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Background and Aims: Adipose tissue (AT) serves as a vital energy storage site and plays a pivotal role in metabolic regulation, exhibiting a high response to insulin. Impairment in this response may closely associate with obesity, and NFAT (nuclear factor of activated T cells) family genes may be involved in the process. However, human data linking NFAT and AT remains elusive. The aim of this study was to assess the expression of NFAT family genes and markers of adipogenesis in subcutaneous adipose tissue (SAT) among normal-weight and overweight/obese individuals before and after weight loss, in relation to insulin sensitivity., Methods and Results: The study included 45 participants, 15 normal-weight (control group) and 30 overweight or obese, who underwent a 12-week dietary intervention (DI) program. Before and after the program hyperinsulinemic-euglycemic clamp and SAT biopsy were conducted. Before DI, a positive correlations was observed in the expression of NFATc1, NFATc4, and NFAT5 with insulin sensitivity. The expression of NFAT family genes and markers of adipogenesis in SAT was lower in individuals with overweight or obesity compared to normal-weight. Additionally, a positive correlation was noted between NFAT family genes and adipogenesis markers both before and after weight loss. Following the DI program, there was an increase in the expression of NFATc3, NFATc4, and NFAT5 in SAT., Conclusion: Decreased SAT expression of NFAT genes in obesity is partly reversed in response to weight loss. NFAT genes in SAT are associated with insulin sensitivity and adipogenesis. Registration number for clinical trial: NCT01393210., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: The beta-2 adrenergic receptor (ADRB2) is involved in energy balance regulation. The objective of our study was to evaluate the role of the rs1042714 genetic variant of ADRB2 gene on weight loss, body composition, and metabolic changes secondary to partial meal replacement (pMR) hypocaloric diet in women with obesity., Methods: We conducted an interventional study in 95 premenopausal women with body mass index ≥ 35 kg/m 2 . The subjects received two intakes per day of a normocaloric hyperproteic formula during 12 wk of a pMR diet. Body weight, body mass index, fat mass, waist circumference, lipid profile, fasting insulin levels, and homeostasis model assessment for insulin resistance were determined. All patients were genotyped rs1042714 and evaluated in a dominant model (CC versus CG + GG)., Results: Genotype frequencies were 31 (37.3%), 38 (45.8%), and 14 (16.9%) for the CC, CG, and GG genotypes, respectively. We found significant interaction effects between ADRB2 variant and pMR-induced changes (CC versus CG + GG) on body weight (-7.1 ± 0.3 versus -13.5 ± 0.5 kg; P = 0.03), body mass index (-0.9 ± 0.1 versus -1.2 ± 0.2 kg/m 2 ; P = 0.03), fat mass (-4.9 ± 0.5 versus -10.2 ±1.2 kg; P = 0.01), waist circumference (-5.1 ± 0.2 versus -10.1 ± 1.9 cm; P = 0.03), glucose (-5.1 ± 1.3 versus -12.5 ± 2.5 mg/dL; P = 0.03), total cholesterol (-18.1 ± 9.3 versus -33.5 ± 4.5 mg/dL; P = 0.03), low-density lipoprotein cholesterol (-9.1 ± 5.3 versus -24.5 ± 4.1 mg/dL; P = 0.04), triacylglycerol levels (-6.1 ± 5.3 versus -31.5 ± 9.5 mg/dL; P = 0.04), fasting insulin levels (-1.8 ± 0.3 versus -6.3 ± 0.5 IU/L; P = 0.03), and homeostasis model assessment for insulin resistance (-0.6 ± 0.3 versus -1.9 ± 0.5 U; P = 0.03). The odds ratio to improve alteration in glucose metabolism adjusted by age and weight loss throughout the study was 0.26 (95% CI, 0.07-0.95; P = 0.02) in G allele carriers., Conclusions: The G allele of rs1042714 predicts the magnitude of weight loss resulting from a pMR diet. These adiposity improvements produce a better improvement of insulin resistance and percentage of impaired glucose metabolism in G allele carriers., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The PERILIPIN1 (PLIN1) gene encodes an adipocyte-associated protein that modulates weight. The objective was to evaluate the role of the rs2289487 genetic variant of the PLIN1 gene on weight loss and glucose metabolism secondary to a partial meal replacement (pMR) hypocaloric diet., Patients and Methods: We conducted an interventional study in 111 postmenopausal obese females with body mass index (BMI) > 35 kg/m2. The subjects received two intakes per day of a normocaloric hyperproteic formula for 12 weeks., Results: After the pMR diet, body weight, (BMI), fat mass, waist circumference, fasting insulin levels and HOMA-IR decreased in both genotype groups. The improvements in these parameters were higher in C allele carriers than in subjects with TT genotype. The percentage of patients who achieved 7.5% weight loss was higher in the C carriers (57.4% vs. 27.6%), (adjusted Odds Ratio 2.14, 95% CI = 1.33-9.40; p = 0.02). The decrease in the percentage of diabetes mellitus or impaired fasting glucose decrease was statistically significant in C allele carriers (30.2% vs. 18.9%; p = 0.01) (OR 0.54, 95% CI = 0.22-0.78; p = 0.02)., Conclusions: The C allele of rs2289487 predicts the magnitude of weight loss resulting from a pMR diet. These adiposity improvements produce a better improvement in insulin resistance and the percentage of impaired glucose metabolism.

