Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/atorvastatin.

AIMS: To examine whether addition of amlodipine (5 mg)/atorvastatin (10 mg) A/A to Therapeutic Lifestyle change intervention (TLC) would beneficially modulate Metabolic Syndrome (MetS) and oxidized low-density lipoprotein (Ox-LDL) levels. METHODS: Patients with MetS (n = 53) were randomized to TLC + placebo or TLC + A/A for 12 months. Anthropometric measurements, blood pressure (BP), lipid profile, plasma Ox-LDL, and area under the curve of free fatty acid (AUCFFA) during oral glucose tolerance test, a marker of adipose tissue health, were assessed before and after the intervention. RESULTS: Twenty-six patients completed the study with an overall improvement of MetS (p = 0.02). TLC + placebo was beneficial in reversing MetS comparable to TLC + A/A (54% vs. 39%; p = 0.08). Both treatments decreased systolic BP (p ≤ 0.01). TLC + A/A also decreased diastolic BP and triglyceride levels. The changes in Ox-LDL levels directly correlated with changes in weight in the TLC-placebo group (r = 0.64; p = 0.04). AUCFFA determined the loss of fat mass (r = 0.472, p = 0.03). CONCLUSIONS: 1) Addition of A/A has the advantage of improving the lipid profile and BP; but TLC alone was comparable to TLC + A/A in improving MetS; 2) weight change determines the TLC-associated change in Ox-LDL levels; and 3) AT metabolic health is a significant predictor of TLC-associated loss of body fat mass.

Risk of Obesity-Related Cardiometabolic Complications in Special Populations: A Crisis in Asians.

The prospect of a significant increase in global health-related costs associated with high cardiometabolic complications of obesity in Asians has encouraged more attention to be focused on the problem of growing obesity prevalence in these populations. Although these studies have shown that cardiometabolic complications occur more frequently and at a lower body mass index (BMI) in Asians than in European populations, the mechanisms involved have yet to be discovered. Ethnic/racial differences in body composition and fat distribution have been studied extensively. Although these studies have shown that increasing BMI is associated with larger increases in body fat content in Asians, growing evidence points to factors other than body fat content and fat distribution in determining a higher prevalence of cardiometabolic complications in these populations. Here, we provide support to our view that earlier onset of adipocyte maturation arrest/insulin resistance during weight gain could be a major factor in increasing the cardiometabolic risk of Asian populations at a lower BMI.

Adipose Tissue Insulin Resistance in Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance (IR) and altered glucose-lipid metabolism. We propose that ectonucleotide pyrophosphate phosphodiesterase-1 (ENPP1), a protein known to induce adipocyte IR, is a determinant of GDM. Our objective was to study ENPP1 expression in adipose tissue (AT) of obese pregnant women with or without GDM, as well as glucose tolerance in pregnant transgenic (Tg) mice with AT-specific overexpression of human ENPP1. METHODS: AT biopsies and blood were collected from body mass index-matched obese pregnant women non-GDM (n = 6), GDM (n = 7), and nonpregnant controls (n = 6) undergoing cesarian section or elective surgeries, respectively. We measured the following: (1) Expression of key molecules involved in insulin signaling and glucose-lipid metabolism in AT; (2) Plasma glucose and insulin levels and calculation of homeostasis model assessment of IR (HOMA-IR); (3) Intraperitoneal glucose tolerance test in AtENPP1 Tg pregnant mice. RESULTS: We found that: (1) Obese GDM patients have higher AT ENPP1 expression than obese non-GDM patients, or controls (P = 0.01-ANOVA). (2) ENPP1 expression level correlated negatively with glucose transporter 4 (GLUT4) and positively with insulin receptor substrate-1 (IRS-1) serine phosphorylation, and to other adipocyte functional proteins involved in glucose and lipid metabolism (P < 0.05 each), (3) AT ENPP1 expression levels were positively correlated with HOMA-IR (P = 0.01-ANOVA). (4) Pregnant AT ENPP1 Tg mice showed higher plasma glucose than wild type animals (P = 0.046-t test on area under curve [AUC]glucose). CONCLUSIONS: Our results provide evidence of a causative link between ENPP1 and alterations in insulin signaling, glucose uptake, and lipid metabolism in subcutaneous abdominal AT of GDM, which may mediate IR and hyperglycemia in GDM.

