Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci.

Stoehr, Jonathan P.; Nadler, Samuel T.; Schueler, Kathryn L.; Rabaglia, Mary E.; Yandell, Brian S.; Metz, Stewart A.; Attie, Alan D.

doi:10.2337/diabetes.49.11.1946

Cited by 134 publications

(126 citation statements)

References 42 publications

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“…The high-fat diet contains 195 g/kg casein, 3 g/kg DL-methionine, 377 g/kg sucrose, 150 g/kg corn starch, 153 g/kg anhydrous milkfat, 10 g/kg corn oil, 1.5 g/kg cholesterol, 60.067 g/kg cellulose, 35 g/kg mineral mix AIN-76 (170915), 4 g/kg calcium carbonate, 10 g/kg vitamin mix Teklad (40060), 1.2 g/kg choline bitartrate, and 0.033 g/kg ethoxyquin (antioxidant).The weight of each mouse within each group was measured weekly; the data are presented as means Ϯ SD (n ϭ 8, P Ͻ 0.001). The glucose tolerance and insulin tolerance were determined as described (21).…”

Section: Methodsmentioning

confidence: 99%

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

Ntambi

Miyazaki

Stoehr

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

996

913

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Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1) and palmitoleate (C16:1), which are components of membrane phospholipids, triglycerides, wax esters, and cholesterol esters. Several SCD isoforms (SCD1-3) exist in the mouse. Here we show that mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased insulin sensitivity, and are resistant to diet-induced weight gain. The protection from obesity involves increased energy expenditure and increased oxygen consumption. Compared with the wild-type mice the SCD1؊͞؊ mice have increased levels of plasma ketone bodies but reduced levels of plasma insulin and leptin. In the SCD1؊͞؊ mice, the expression of several genes of lipid oxidation are up-regulated, whereas lipid synthesis genes are down-regulated. These observations suggest that a consequence of SCD1 deficiency is an activation of lipid oxidation in addition to reduced triglyceride synthesis and storage.S tearoyl-CoA desaturase (SCD) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. It catalyzes the introduction of the cis double bond in the ⌬9 position of fatty acyl-CoA substrates. The preferred desaturation substrates are palmitoyl-CoA and stearoyl-CoA, which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively (1-4). These fatty acids are requisite components of membrane phospholipids, triglycerides, cholesterol esters, and wax esters (5-7). Effects on composition of phospholipids ultimately determine membrane fluidity, and the effects on the composition of cholesterol esters and triglycerides can affect lipoprotein metabolism and adiposity. SCD expression is sensitive to dietary factors including polyunsaturated fatty acids, cholesterol and vitamin A, hormonal changes (i.e., insulin and glucagon), developmental processes, temperature changes, thiazolinediones, metals, alcohol, peroxisomal proliferators, and phenolic compounds (3). High SCD activity has been implicated in a wide range of disorders including diabetes, atherosclerosis, cancer, obesity, and viral infection (3,(8)(9)(10)(11)(12)(13).The existence of multiple SCD isoforms in mice (6, 14-18) and rats makes it difficult to determine the role of each isoform in lipid metabolism. New insights into the physiological role of the SCD1 gene and its endogenous products came from recent studies of the asebia mouse strains (ab j and ab 2j ) that have naturally occurring mutations in SCD1 (17-19) as well as a laboratory mouse model with a targeted disruption (SCD1Ϫ͞Ϫ) (6). We used these animal models to show that SCD1Ϫ͞Ϫ mice are deficient in hepatic triglycerides and cholesterol esters (7,20). The levels of palmitoleate (16:1) and oleate (18:1) are reduced, whereas palmitate and stearate are increased in the lipid fractions of SCD1Ϫ͞Ϫ mice. On a high carbohydrate diet supplemented with triolein, the cholesterol ester levels are corrected but the triglyceride levels are not reversed to the ...

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Section: Methodsmentioning

confidence: 99%

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

Ntambi

Miyazaki

Stoehr

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

996

913

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“…BTBR Scd1 Ϫ/Ϫ mice were created from SV129 Scd1 Ϫ/Ϫ (14) mice using marker-assisted backcrossing (15) for at least six generations. BTBR leptin ob/ob mice were independently created from B6 leptin ob/ϩ mice using marker-assisted backcrossing for at least six generations (8 Ϫ/Ϫ mice. Mice were housed on a 12-h light-dark cycle, lights on at 0600 h. Mice had free access to a chow diet of roughly 6% fat (by mass; Purina 5008) and water except during fasts.…”

Section: Methodsmentioning

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

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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“…In an F2 intercross between two strains differing in susceptibility to obesity-induced diabetes, we mapped T2dm2, a quantitative trait locus (QTL) on mouse chromosome 19 affecting fasting insulin levels (13). Using interval-specific congenic mouse strains, we recently identified SorCS1 as the gene underlying T2dm2 (14).…”

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confidence: 99%

SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

et al. 2007

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OBJECTIVE-A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. RESULTS-We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. RESEARCH DESIGN AND METHODS-WeCONCLUSIONS-Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes. Diabetes

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Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci.

Cited by 134 publications

References 42 publications

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

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

SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

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