Background: The SNP (rs7139228) of the RETN gene is a polymorphism that has been associated with metabolic disorder in subjects with obesity, and its effect on metabolic response after dietary intervention has not been evaluated., Objective: Our objective was to analyse the effects of the polymorphism of the RETN gene rs7139228 on metabolic changes secondary to weight loss with a hypocaloric Mediterranean diet., Design: 1000 obese Caucasian patients were evaluated. An anthropometric evaluation and a biochemical analysis were performed before and after 12 weeks of a hypocaloric Mediterranean diet. The statistical analysis was performed as a dominant model (GG vs GA+AA)., Results: Improvements in anthropometric parameters, leptin levels and systolic blood pressure were similar in both genotype groups. In non- A allele carriers, levels of resistin, insulin, HOMA-IR, triglycerides and C-reactive protein decreased. The improvements were statistically significant in this group; resistin (-1.3+0.1ng/dL: p=0.02), triglycerides (-22.9+4.9mg/dl: p=0.02), CRP (-2.7+0 0.4mg/dl: p=0.02), insulin -6.5+1.8 mIU/L: p=0.02) and HOMA-IR (-2.2+0.8: p=0, 03). In addition, insulin, HOMA-IR and resistin levels were higher in A allele carriers than in non-carriers. Finally, the prevalence of metabolic syndrome and hyperglycaemia were higher in A allele carriers, and these percentages only decreased after intervention in non-A allele carriers., Conclusion: The A rs7139228 allele is associated with a worse metabolic response (insulin, HOMA-IR, triglycerides and CRP) after weight loss with a hypocaloric Mediterranean diet. A non-significant decrease in the prevalence of metabolic syndrome and hyperglycaemia were detected in A allele carriers., (Copyright © 2022 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: One genetic variant (rs1121980) of FTO gene has been related with body mass index and visceral adiposity. The objective of our study was to investigate the role of rs1121980 genetic variant of FTO gene on weight loss and metabolic changes secondary to a partial meal replacement (pMR) hypocaloric diet., Patients and Methods: We conducted an interventional study on 219 obese Caucasian subjects with body mass index (BMI) > 30 kg/m2. The subjects received two intakes per day of a normocaloric hyperproteic formula for 12 weeks. Adiposity and biochemical parameters (lipid profile, insulin, homeostasis model assessment (HOMA-IR) and glucose) were determined., Results: After the pMR diet, body weight, BMI, fat mass, waist circumference, blood pressure, total-cholesterol, LDL-cholesterol, triglyceride, fasting insulin levels and HOMA-IR decreased in both genotype groups. The improvements in adiposity parameters and some biochemical parameters (insulin, HOMA-IR, triglyceride levels) were bigger in non-T allele carriers than in T allele carriers. The percentage of patients who achieved 7.5% weight loss was higher in the non-T carriers (76.7% vs. 48.4%), also with a different average of weight loss (-12.3±0.3 kg vs. -5.9±0.5 kg: p=0.01). The odds ratio to achieve 7.5% of weight loss was (OR= 2.22, 95% CI=1.24-4.01; p=0.02)., Conclusions: Non-T allele carriers of rs1121980 show a higher magnitude of weight loss and improvement in adiposity parameters, insulin, HOMA-IR and triglyceride levels resulting from a pMR diet than T allele carriers.

Background: The single nucleotide polymorphism (SNP) (rs10401670) of the RETN gene has been associated with metabolic disorder in obese subjects and has scarcely been evaluated after dietary interventions. The present study aimed to analyse the effects of the rs10401670 RETN gene polymorphism on metabolic changes secondary to weight loss and secondary to a high-fat hypocaloric diet with a Mediterranean dietary pattern., Methods: A Caucasian population comprising 284 obese patients without diabetes mellitus was analysed. Before and after 3 months of a high-fat hypocaloric diet with a Mediterranean pattern, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. A statistical analysis was conducted for the combined CT and TT as a group and for wild-type CC as a second group., Results: Decreases in weight, body mass index (BMI), fat mass, systolic blood pressure and waist circumference were similar in both genotypes groups. In T allele carriers, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides and C-reactive protein levels were decreased. The decrease in these parameters was statistically significant for triglycerides (-22.3 ± 9.3 mg dl -1 : p = 0.03), C-reactive protein (-2.8 ± 0.5 mg dl -1 : p = 0.03), insulin (-7.4 ± 2.9 mUI L -1 : p = 0.03) and HOMA-IR (-2.4 ± 1.0: p = 0.02). Leptin levels were decreased in both genotypes groups after the hypocaloric diet, as well as the anthropometric parameters BMI, weight, waist circumference and fat mass. Resistin and adiponectin levels remained unchanged in both groups., Conclusions: In the present study, we have detected a significant association between the T allele of this SNP and a better response of insulin resistance, triglycerides and C-reactive protein compared to non T allele carriers after weight loss with a high-fat hypocaloric diet and a Mediterranean diet., (© 2021 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Roux-en-Y gastric bypass (RYGB) is the most efficient intervention in morbid obesity and promotes metabolic improvements in several peripheral tissues. However, the underlying molecular mechanisms are still poorly understood. To further understand the effects of RYGB on peripheral tissues transcriptomes, we determined transcriptome signatures in pancreatic islets, adipose and liver tissue from diet-induced obese (DIO) rats model following RYGB. Whereas RYGB led to discrete gene expression changes in pancreatic islets, substantial transcriptome changes were observed in metabolic and immune signaling pathways in adipose tissue and the liver, indicating major gene adaptive responses in fat-storing tissues. Compared to RYGB DIO rats, peripheral tissue transcriptome signatures were markedly different in caloric restricted weight matching DIO rats, implying that caloric restriction paradigms do not reflect transcriptomic regulations of RYGB induced weight loss. The present gene expression study may serve as a basis for further investigations into molecular regulatory effects in peripheral tissues following RYGB-induced weight loss., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Some studies have demonstrated that the allele A of FTO rs9939609 is related to both higher waist circumference and body mass index. Subsequently, some designs related biochemical variables and body weight changes with this genetic variant. We decide to analyze the effects of rs9939609 genetic variant of FTO gene on metabolic parameters and weight loss secondary to partial meal replacements hypocaloric diets (pMRHDs) in obese subjects., Patients and Methods: This was a non-randomized, single-treatment study with a formula-diet in 44 obese subjects. The patients received nutritional education and a pMRHDs with two intakes of normocaloric hyperproteic formula during 12 weeks. Anthropometric parameters and biochemical profiles were measured at basal time and after 12 weeks. The variant of FTO gene rs9939609 was determined., Results: Genotype distribution (n=44) was (16 TT (36.4%), 17 TA (38.6%) and 11 AA (25.0%)). After the pMRHD, body weight, body mass index (BMI), fat mass, waist circumference, serum leptin levels and systolic blood pressure improved in both genotypes without statistical differences in both branches. After dietary intervention with pMRHD, subjects with A allele showed a significant improvement in total cholesterol levels (TT vs. TA+AA) (-3.8±1.4 md/dL vs. -12.6±1.7 mg/dl: p=0.01), LDL-cholesterol (-0.2±1.5 md/dL vs. -10.5±1.9 mg/dl: p=0.02), insulin levels (-1.9±0.2 mU/L vs. -3.8±0.3 mU/L: p=0.02) and HOMA-IR (-0.6±0.2 units vs. -1.1±0.1 units: p=0.01)., Conclusions: Our data suggest that the genetic variant (rs9939609) of FTO gene showed better improvement of LDL-cholesterol, insulin and HOMA-IR in subjects with A allele.

