Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

Flowers, Jessica B.; Oler, Angie T.; Nadler, Samuel T.; Choi, Youn Jeong; Schueler, Kathryn L.; Yandell, Brian S.; Kendziorski, Christina; Attie, Alan D.

doi:10.1152/ajpendo.00370.2006

Cited by 33 publications

(28 citation statements)

References 92 publications

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“…Hyperinsulinemic-euglycemic clamp. Surgery, experimental procedures, and calculations have been previously described in detail (13). Scd1 Ϫ/Ϫ mice required a high rate of glucose infusion.…”

Section: Methodsmentioning

confidence: 99%

“…Insulin resistance is often correlated with abdominal obesity. The BTBR mouse strain has excess abdominal obesity associated with insulin resistance in heart, soleus muscle, and adipose tissue (9,(11)(12)(13). In the present study, we measured the effect of SCD1 deficiency on insulin action in vivo during a 2-h hyperinsulinemic-euglycemic clamp in BTBR Scd1 ϩ/ϩ and Scd1 Ϫ/Ϫ mice.…”

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confidence: 99%

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Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

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134

122

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The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet-and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin ob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ϳ70%. In response to a glucose challenge, Scd1 Ϫ/Ϫ leptin ob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1 Ϫ/Ϫ leptin ob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of ␤-cells, resulting in an increased risk of diabetes. Diabetes 56:1228-1239, 2007 S tearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids by introducing a cis double bond in the ⌬9 position of saturated 16-and 18-carbon fatty acyl-CoA substrates. The products of SCD, palmitoleoyl-CoA and oleoylCoA, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, cholesterol esters, and wax esters (1). Various diseases, including cancer, obesity, diabetes, and atherosclerosis, are associated with an imbalance in the ratio of saturated to monounsaturated fatty acids (2). Two human and four mouse isoforms of SCD have been characterized. SCD1 is the primary isoform found in lipogenic tissues.Loss of Scd1 is protective against obesity (3-5). The decreased adiposity in the Scd1 Ϫ/Ϫ mice is due to reduced lipid synthesis and increased energy expenditure through enhanced fatty acid oxidation (3). Scd1 Ϫ/Ϫ mice have an increase in insulin signaling and glucose uptake in muscle and brown adipose tissue (6,7).Leptin-deficient BTBR leptin ob/ob mice are a particularly useful animal model for studying obesity-related diabetes. Unlike the B6 leptin ob/ob mice, which develop only moderate hyperglycemia, BTBR leptin ob/ob mice become severely diabetic (8 -10). The diabetic BTBR leptin ob/ob mice have increased Scd1 expression in muscle and decreased expression in adipose tissue and liver, compared with nondiabetic B6 leptin ob/ob mice (10). Insulin resistance is often correlated with abdominal obesity. The BTBR mouse strain has excess abdominal obesity associated with ins...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

Self Cite

134

122

View full text Add to dashboard Cite

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“…The rapid onset and reversibility of morphologically advanced DN make this model uniquely suited for interventional studies1112. The BTBR mouse strain is hyperinsulinemic and predisposed to obesity1314. Mutant mice lacking the hormone leptin ( ob/ob ) are mildly hyperglycemic and develop pronounced obesity15.…”

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confidence: 99%

Carnosine Attenuates the Development of both Type 2 Diabetes and Diabetic Nephropathy in BTBR ob/ob Mice

Albrecht

Schilperoort

Zhang

et al. 2017

Sci Rep

114

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We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

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“…JF1 mice fed high-fat diet develop early-onset type 2 diabetes and obesity, and were ranked the fattest out of 40 mouse strains tested when fed AIN-76A diet (24). BTBR mice are prone to insulin resistance and abdominal obesity (25). Thus, difficulties in utilizing carbohydrates may contribute to the strong Fat-P preference demonstrated by the JF1 and BTBR strains, just as diabetic rats avoid the diet previously associated with a glucose load (26) and choose a low-carbohydrate, high-fat diet (27).…”

Section: Discussionmentioning

confidence: 99%

Macronutrient selection by seven inbred mouse strains and three taste-related knockout strains

Tordoff

Downing

Voznesenskaya

2014

Physiology & Behavior

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Many animals thrive when given a choice of separate sources of macronutrients. How they do this is unknown. Here, we report some studies comparing the spontaneous choices between carbohydrate-and fat-containing food sources of seven inbred mouse strains (B6, BTBR, CBA, JF1, NZW, PWD and PWK) and three mouse models with genetic ablation of taste transduction components (T1R3, ITPR3 and CALHM1). For 8 days, each mouse could choose between sources of carbohydrate (CHO-P; sucrose-corn-starch) and fat (Fat-P; vegetable shortening) with each source also containing protein (casein). We found that the B6 and PWK strains markedly preferred the CHO-P diet to the Fat-P diet, the BTBR and JF1 strains markedly preferred the Fat-P diet to the CHO-P diet, and the CBA, NZW and PWD strains showed equal intakes of the two diets (by weight). Relative to their WT littermates, ITPR3 and CALHM1 KO mice had elevated Fat-P preferences but T1R3 KO mice did not. There were differences among strains in adaption to the diet choice and there were differences in response between males and females on some days. These results demonstrate the diverse responses to macronutrients of inbred mice and they point to the involvement of chemosensory detectors (but not sweetness) as contributors to macronutrient selection.

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Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

Cited by 33 publications

References 92 publications

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Carnosine Attenuates the Development of both Type 2 Diabetes and Diabetic Nephropathy in BTBR ob/ob Mice

Macronutrient selection by seven inbred mouse strains and three taste-related knockout strains

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