In vivo triglyceride synthesis in subcutaneous adipose tissue of humans correlates with plasma HDL parameters.

BACKGROUNDS AND AIMS: Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. METHODS: The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after (2)H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. RESULTS: Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. CONCLUSIONS: Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions.

Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses.

Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte-specific ecto-nucleotide pyrophosphate phosphodiesterase over-expressing transgenic (AtENPP1-Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high-fat diet, AtENPP1-Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high-fat diet-fed AtENPP1-Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down-regulation of insulin receptor expression, and up-regulation of the free fatty acid receptor 1.

Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study.

CONTEXT: Liraglutide is a glucagon-like peptide-1 analog and glucose-lowering agent whose effects on cardiovascular risk markers have not been fully elucidated. OBJECTIVE: We evaluated the effect of liraglutide on markers of oxidative stress, heme oxygenase-1 (HO-1), and plasma ghrelin levels in patients with type-2 diabetes mellitus (T2DM). DESIGN AND SETTING: A prospective pilot study of 2 months' duration has been performed at the Unit of Diabetes and Cardiovascular Prevention at University of Palermo, Italy. Patients and Intervention(s): Twenty subjects with T2DM (10 men and 10 women; mean age: 57 ± 13 y) were treated with liraglutide sc (0.6 mg/d for 2 wk, followed by 1.2 mg/d) in addition to metformin (1500 mg/d orally) for 2 months. Patients with liver disorders or renal failure were excluded. MAIN OUTCOME MEASURE(S): Plasma ghrelin concentrations, oxidative stress markers, and heat-shock proteins, including HO-1 were assessed. RESULTS: The addition of liraglutide resulted in a significant decrease in glycated hemoglobin (HbA1c) (8.5 ± 0.4 vs 7.5 ± 0.4%, P < .0001). In addition, plasma ghrelin and glutathione concentrations increased (8.2 ± 4.1 vs 13.6 ± 7.3 pg/ml, P = .0007 and 0.36 ± 0.06 vs 0.44 ± 0.07 nmol/ml, P = .0002, respectively), whereas serum lipid hydroperoxides and HO-1 decreased (0.11 ± 0.05 vs 0.04 ± 0.07 pg/ml, P = .0487 and 7.7 ± 7.7 vs 3.6 ± 1.8 pg/ml, P = .0445, respectively). These changes were not correlated with changes in fasting glycemia or HbA1c. CONCLUSIONS: In a 2-months prospective pilot study, the addition of liraglutide to metformin resulted in improvement in oxidative stress as well as plasma ghrelin and HO-1 concentrations in patients with T2DM. These findings seemed to be independent of the known effects of liraglutide on glucose metabolism.

Changes in fat distribution in children following severe burn injury.

BACKGROUND: Children with severe cutaneous burn injury show persistent metabolic abnormalities, including inflammation and insulin resistance. Such abnormalities could potentially increase their future risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). This could be related to changes in body composition and fat distribution. METHODS: We studied body composition, fat distribution, and inflammatory cytokines changes in children with severe burn injury up to 6 months from discharge. Sixty-two boys and 35 girls (burn ≥30% of total body surface area) were included. RESULTS: We found a decrease in total body fat and subcutaneous peripheral fat at 6 months (6% and 2%, respectively; P<0.05 each). An inverse correlation between the decrease in peripheral fat content at 6 months and the extent of burn injury (r=-041, P=0.02) was also observed. In addition, there was a 12% increase in serum tumor necrosis factor-α (TNF-α) (P=0.01 vs. discharge) and 9% decrease in serum interleukin-10 (IL-10) (P<0.0001 vs. discharge) over 6 months after burn. CONCLUSION: Severe burn injury in children is associated with changes in body fat content and distribution up to 6 months from hospital discharge. These changes, accompanied by persisting systemic inflammation, could possibly mediate the observed persistence of insulin resistance, predisposing burn patients to the development of T2DM and CVD.

Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance.

The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level (P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA (P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid.

Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study.

BACKGROUND: Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown. METHODS: A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound. RESULTS: After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 ± 0.47 to 0.94 ± 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied. CONCLUSIONS: Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01715428.

Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin-resistant humans.