Background & Aims: The risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with biochemical parameters and obesity. We study the effect of this SNP on insulin resistance and weight loss secondary to two hypocaloric diets., Methods: 270 obese subjects were randomly allocated during 9 months (Diet HP: a high protein/low carbohydrate vs. Diet S: a standard severe hypocaloric diets). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated., Results: All adiposity parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of adiposity parameters was higher in non-G allele carriers than G allele carriers. After weight loss with Diet HP, (CC vs. CG + GG at 9 months); total cholesterol (delta: -9.9 ± 2.4 mg/dl vs. -4.8 ± 2.2 mg/dl:p < 0.05), LDL-cholesterol (delta: -8.3 ± 1.9 mg/dl vs. -5.1 ± 2.2 mg/dl: p < 0.05), insulin (delta: -4.7 ± 0.8 UI/L vs. -0.9 ± 1.0 UI/L: p < 0.05), triglycerides (delta: -17.7 ± 3.9 mg/dl vs. -6.1 ± 2.8 mg/dl: p < 0.05) and HOMA IR (delta: -0.8 ± 0.2 units vs. -0.2 ± 0.1 units: p < 0.05) improved only in no G allele carriers. After weight loss with Diet S in non G allele carriers, insulin levels (delta (CC vs. CG + GG): -3.4 ± 0.6 UI/L vs. -1.2 ± 0.4 UI/L: p < 0.05), triglycerides (delta: -29.2 ± 3.4 mg/dl vs. -8.2 ± 3.8 mg/dl: p < 0.05), HOMA-IR (delta (CC vs. CG + GG): -1.1 ± 0.2 units vs. -0.1 ± 0.1 units: p < 0.05), total cholesterol (delta: -15.9 ± 7.4 mg/dl vs. -5.8 ± 2.9 mg/dl:ns) and LDL-cholesterol (delta: -13.7 ± 5.9 mg/dl vs. -6.0 ± 2.9 mg/dl: ns) decreased, too., Conclusions: our study detected a relationship of rs10830963 variant of MTNR1B gene with adiposity changes, cholesterol changes and insulin resistance modification induced by two different hypocaloric during 9 months., Competing Interests: Declaration of competing interest All authors (Author 1, Author 2, Author 3 and Author 4) declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) attenuate leptin and insulin signaling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonize hypothalamic leptin and insulin signaling and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhances CNS leptin and insulin sensitivity, represses feeding, and increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreases TCPTP expression, represses feeding, increases browning, promotes weight loss, and improves glucose metabolism in obese mice. Our findings causally link heightened hypothalamic PTP1B and TCPTP with leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to promote weight loss in obesity., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPS) have been related with adiponectin levels and risk for obesity. Our aim was to analyze the effects of rs1501299 ADIPOQ gene polymorphism on total adiponectin levels, insulin resistance and weight loss after a Mediterranean hypocaloric diet in obese subjects., Methods: A Caucasian population of 82 obese patients was analyzed, before and after 3 months on a Mediterranean hypocaloric diet. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed., Results: After dietary treatment and in wild type group, weight, BMI, fat mass, leptin levels, systolic blood pressure and waist circumference decreases were similar to the mutant type group. In wild type group, the decrease in total cholesterol was -28.1 ± 15.3 mg/dl (mutant group: -12.6 ± 16.7 mg/dl:p = 0.009), LDL- cholesterol was -31.8 ± 20.5 mg/dl (-12.2 ± 11.5 mg/dl:p = 0.006), fasting glucose plasma -4.8 ± 2.5 mg/dL (-0.5 ± 0.1 mg/dL:p = 0.02), insulin -3.6 ± 1.5 mUI/L (+0.6 ± 1.1 mUI/L:p = 0.02) and HOMA-IR -1.2 ± 0.9 (-0.1 ± 1.1:p = 0.03)., Conclusion: The present study suggests that T allele of ADIPO (rs1501299) could be a predictor of a lack of response of HOMA-IR, insulin, fasting glucose and LDL cholesterol secondary to a Mediterranean hypocaloric diet in obese subjects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: A common G-to-A transition (rs670) of the Apoprotein subtype 1 APOA1 gene has been evaluated. The presence of the A allele has been related with increased activity. We investigated the role of this genetic variant (rs670) on lipoprotein levels and anthropometric parameters after biliopancreatic diversion (BPD) surgery in morbid obese patients., Patients and Methods: Sixty-three patients with morbid obesity without diabetes mellitus type 2 were enrolled. Biochemical and anthropometric evaluation were registered before and after one, two and three years follow-up., Results: Genotype distribution was 73% (n=46) GG, 25.6% (n=16) GA and 1.4% (n=1) AA for the rs670 polymorphism. Percent excess weight loss, anthropometric and biochemical parameters improved in both groups (GG vs. GA±AA). The decrease of fasting insulin levels at 1 years (delta: -3.7±1.4 mUI/L vs. -2.9±1.2 mUI/L; p=0.02), 2 years (delta: -4.8±0.3 mUI/L vs. -4.0±0.2 mUI/L; p=0.01) and 3 years (delta: -6.7±3.1 mUI/L vs. -3.9±2.1 mUI/L; p=0.03) was higher in A allele carriers than in non carriers. The improvement of HOMA-IR levels at 1 years (delta: -3.7±1.4 mUI/L vs. -2.9±1.2 mUI/L; p=0.02), 2 years (delta: -4.8±0.3 mUI/L vs. -4.0±0.2 mUI/L; p=0.01) and 3 years (delta: -6.7±3.1 mUI/L vs. -3.9±2.1 mUI/L; p=0.03) was also higher in A allele carriers than non-carriers. Finally, the increase of HDL-cholesterol levels at 1 years (delta: 2.2±0.6 mg/dl vs. -1.2±0.2 mg/dl; p=0.001), 2 years (delta: 2.5±0.4 mg/dl vs. 0.3±0.1 mg/dl; p=0.01) and 3 years (delta: 2.4±0.6 mg/dl vs. 0.4±2.3 mg/dl; p=0.02) was higher in A allele carriers than non-carriers., Conclusions: This variant of the APOA1 gene showed important effects on HDL-cholesterol, HOMA-IR and insulin resistance after DBP for 3 years.

