycolysis and glycogen/lipid synthesis account for the majority of insulin-stimulated glucose uptake (18). Muscle and white and brown adipose tissue glucose uptake was calculated from the plasma 2-deoxy-D-[1-14C] glucose concentration profile (using plasma 14C counts at 80–120 min, the area under the curve was calculated by trapezoidal approximation) and tissue 2-deoxy-D-[1-14C] glucose-6-phosphate content as described previously (17).
Biochemical and hormonal assays
Glucose was measured using a Glucometer Elite (Bayer, Elkhart, IN). Insulin and adiponectin (no. SRI-13K and no. MADP-60HK, respectively, Linco Research, St. Charles, MO), triglycerides (no. 337-B, Sigma, St. Louis, MO), and nonesterified fatty acids (no. 13831175, Roche Molecular Biochemicals, Indianapolis, IN) were quantitated with the indicated kits. Liver triglycerides were measured by solvent extraction followed by a radiometric assay for glycerol as previously described (19, 20, 21).
Triglyceride clearance test
Clearance of triglycerides (400 µl peanut oil, delivered by gavage) from the circulation was measured in mice previously fasted for 4 h. Blood was taken before gavage and hourly for 6 h after gavage, and plasma triglycerides were measured as described above.
RNA analysis
Total RNA extraction, Northern blots, and quantitation by phosphorimager were done as previously described, using probes excised from plasmids (22).
Statistical analysis
Data are expressed means ± SE. Statistical significance between the groups was determined with SigmaStat (SPSS Inc, Chicago, IL) using two-way ANOVA or t test, as appropriate.
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Results |
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). FVB ob/ob mice were 3 g heavier than B6 ob/ob mice, the same as the difference between wild-type mice of B6 and FVB strains. The body length of ob/ob mice of both strains was higher relative to respective wild-type controls. FVB mice were significantly longer relative to respective B6 groups. Liver weights in ob/ob mice were 3.1- and 2.5-fold greater than wild-type B6 and FVB controls, respectively (Table 1). The difference in liver weight was paralleled by a difference in liver triglycerides, significantly higher in the B6 ob/ob mice, indicating greater liver steatosis in the B6 ob/ob mice. No significant difference in liver triglycerides was observed between B6 and FVB wild-type groups (Table 1).
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). Brown adipose tissue weight was increased in ob/ob mice, with no significant strain-related differences (Table 1).
Blood glucose was moderately (1.7-fold) elevated in B6 ob/ob mice as compared with wild-type littermates, whereas FVB ob/ob mice were severely diabetic, with blood glucose levels 4-fold higher than in wild-type mice and 2-fold higher than in B6 ob/ob mice (Table 2). Insulin levels were comparably increased in ob/ob mice of both strains, 40-fold higher than in wild-type mice (Table 2). Triglyceride levels were significantly elevated in ob/ob mice and by the FVB background (in both wild-type and ob/ob mice, Table 2).
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). Interestingly, no difference in adiponectin levels was found between B6 ob/ob and wild-type mice or between B6 and FVB wild-type mice. Adiponectin mRNA expression in white adipose tissue of B6 ob/ob mice was 3-fold lower than in wild-type mice; whereas in FVB ob/ob mice, it was further reduced, being 12-fold decreased relative to wild-type mice. Resistin mRNA expression in white adipose tissue followed the same pattern as that of adiponectin, with a 4-fold reduction in B6 ob/ob and 14-fold reduction in FVB ob/ob mice relative to wild-type controls.
Triglyceride clearance is strongly affected by genetic background
A possible contribution to the greater liver triglycerides in the B6 ob/ob mice is increased hepatic triglyceride clearance. Because we have observed that B6 vs. FVB genetic background significantly affects lipid handling (12), we studied triglyceride clearance after an oral lipid load in the ob/ob mice. Two profound effects were seen. We confirmed that wild-type B6 mice have much more rapid triglyceride clearance than do wild-type FVB mice. Triglyceride clearance was also reduced by the ob/ob mutation but with an effect smaller in magnitude than that of background genotype (Fig. 1).
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). Fasting insulin levels were 4-fold higher in ob/ob mice of both strains as compared with wild-type controls (Table 3). Basal endogenous glucose production was significantly decreased in B6 ob/ob mice as compared with the rest of the groups (Fig. 2), possibly reflecting their decreased body temperature after fasting at the start of the clamp (data not shown).
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). Whole-body glycolysis was similarly reduced greatly in ob/ob mice but less so on the B6 than the FVB background. Whole-body glycogen/lipid synthesis was decreased to the same extent in B6 and FVB ob/ob mice (Fig. 3).
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). In ob/ob mice of both strains, the clamp endogenous glucose production remained high, reflecting severe liver insulin resistance (Fig. 2). However, when expressed as the percent suppression of basal endogenous glucose production, in FVB ob/ob mice this value was suppressed by 27%; whereas in B6 ob/ob mice, glucose production actually increased from the basal values (P = 0.06, B6 ob/ob vs. FVB ob/ob mice).