The purpose of this study was to evaluate the variability of subcutaneous abdominal adipose tissue (AT) dynamics in obese subjects with a wide range of insulin sensitivity (IS) and the correlation between these two metabolic measures. Ten obese (BMI 30-40 kg/m²) nondiabetic subjects with (n = 6) and without (n = 4) the metabolic syndrome were studied following a 12-wk ²H2O labeling period. Subcutaneous abdominal AT biopsies were collected. Deuterium incorporation into triglyceride (TG)-glycerol and TG-palmitate were measured by gas chromatography-mass spectrometry for the calculation of fractional TG synthesis (fTG) and fractional de novo lipogenesis (fDNL). Muscle IS and insulin-mediated nonesterified fatty acid (NEFA) suppression (a measure for adipose IS) indexes were derived from the oral glucose tolerance test (OGTT). The ability of subcutaneous abdominal AT to synthesize lipids varied significantly in obese subjects (fTG range 7-28%, fDNL range 1.1-4.6%) with significantly lower values (>35% reduction) for both parameters in obese with the metabolic syndrome. fTG correlated positively with muscle IS (r = 0.64, P = 0.04) and inversely with NEFA suppression during the OGTT (r = -0.69, P = 0.03). These results demonstrate a large variability in subcutaneous abdominal AT lipid turnover in obesity. Moreover, a reduced capacity for subcutaneous abdominal AT fat storage is associated with muscle and adipose tissue insulin resistance as well as with the metabolic syndrome, thus identifying a form of obesity at heightened risk for type 2 diabetes and cardiovascular disease.

Adipose tissue collagen and inflammation in nonobese Asian Indian men.

OBJECTIVE: Obesity is thought to be the driving force for activation of adipose tissue (AT) collagen production and inflammation as well as systemic insulin resistance. The objective of this study was to determine whether these AT abnormalities can be found independent of obesity in the presence of systemic insulin resistance. RESEARCH DESIGN AND METHODS: Thirty-eight normoglycemic men (14 Asian Indians and 24 white) were enrolled in the study and matched for age, body mass index, and total body fat. Subjects underwent anthropometric measurement, total body fat determination by underwater weighing, euglycemic-hyperinsulinemic clamps, and abdominal sc AT biopsy for mRNA extraction and gene expression determination. Fasting blood was collected for adipokine measurements. RESULTS: Both groups were matched for age, body mass index, and percentage of total body fat. Subcutaneous abdominal AT mRNA expression was significantly higher for Col6a3 as well as genes associated with inflammation, CD68, MAC1, and MCP1 in Asian Indians compared with whites. Asian Indian men had significantly lower rates of glucose disposal and lower plasma adiponectin concentration. Plasma high-sensitivity C-reactive protein levels showed a trend towards higher levels in Asian Indian men. CONCLUSIONS: Increased col6a3 and macrophage infiltration in AT along with increased systemic insulin resistance is present independent of body fat content in young Asian Indian men, thus suggesting that AT dysfunction associates with systemic insulin resistance regardless of AT mass.

Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis.

CONTEXT: Reduced insulin signaling in insulin secreting ß-cells causes defective insulin secretion and hyperglycemia in mice. OBJECTIVE: We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH). DESIGN: Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607). RESULTS: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001). CONCLUSIONS: Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces ß-cell function and impairs glucose homeostasis.

Heterogeneity in subcutaneous adipose tissue morphology and metabolic complications in overweight and obese women.

OBJECTIVE: The aim of this study was to assess morphological features of intact adipose tissue (AT) ex vivo from both subcutaneous (s.c.) abdominal and gluteal areas using a novel approach of multiphoton autofluorescence microscopy (MPAM) combined with second harmonic generation microscopy (SHGM), and to assess the relationship between morphological features in the two AT sites and insulin resistance to peripheral glucose disposal. METHOD: This study was a cross-sectional evaluation of AT morphology feature and peripheral insulin resistance. SUBJECTS: Fourteen overweight/obese premenopausal women underwent body composition studies, hyperinsulinemic-euglycemic clamps, and needle biopsy of both the s.c. abdominal and gluteal AT areas. MPAM combined with SHGM was used to measure adipocyte maximal diameter and collagen fiber bundle thickness within a sampled image volume after three-dimensional visualization. RESULTS: Higher body mass index (BMI) was associated with larger adipocyte diameter in s.c. abdominal, but not gluteal, AT. Higher adipocyte diameter was associated with higher pericellular collagen thickness. Adipocyte diameter in s.c. abdominal, but not gluteal, AT was associated positively with leptin and negatively with adiponectin plasma levels and peripheral glucose disposal rate. The latter correlation was no longer significant after adjustment for collagen thickness. CONCLUSION: In overweight/obese premenopausal women, larger adipocyte diameter in s.c. abdominal, but not gluteal, AT associates with low plasma adiponectin and systemic insulin resistance, and suggests that increased collagen thickness (obesity-related scarring) could contribute to these findings.