Objective: The aim of this study was to analyze the effects of rs670 APOA1 gene polymorphism on obesity parameters, lipid profile, glucose metabolism markers, blood pressure and adipokine levels after a hypocaloric diet with Mediterranean pattern., Material and Methods: A population of 82 obese patients was studied before and after 12 weeks on a hypocaloric diet (500 kcal per day) in an interventional study of one arm. GG and GA + AA subjects receiving the same diet. Anthropometric measures and biochemical parameters (lipid profile, glucose metabolism, blood pressure and adipokine levels) were measured. Genotype of ApoA1 gene polymorphism (rs670) was evaluated. The A allele is the risk allele., Results: After dietary intervention and in both genotype groups (GG vs. GA + AA), body mass index (BMI) (delta: -1.0 ± 0.8 kg/m 2 vs. -1.4 ± 1.0 kg/m 2 : p = 0.02), weight (delta: -2.6 ± 2.1 kg vs. -3.6 ± 2.2 kg: p = 0.03), fat mass (delta: -1.6 ± 1.1 kg vs. -3.2 ± 1.0 kg: p = 0.01) and waist circumference (delta: -1.8 ± 0.6 cm vs. -2.2 ± 1.1 cm: p = 0.02) decreased. The decrease of the anthropometric parameters was higher in A allele carriers than non-A allele carriers. In A allele carriers, total cholesterol (delta: -11.1 ± 7.1 mg/dl vs. -20.1 ± 9.0 mg/dl: p = 0.02), LDL cholesterol (delta: -10.7 ± 4.1 mg/dl vs. -21.2 ± 8.0 mg/dl: p = 0.01), insulin levels (delta: -0.6 ± 0.8 UI/L vs. 3.7 ± 1.1 UI/L; p = 0.002) and insulin resistance with HOMA-IR (delta: -0.2 ± 0.3 units vs. 0.8 ± 0.4 units; p = 0.01) decreased. The improvement of leptin was similar in both genotype groups. Resistin and adiponectin levels remained unchanged after dietary intervention., Conclusion: In this study the APOA1 (rs670) gene showed important effects on body weight, adiposity, LDL-cholesterol levels and insulin resistance after 12 weeks of the dietary intervention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To determine whether weight-loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1α (HNF1A) rs7957197 on weight loss and improvement of insulin resistance., Materials and Methods: We analysed the interaction between HNF1A rs7957197 and weight-loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults., Results: In the POUNDS Lost trial, we found that a high-fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high-fat diet group (P = .04, .03 and .01, respectively)., Conclusions: Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high-fat diet., (© 2018 John Wiley & Sons Ltd.)

Objective: To evaluate safety and efficacy of IONIS-PTP-1B Rx , a second-generation 2'- O -methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy., Research Design and Methods: In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m 2 ) with type 2 diabetes (HbA 1c ≥7.5% [58 mmol/mol] and ≤10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1B Rx 200 mg ( n = 62) or placebo ( n = 30) once weekly for 26 weeks., Results: Mean baseline HbA 1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1B Rx reduced mean HbA 1c levels by -0.44% (-4.8 mmol/mol; P = 0.074) from baseline and improved leptin (-4.4 ng/mL; P = 0.007) and adiponectin (0.99 μg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA 1c was significantly reduced (-0.69% [-7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (-33.2 μmol/L; P = 0.005) and glycated albumin (-1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1B Rx versus placebo (-2.6 kg; P = 0.002) independent of HbA 1c reduction ( R 2 = 0.0020). No safety concerns were identified in the study., Conclusions: Compared with placebo, IONIS-PTP-1B Rx treatment for 26 weeks produced prolonged reductions in HbA 1c , improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect., (© 2018 by the American Diabetes Association.)

Background: Several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPS) have been related with adiponectin levels and risk for obesity., Objective: The aim of our study was to analyze the effect of rs1501299 ADIPOQ gene polymorphism and dietary intake on total adiponectin levels and insulin resistance after two hypocaloric diets in obese subjects., Material and Methods: A Caucasian population of 284 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (I: moderate carbohydrates vs II: low fat). Before and after 12 weeks on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were realized. The statistical analysis was performed for the combined GT and TT as a group (mutant) and GG as second group (wild) (dominant model)., Results: The genotype distribution was 149 GG, 124 GT and 21 TT. With caloric restriction strategies, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, total LDL cholesterol, LDL cholesterol and leptin levels decreased. Only in subjects with GG genotype, diet I and II decreased fasting insulin levels, HOMA-IR and adiponectin levels. The improvement was similar with both diets; insulin concentrations (Diet I: -4.7 ± 1.4 mUI/L vs. Diet II: -5.9 ± 1.9 mUI/L: p = .76), HOMA-IR (Diet I: -1.4 ± 0.6 units vs. Diet II: -2.0 ± 0.7 units: p = .56) and adiponectin levels (Diet I: -10.2 ± 3.4 ng/dl vs. Diet II: -14.0 ± 2.9 ng/dl: p = .33)., Conclusion: The GG genotype of ADIPOQ gene variant (rs1501299) is associated with an increase in adiponectin levels and a decrease of insulin and HOMA-IR after weight loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Role of BDNF variants on change in body weight and cardiovascular risk factors after weight loss remains unclear in obese patients., Objective: Our aim was to analyze the effects of rs10767664 BDNF gene polymorphism on body weight, cardiovascular risk factors and serum adipokine levels after a standard hypocaloric diet in obese subjects., Design: A Caucasian population of 80 obese patients was analyzed before and after 3months on a standard hypocaloric diet., Results: Fifty patients (62.5%) had the genotype AA and 30 (37.5%) subjects had the next genotypes; AT (25 patients, 31.3%) or TT (5 study subjects, 6.3%) (second group). In non T allele carriers, the decreases in weight-3.4±2.9kg (T allele group -1.7±2.0kg:p=0.01), BMI -1.5±0.2kg (T allele group -1.2±0.5kg:p=0.02), fat mass-2.3±1.1kg (T allele group -1.7±0.9kg:p=0.009), waist circumference-3.8±2.4cm (T allele group -2.1±3.1cm:p=0.008), triglycerides -13.2±7.5mg/dl (T allele group +2.8±1.2mg/dl:p=0.02), insulin -2.1±1.9mUI/L (T allele group -0.3±1.0mUI/L:p=0.01), HOMA-IR -0.9±0.4 (T allele group -0.1±0.8:p=0.01) and leptin -10.1±9.5ng/dl (T allele group -3.1±0.2ng/dl:p=0.01) were higher than T allele carriers., Conclusion: rs10767664 variant of BDNF gene modify anthropometric and biochemical changes after weight loss with a hypocaloric diet., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The effects of rs1501299 variant of ADIPO gene on weight loss after bariatric surgery have not been evaluated. We decided to investigate the role of this genetic variant on anthropometric and biochemical outcomes such as serum adiponectin levels after biliopancreatic diversion (BPD) surgery in morbidly obese patients during 3 years., Material and Methods: A sample of 64 patients with morbid obesity without diabetes mellitus was operated. Biochemical and anthropometric evaluation were realized at basal visit and at each visit during 3 years (1, 2, and 3 years)., Results: Percent excess weight loss, body mass index, weight, waist circumference, fat mass, blood pressure, fasting glucose, LDL cholesterol, total cholesterol, and triglycerides levels improved in both genotype groups. Fasting insulin levels and HOMA-IR decreased significantly only in non-T allele carriers. The decrease of fasting insulin levels at 3 years (delta -9.2 ± 3.4 vs -2.9 ± 2.2 mUI/L; p = 0.01) and HOMA-IR (delta -1.3 ± 0.3 vs -0.8 ± 0.4 units; p = 0.03) were higher in non-T allele carriers than T carriers. Adiponectin levels increased in all times after surgery in non-T allele carriers, too. The increase of adiponectin levels at 3 years (delta 12.2 ± 3.6 vs 1.8 ± 1.2 ng/mL; p = 0.01) was higher in non-T allele carriers than T carriers., Conclusion: Non-T allele of ADIPOQ gene variant (rs1501299) is associated with increases in adiponectin levels and better improvements of insulin and HOMA-IR after BPD massive weight loss. These parameters remained unchanged in T allele carriers.