Glucose uptake measured directly in muscle, white, and brown adipose tissue was severely reduced in ob/ob mice of both strains as compared with controls (Fig. 4). Muscle glucose uptake of B6 ob/ob mice was 40% higher than in FVB ob/ob mice, whereas no strain difference was found in white or brown adipose tissue glucose uptake.
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). The increase of lipogenic genes was generally more pronounced on B6 genetic background, with SCD-1 being 2.1-fold higher in B6 wild-type compared with FVB wild-type, and 3.4-fold higher in B6 ob/ob compared with FVB ob/ob.
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Discussion |
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, resistin, adiponectin, and others), or by a combination of both (23, 24, 25, 26). We showed previously that both wild-type B6 and lipoatrophic A-ZIP/F-1 B6 mice have much faster triglyceride clearance than wild-type and A-ZIP/F-1 mice of FVB background, with more pronounced lipid deposition into the liver (12). Repartitioning of triglycerides from the muscle to the liver worsened liver insulin resistance but improved muscle insulin resistance, leading to milder diabetes (12). The B6 vs. FVB strain differences in triglyceride clearance in ob/ob mice were similar to those previously observed in A-ZIP/F-1. The same was true for liver triglyceride accumulation, which was more pronounced in B6 relative to FVB ob/ob mice. Thus, triglyceride handling is strongly affected by genetic background under highly divergent conditions: a lack of fat in A-ZIP/F-1 mice and excessive fat accumulation in ob/ob mice. As a result, B6 mice have increased capacity to store triglyceride in the liver, partially protecting muscle from lipid overload and thus from development of more severe insulin resistance. We also studied the adipose-derived hormones, adiponectin and resistin, to examine their possible role in strain-related differences in diabetes/insulin resistance of ob/ob mice. Circulating adiponectin levels are usually inversely related to obesity and insulin resistance (27, 28, 29). In mice, acute adiponectin administration decreased blood glucose and increased fatty acid oxidation in the skeletal muscle (30) and liver insulin sensitivity measured by euglycemic-hyperinsulinemic clamp (31). Moreover, transgenic mice lacking adiponectin are more prone to diet-induced insulin resistance relative to wild-type controls (29, 32). Here, we show that relatively less diabetic B6 ob/ob mice had normal circulating adiponectin levels in contrast to a 50% reduction in FVB ob/ob mice. Normal circulating adiponectin levels in B6 ob/ob mice contrasted with clearly (3-fold) decreased adipose tissue adiponectin mRNA expression. Our data thus suggest that circulating adiponectin levels do not necessarily correlate with its adipose tissue mRNA expression. Moreover, circulating adiponectin in B6 ob/ob mice at the age of 10 wk did not behave as a precise measure of insulin sensitivity, because its concentrations in severely insulin-resistant B6 ob/ob mice did not differ from those of B6 wild-type mice with normal insulin sensitivity. Normal circulating adiponectin levels in B6 ob/ob mice could have contributed to the milder diabetes of this strain relative to FVB ob/ob mice. The importance of this contribution, however, remains questionable, in the light of the results of our previous study that compared lipoatrophic A-ZIP/F-1 mice on the same genetic backgrounds (12). A-ZIP/F-1 mice have almost complete lack of white adipose tissue and thus do not produce any adipose tissue-derived hormones, including adiponectin (12, 33). Despite this fact, strain-related differences in lipid handling and insulin sensitivity in A-ZIP/F-1 mice were very similar to those observed in ob/ob mice in this study.
Increased circulating resistin levels were proposed to link obesity to insulin resistance (34). However, others reported decreased resistin mRNA expression in adipose tissue of obese mice and humans (35, 36). The role of resistin as a causal factor in the development of insulin resistance is thus controversial. Our data show that resistin adipose tissue mRNA levels were 4-fold decreased in B6 ob/ob mice and even more (14-fold) decreased in more diabetic and insulin-resistant FVB ob/ob mice compared with wild-type mice. These results argue against an etiologic role for resistin in the strain-related differences studied herein.
In summary, we show here that different genetic background strongly modifies the severity of diabetes, insulin resistance, and response to fasting in genetically leptin-deficient ob/ob mice. Identification of background modifier genes could bring further insight into the mechanism of development of diabetes and insulin resistance relevant for human biology.
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Footnotes |
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Present address for M.L.R.: Merck Research Laboratories, Rahway, New Jersey 07065
Abbreviation: ScD-1, Stearoyl-coenzyme A desaturase-1.
Received February 18, 2004.
Accepted for publication March 25, 2004.
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), B6 ob/ob (
), FVB WT (
), and FVB ob/ob (
) mice. Values are means ± SE, with n = 5–6/group. The areas under curves (mean ± SE) are 790 ± 80 for B6 WT, 1296 ± 130 for B6 ob/ob, 1915 ± 234 for FVB WT, and 3515 ± 640 for FVB ob/ob mice.