Adipose tissue dysfunction in humans: a potential role for the transmembrane protein ENPP1.

CONTEXT: Adipose tissue (AT) helps to regulate body fat partitioning and systemic lipid/glucose metabolism. We have recently reported lipid/glucose metabolism abnormalities and increased liver triglyceride content in an AT-selective transgenic model overexpressing ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), the AdiposeENPP1-Tg mouse. OBJECTIVE: The aim of the study was to test the translational hypothesis that AT-ENPP1 overexpression associates with AT dysfunction (changes in AT gene expression, plasma fatty acid, and adipokine levels), increased liver triglyceride deposition, and systemic insulin resistance in humans. DESIGN/SETTING/PARTICIPANTS: A total of 134 young normoglycemic men and women were subjected to body composition studies, hyperinsulinemic-euglycemic clamps, and AT needle biopsy. Twenty men also had liver/muscle nuclear magnetic resonance spectroscopy. MAIN OUTCOME MEASURES: Predetermined measures included AT expression of ENPP1 and other lipid metabolism/inflammation genes, plasma adipokines, and nonesterified fatty acid (NEFA) levels, liver/muscle triglyceride content, and the systemic glucose disposal rate. RESULTS: After statistical adjustment for body fat content, increasing AT-ENPP1 was associated with up-regulation of genes involved in NEFA metabolism and inflammation, increased postabsorptive NEFA levels, decreased plasma adiponectin, increased liver triglyceride content, and systemic insulin resistance in men. In women, there were no changes in plasma adiponectin, NEFAs, or glucose disposal rate associated with increasing AT-ENPP1, despite increased expression of lipid metabolism and inflammation genes in AT. CONCLUSIONS: Increased AT-ENPP1 is associated with AT dysfunction, increased liver triglyceride deposition, and systemic insulin resistance in young normoglycemic men. These findings are concordant with the AdiposeENPP1-Tg phenotype and identify a potential target of therapy for health complications of AT dysfunction, including type 2 diabetes and cardiovascular disease.

Fat distribution and insulin resistance in young adult nonobese Asian Indian women.

Although Asian Indian (people of Indian subcontinent descent) men are shown to have higher total and truncal body fat as well as greater insulin resistance compared to white men matched for total body fat and age, data in women are not conclusive. The objective of this study was to compare total and regional fat distribution and insulin sensitivity between healthy young premenopausal Asian Indian and white women of similar body mass index (BMI). Twenty Asian Indian women (65% immigrants and 35% first generation living in Dallas) and 31 white women of similar age and BMI [age 24±3 vs. 25±4; BMI 22±4 vs. 23±5; mean±standard deviation (SD) in Asian Indian and white, respectively] without diabetes were evaluated with anthropometric measurements, underwater weighing for percentage of total body fat mass, magnetic resonance imaging of whole abdomen for measurement of abdominal subcutaneous and intraperitoneal fat mass, and euglycemic-hyperinsulinemic clamp study for measurement of insulin sensitivity. There were no differences in waist or hip circumference, total body subcutaneous abdominal or intraperitoneal fat mass, fasting plasma glucose, and insulin levels between Asian Indian women and white women. The peripheral glucose disposal rate (Rd) during hyperinsulinemic-euglycemic clamp was found to be almost identical in the two study groups (median value of 6.9 and 6.8 mg/min per kg of body weight, for Asian Indians and whites, respectively). For similar total or regional fat content, the glucose disposal rate was comparable in the two study groups. In conclusion, we demonstrate that young Asian Indian women do not have excess abdominal or intraperitoneal fat or insulin resistance for similar BMI compared to white women of European descent.

Metabolic consequences of ENPP1 overexpression in adipose tissue.

Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct (AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1-TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr(1361) and Akt Ser(473). These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.