Background: A low-calorie diet (LCD) reduces fat mass excess, improves insulin sensitivity, and alters adipose tissue (AT) gene expression, yet the relation with clinical outcomes remains unclear. Objective: We evaluated AT transcriptome alterations during an LCD and the association with weight and glycemic outcomes both at LCD termination and 6 mo after the LCD. Design: Using RNA sequencing (RNAseq), we analyzed transcriptome changes in AT from 191 obese, nondiabetic patients within a multicenter, controlled dietary intervention. Expression changes were associated with outcomes after an 8-wk LCD (800-1000 kcal/d) and 6 mo after the LCD. Results were validated by using quantitative reverse transcriptase-polymerase chain reaction in 350 subjects from the same cohort. Statistical models were constructed to classify weight maintainers or glycemic improvers. Results: With RNAseq analyses, we identified 1173 genes that were differentially expressed after the LCD, of which 350 and 33 were associated with changes in body mass index (BMI; in kg/m 2 ) and Matsuda index values, respectively, whereas 29 genes were associated with both endpoints. Pathway analyses highlighted enrichment in lipid and glucose metabolism. Classification models were constructed to identify weight maintainers. A model based on clinical baseline variables could not achieve any classification (validation AUC: 0.50; 95% CI: 0.36, 0.64). However, clinical changes during the LCD yielded better performance of the model (AUC: 0.73; 95% CI: 0.60, 0.87]). Adding baseline expression to this model improved the performance significantly (AUC: 0.87; 95% CI: 0.77, 0.96; Delong's P = 0.012). Similar analyses were performed to classify subjects with good glycemic improvements. Baseline- and LCD-based clinical models yielded similar performance (best AUC: 0.73; 95% CI: 0.60, 0.86). The addition of expression changes during the LCD improved the performance substantially (AUC: 0.80; 95% CI: 0.69, 0.92; P = 0.058). Conclusions: This study investigated AT transcriptome alterations after an LCD in a large cohort of obese, nondiabetic patients. Gene expression combined with clinical variables enabled us to distinguish weight and glycemic responders from nonresponders. These potential biomarkers may help clinicians understand intersubject variability and better predict the success of dietary interventions. This trial was registered at clinicaltrials.gov as NCT00390637., (© 2017 American Society for Nutrition.)

Background: The SNP 3'UTR C/T (rs10401670), it is a polymorphism that has been associated with diabetes mellitus and it has been scarcely studied before. As far as we know, no studies on interaction among diet intervention, rs10401670 variant of RETN and metabolic response has been realized., Objective: Our aim was to analyze the effects of the rs10401670 RETN gene polymorphism on insulin resistance response and metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adults obese patients without diabetes mellitus., Design: A Caucasian population of 135 obese patients without diabetes mellitus was analyzed. Before and after 3 months on a low fat hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined CT and TT as a group (minor allele group) and wild type CC as second group (major allele group) (dominant model)., Results: Forty nine patients (36.3%) had the genotype CC (major allele group) and 86 (63.7%) patients had the next genotypes; CT (67 patients, 49.6%) or TT (19 patients, 14.1%) (minor allele group). After dietary treatment and in major allele group, weight, BMI, fat mass, systolic blood pressure and waist circumference decreases were similar than minor allele group. In T allele carriers, fasting plasma glucose, insulin, HOMA-IR, total cholesterol and LDL cholesterol levels decreased significantly. In non T allele carriers and after dietary treatment, only LDL cholesterol and total cholesterol decreased. In non T Allele carriers, the decrease in total cholesterol was -15.1 ± 18.3 mg/dl (decrease in T Allele carriers -18.3 ± 15.7 mg/dl: p > 0.05), LDL-cholesterol was -14.3 ± 18.5 mg/dl (decrease in T Allele carriers -17.3 ± 10.1 mg/dl:p > 0.05), fasting glucose plasma -2.2 ± 1.5 mg/dL (decrease in T Allele carriers -4.8 ± 1.2 mg/dL: p = 0.02), insulin -1.1 ± 2.0 mUI/L (decrease in T Allele carriers -6.3 ± 1.9 mUI/L: p = 0.001) and HOMA-IR -0.2 ± 1.0 (decrease in T Allele carriers -1.8 ± 1.4: p = 0.005). Leptin levels decrease in both genotypes after dietary treatment (-21.1 ± 8.5 ng/dL in nonT Allele carriers vs -16.2 ± 10.2 ng/dL in T Allele carriers:p > 0.05). Resistin remained unchanged in both groups., Conclusion: In our study in non-diabetic obese subjects, we describe an association of rs10401670T allele with a better metabolic response (glucose, insulin and HOMA-IR) secondary to weight loss with a hypocaloric diet., (Copyright © 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Polymorphisms of a single nucleotide in RETN have been associated with indexes of insulin resistance. Our aim was to analyze the effects of the rs1862513 RETN gene polymorphism on insulin resistance, insulin levels, and resistin levels changes after 3 months of a low-fat hypocaloric diet., Design: A Caucasian population of 133 obese patients was analyzed before and after 3 months on a low-fat hypocaloric diet., Results: Fifty-six patients (42.1%) had the genotype GG (wild group) and 77 (57.9%) patients had the other genotypes; GC (59 patients, 44.4%) or CC (18 patients, 13.5%; mutant group). In wild and mutant genotype groups, weight, body mass index, fat mass, waist circumference, and systolic blood pressure decreased. In the wild genotype group, the decrease in total cholesterol was -13.1 ± 25.3 mg/dL (vs. -4.4 ± 13.7 mg/dL in mutant group: p = 0.004 for group deltas), low density lipoprotein (LDL)-cholesterol was -13.0 ± 21.5 mg/dL (-4.3 ± 10.5 mg/dL: p = 0.007), glucose -7.2 ± 3.5 mg/dL (-0.8 ± 0.2 mg/dL: p = 0.01), insulin -5.6 ± 2.5 mUI/L (-2.9 ± 1.2 mUI/L: p = 0.03) and homeostasis model assessment-insulin resistance (HOMA-IR) -2.5 ± 1.1 (-0.6 ± 1.4: p = 0.02). Leptin levels decreased in both genotypes (-10.1 ± 9.5 ng/dL in wild type group vs. -13.1 ± 0.2 ng/dL in mutant type group: p > 0.05)., Conclusion: The present study suggests that the G/G genotype of RETN rs1862513 could be a predictor of the reduction of HOMA-IR, insulin, fasting glucose and LDL cholesterol secondary to a hypocaloric diet in obese subjects., (© 2016 S. Karger AG, Basel.)

Aims/hypothesis: Vitamin D and related genetic variants are associated with obesity and insulin resistance. We aimed to examine whether vitamin D metabolism-related variants affect changes in body weight and insulin resistance in response to weight-loss diets varying in macronutrient content., Methods: Three vitamin D metabolism-related variants, DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs2282679, were genotyped in 732 overweight/obese participants from a 2 year weight-loss trial (POUNDS Lost). We assessed genotype effects on changes in body weight, fasting levels of glucose and insulin, and HOMA-IR at 6 months (up to 656 participants) and 2 years (up to 596 participants) in response to low-protein vs high-protein diets, and low-fat vs high-fat diets., Results: We found significant interactions between DHCR7 rs12785878 and diets varying in protein, but not in fat, on changes in insulin and HOMA-IR at both 6 months (p for interaction <0.001) and 2 years (p for interaction ≤ 0.03). The T allele (vitamin-D-increasing allele) of DHCR7 rs12785878 was associated with greater decreases in insulin and HOMA-IR (p < 0.002) in response to high-protein diets, while there was no significant genotype effect on changes in these traits in the low-protein diet group. Generalised estimating equation analyses indicated significant genotype effects on trajectory of changes in insulin resistance over the 2 year intervention in response to high-protein diets (p < 0.001). We did not observe significant interaction between the other two variants and dietary protein or fat on changes in these traits., Conclusions/interpretation: Our data suggest that individuals carrying the T allele of DHCR7 rs12785878 might benefit more in improvement of insulin resistance than noncarriers by consuming high-protein weight-loss diets., Trial Registration: ClinicalTrials.gov NCT00072995.

Introduction: common polymorphisms (rs9939609) of the fat mass and obesity associated gene (FTO) have been linked to obesity., Objectives: our aim was to investigate the role of this polymorphism on insulin resistance, metabolic changes and weight loss secondary to a high monounsaturated fat vs a high polyunsaturated fat hypocaloric diets., Material and Methods: a sample of 233 obese subjects was enrolled in a prospective way. In the basal visit, patients were randomly allocated during 3 months to; Diet M (high monounsaturated fat hypocaloric diet) or Diet P (high polyunsaturated fat hypocaloric diet)., Results: after treatment with two diets and in both genotypes, weight, fat mass and waist circumference decreased. Lower levels of body mass index (BMI), weight and fat mass were detected after Diet P in A allele carriers than TT genotype subjects. With the diet type P and in both genotypes (TT and AT + AA), total cholesterol levels (-15.3 + 35.1 mg/dl vs -11.6 + 32.1 mg/dl: p > 0.05) and LDL cholesterol levels (-11.5 + 34.1 mg/dl vs -8.5 + 30.1 mg/dl: p > 0.05) decreased. In A allele carriers a significant decreased was detected in insulin levels (-2.8 + 2.1 UI/L vs -1.3 + 8.0 UI/L: p < 0.05) and HOMA index (-1.0 + 1.3 vs -0.2 + 2.1: p > 0.05), too. With the diet M and in both genotype groups, leptin levels (-8.0 + 17.1 ng/ ml vs -4.9 + 18.7 ng/ml: p > 0.05) decreased. Conclusiones: metabolic improvement secondary to weight loss was better in A carriers with a high polyunsaturated fat hypocaloric diet., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Objective: A common variant rs236918 in the PCSK7 gene has the strongest association with iron homeostasis and is related to insulin resistance. Dietary carbohydrate (CHO) modulates the genetic effect on insulin resistance. We examined whether 2-year weight-loss diets modify the effect of PCSK7 genetic variants on changes in fasting insulin levels and insulin resistance in a randomized, controlled trial., Research Design and Methods: Data were analyzed in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which is a randomized, controlled 2-year weight-loss trial using diets that differed in macronutrient proportions. PCSK7 rs236918 was genotyped in 730 overweight or obese adults (80% whites) in this trial. We assessed the progression in fasting insulin and glucose levels, and insulin resistance by genotypes., Results: During the 6-month weight-loss phase, the PCSK7 rs236918 G allele was significantly associated with greater decreases in fasting insulin levels in the high-dietary CHO group (P for interaction = 0.04), while the interaction for changes in HOMA-insulin resistance (HOMA-IR) (P for interaction = 0.06) did not reach significant levels in white subjects. The G allele was significantly associated with a greater decrease in fasting insulin levels and HOMA-IR in response to high dietary CHO levels (P = 0.02 and P = 0.03, respectively). From 6 months to 2 years (weight-regain phase), the interactions became attenuated due to the regaining of weight (P for interactions = 0.08 and 0.06, respectively). In addition, we observed similar and even stronger results in the whole-study samples from the trial., Conclusions: Our data suggest that PCSK7 genotypes may interact with dietary CHO intake on changes in insulin sensitivity in the white Americans., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to type 2 diabetes mellitus (T2DM) and insulin resistance (IR). We hypothesized that the difference in genotype may be one of the factors that affect the outcome of intervention. We genotyped 448 men with fasting glucose≥5.6 mM/L, including 371 in subjects with K allele (KK) (69 control group [CG]; and 302 intervention group [IG]) and 77 in subjects with Q allele (KQ+QQ) (13 CG and 64 IG). The web-based intervention based on a lifestyle modification was delivered by e-mail once a month for 10 months. In the KK, IG demonstrated significantly decreased levels of fasting serum insulin (FSI) as compared to CG and homeostasis model of assessment of insulin resistance (HOMA-IR). In the KQ+QQ IG group, hemoglobin A1c (HbA1c), FSI and HOMA-IR were significantly decreased, and showed further reduction in the HOMA-IR than KQ+QQ CG. After analysis of covariance, K121Q did significantly influence the change of HbA1c in CG after appropriate adjustment. In a multivariate model, BMI change predicted HOMA-IR change (adjusted β=0.801; P=0.022) in KK IG subjects with T2DM. ENPP1 K121Q did not influence the change in IR. However, individuals with T2DM carrying the K121 variant are very responsive to the effect of BMI reduction on HOMA-IR.

Objective: FSP27 KO mice showed enhanced expression of mitochondrial genes, increased mitochondrial activity and smaller lipid droplets. Here, we aimed to investigate lipid droplet protein (CIDEC/FSP27 and perilipinA (PLIN1)) gene expression in human adipose tissue in association with obesity, insulin resistance and mitochondrial gene expression., Design and Subjects: In cohort 1, CIDEC/FSP27, PLIN1, adipogenic (FASN, ACACA, PPARG, GLUT4) and mitochondrial (PPARGC1A, PPARGC1B, TFAM, MT-CO3) gene expression were analyzed in 171 adipose tissue samples (88 visceral adipose tissue (VAT) and 83 subcutaneous adipose tissue (SAT) depots) and in a time course experiment in human subcutaneous and visceral preadipocytes using real-time PCR. In cohort 2, the effects of bariatric surgery-induced weight loss were also evaluated in six caucasian morbidly obese women. Additionally, in cohort 2 FSP27 and PLIN1 protein levels were measured using western blotting., Results: CIDEC/FSP27 (1.03±0.52 vs 0.49±0.23 relative gene expression unit (R.U.), P<0.0001) and PLIN1 (1.32±0.82 vs 0.63±0.42 R.U., P<0.0001) gene were significantly more expressed in SAT than in VAT. In VAT, CIDEC/FSP27 and PLIN1 gene expression decreased with body mass index, percent fat mass, fasting glucose, fasting insulin, HOMA and were positively associated with adipogenic (PPARG, GLUT4, FASN and ACACA) and mitochondrial biogenesis (PPARGC1A, PPARGC1B, TFAM and MT-CO3)-related genes. Mitochondrial gene expression increased during adipocyte differentiation in parallel to FSP27 and PLIN1 and other adipogenic genes. After bariatric surgery-induced weight loss, PLIN1 and CIDEC/FSP27 gene and protein expression in SAT increased significantly in parallel to adipogenic and mitochondrial genes., Conclusion: These findings suggest a positive functional interaction between CIDEC/FSP27, PLIN1 and mitochondrial biogenesis-related genes in human adipose tissue.

Context: Deletion of the death receptor Fas (CD95) in adipocytes of mice is associated with improved insulin sensitivity and reduced adipose tissue (AT) inflammation., Objective: Here we investigate the relationship of AT Fas with human obesity., Design and Methods: In paired samples of omental and sc AT from 256 lean and obese (including insulin-sensitive and insulin-resistant subgroups; n=60) participants, we investigated whether Fas and Fas-ligand (FasL) mRNA expression is fat depot-specific, altered in obesity, and related to measures of AT inflammation and insulin sensitivity. In addition, AT Fas mRNA expression was measured in 16 obese patients after significant weight loss of 45±6.3 kg in the context of a two-step bariatric surgery strategy., Results: Fas and FasL are significantly higher expressed in omental (OM) compared to sc AT. Fas expression correlates with body mass index (OM, r2=0.44; sc, r2=0.14), AT macrophage infiltration (OM, r2=0.36; sc, r2=0.16), and glucose infusion rate in euglycemic-hyperinsulinemic clamps (OM, r2=0.17; sc, r2=0.13) (P<.05 for all). FasL expression most strongly correlates with adipocyte size (OM, r2=0.32; sc, r2=0.17) and AT macrophage infiltration (OM, r2=0.46; sc, r2=0.02). Insulin-sensitive obese individuals had significantly lower Fas and FasL expression than insulin-resistant obese individuals. Significant weight loss 12 months after gastric sleeve resection is associated with a significantly reduced Fas expression in OM and sc fat depots., Conclusions: Independently of body weight, increased Fas expression may contribute to impaired insulin sensitivity and AT dysfunction in obesity. Moreover, significant weight loss reduces Fas expression in OM and sc fat depots.

Objective: The aim of our study was to investigate the role of Trp64Arg polymorphism of the beta 3-adrenergic receptor (beta 3-AR) gene on metabolic changes and weight loss secondary to a high monounsaturated fat versus a high polyunsaturated fat hypocaloric diet in obese subjects., Material and Methods: A population of 260 obese subjects was analyzed. In the basal visit, patients were randomly allocated for 3 months to either diet M (high monounsaturated fat hypocaloric diet) or diet P (high polyunsaturated fat hypocaloric diet)., Results: There were no significant differences between the positive effects (on weight, body mass index, waist circumference, fat mass) in either genotype group with both diets. With diet P and in genotype Trp64Trp, glucose levels (-6.7 ± 12.1 vs. -1.2 ± 2.2 mg/dl; p < 0.05), total cholesterol (-11.2 ± 8.1 vs. -1.0 ± 7.1 mg/dl; p < 0.05), low-density lipoprotein (LDL) cholesterol (-9.7 ± 10.1 vs. -2.2 ± 8.1 mg/dl; p < 0.05), triglycerides (-11.7 ± 13.1 vs. +1.7 ± 10.3 mg/dl; p < 0.05), homeostasis model assessment for insulin resistance (HOMA-R; -0.7 ± 1.1 vs. -0.3 ± 2.1 units; p < 0.05) and insulin levels (-1.8 ± 4.6 vs. -1.0 ± 9.1 mIU/l; p < 0.05) decreased., Conclusion: The metabolic effect of weight reduction by the two hypocaloric diets is greatest in subjects with the normal homozygous beta 3-AR gene. Improvements in total cholesterol, LDL cholesterol, triglyceride, glucose, insulin and HOMA-R levels were better than in the heterozygous group., (Copyright © 2013 S. Karger AG, Basel.)

Background: Glucose-dependent insulinotropic polypeptide [also known as gastric inhibitory polypeptide (GIP)] and its receptor (GIPR) may link overnutrition to obesity, insulin resistance, and type 2 diabetes. A GIPR variant rs2287019 was recently associated with obesity and glucose metabolism., Objective: We aimed to examine whether weight-loss diets that vary in fat content may modify the effect of this variant on changes in body weight, fasting glucose, and insulin resistance in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial., Design: We genotyped the GIPR rs2287019 in 737 overweight adults who were randomly assigned to 1 of 4 weight-loss diets that varied in macronutrient contents for 2 y. We assessed the percentage changes in body weight, fasting glucose, and insulin resistance (HOMA-IR) across genotypes by the low-fat and high-fat diets., Results: At 6 mo of diet intervention, the T allele of rs2287019 was associated with greater weight loss (β ± SE: -1.05 ± 0.56%; P = 0.06) and greater decreases in fasting glucose (β ± SE: -2.33 ± 0.86%; P = 0.006), fasting insulin (β ± SE: -8.76 ± 4.13%; P = 0.03), and HOMA-IR (β ± SE: -10.52 ± 4.39%; P = 0.01) in participants who were assigned to low-fat diets, whereas there was no significant genotype effect on changes in these traits in the group assigned to the high-fat diet (all P > 0.44; P-interaction = 0.08, 0.04, 0.10, and 0.07, respectively). After correction for multiple tests (significant P = 0.008), the genotype effect on changes in fasting glucose remained significant. Sensitivity analysis in white participants showed that the interactions were more evident on changes in insulin and HOMA-IR (P-interaction < 0.008)., Conclusion: The T allele of GIPR rs2287019 is associated with greater improvement of glucose homeostasis in individuals who choose a low-fat, high-carbohydrate, and high-fiber diet. The POUNDS LOST trial was registered at clinicaltrials.gov as NCT00072995.

Background: Common genetic variants in the insulin receptor substrate 1 (IRS1) gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial., Methods and Results: We genotyped IRS1 rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to 1 of 4 diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin (P=0.009), HOMA-IR (P=0.015), and weight loss (P=0.018) than those without this genotype in the highest-carbohydrate diet group whereas an opposite genotype effect on changes in insulin and HOMA-IR (P≤0.05) was observed in participants assigned to the lowest-carbohydrate diet group. No significant differences were observed across genotypes in the other 2 diet groups. The tests for genotype by intervention interactions were all significant (P<0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest-carbohydrate diet group (P<0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR (P for genotype-time interaction ≤0.009) in participants with the CC genotype than those without this genotype across 2-year intervention., Conclusions: Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet., Clinical Trial Registration: http:www.clinicaltrials.gov. Unique identifier: NCT00072995.

Context: Genome-wide association studies have shown that the melatonin receptor 1B (MTNR1B) gene locus is strongly associated with fasting glucose and β-cell function. However, data are rather limited to the adult population and normal-weight children. So far, little is known whether similar associations are present in overweight and obese children and adolescents., Objective: The aim is to investigate an MTNR1B polymorphism in a sample of 310 overweight and obese children and adolescents (mean body mass index standard deviation score (BMI-SDS)): 2.74 (± 0.55), mean age: 14 (± 2) years), who participated in a short-term weight-loss program based on energy reduction, physical activity, and behavior therapy., Methods: We investigated an association between genotype and fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and of β-cell function (HOMA-B), and anthropometric parameters and their change during intervention., Results: The minor G allele of polymorphism rs10830963 was significantly associated with increased fasting glucose (0.205  mmol/l, P<0.0001) and decreased HOMA-B (-0.353, P < 0.0001). Categorizing the sample into BMI-SDS groups, these significant associations were abolished in children with BMI-SDS below 2.5 but remained in those with higher BMI-SDS values with stronger β-estimates. The P value for the genotype × BMI-SDS category interaction was 0.012 for fasting glucose and 0.083 for HOMA-B. There was no significant association between genotype and anthropometric parameters and their change during intervention., Conclusions: This is the first single study, replicating the association between the MTNR1B locus and diabetes-related traits in overweight and obese children and adolescents. The effect sizes in children and adolescents seem to be stronger than in adults and differed among BMI-SDS categories.

It has been demonstrated that the polymorphism 385 C/A of fatty acid amide hydrolase was associated with obesity. We decided to investigate the role of a polymorphism (cDNA 385 C->A) on insulin resistance and weight loss secondary to a low-fat vs a low-carbohydrate diet. A population of 248 patients with obesity was analyzed. Basal measurements were performed, and values were compared to those at the end of a 3-month period in which subjects received either diet I (low fat) or diet II (low carbohydrate). One hundred seventy-eight patients (71.8%) had the genotype C358C (wild-type group), and 70 (28.2%) patients had the genotype C358A (62 patients, 25%) or A358A (8 patients, 3.2%) (mutant-type group). With diet I, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in the wild-type and mutant-type groups. With diet II, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in both genotypes. With diet I, leptin, glucose, total cholesterol, triglyceride, insulin, and homeostasis model assessment for insulin sensitivity (HOMA) decreased in the wild-type group. In the mutant-type group, only cholesterol decreased in a significant way. With diet II, leptin, interleukin-6, glucose, total cholesterol, low-density lipoprotein cholesterol, insulin, HOMA, and C-reactive protein decreased in the wild-type genotype. The allele A358 of fatty acid amide hydrolase was associated with a lack of improvement on glucose insulin, HOMA, and leptin levels in both diets after weight loss., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The skeleton is regarded recently as an endocrine organ that affects energy metabolism. However, there are very limited data available concerning the relationships between the osteoblast-derived hormone osteocalcin, weight status, adiponectin and leptin in obese humans, especially in children., Methods: We analyzed osteocalcin, adiponectin, leptin and insulin resistance (IR) index homeostasis model assessment (HOMA) in 60 obese and 19 age- and gender-matched normal weight children. Furthermore, these parameters were determined in 60 obese children after participating in an outpatient 1-year lifestyle intervention based on exercise, behavior and nutrition therapy., Results: Sixty obese children had significantly lower osteocalcin levels (26.8+/-0.8 ng ml(-1)) than 19 normal weight controls (32.2+/-2.3 ng ml(-1)). Boys (29.9+/-1.1 ng ml(-1)) showed significantly (P=0.046) higher osteocalcin levels compared with girls (26.4+/-1.2 ng ml(-1)). In stepwise multiple linear regression analysis adjusted for age, gender and pubertal stage, osteocalcin was significantly negatively related to leptin and HOMA, but not to adiponectin. Changes of osteocalcin in the course of 1 year correlated significantly negatively with changes of IR index HOMA (r=-0.25), standard deviation score-body mass index (SDS-BMI) (r=-0.33) and leptin (r=-0.50). Substantial weight loss in 29 obese children led to a significant increase in osteocalcin and a significant decrease in leptin and HOMA. In 31 obese children without substantial weight loss, osteocalcin levels did not change significantly in the course of 1 year., Conclusion: Osteocalcin levels were lower in obese children and were related to IR and leptin both in cross-sectional and longitudinal analyses. Therefore, osteocalcin might be a new promising link between obesity and IR.

Objective: The mechanisms underlying the association of the increased albumin excretion rate (AER) with adiposity have yet to be clarified. We therefore investigated (1) the predictors of AER after 3 months of lifestyle intervention in a large cohort of nondiabetic obese women and (2) the relationships between AER and the adipose tissue gene expression of adipokines linked to inflammation and insulin resistance., Subjects: A total of 269 obese nondiabetic women (age 49.9+/-13.1 years, body mass index (BMI) 36.8+/-4.6 kg m(-2)) participated in this program. Measurements used were anthropometrics parameters, blood pressure, oral glucose tolerance test, lipids, creatinine, AER, homeostasis model assessment of insulin resistance (HOMA-IR) and glomerular filtration rate at baseline and after 3 months of lifestyle intervention. At baseline, in a subgroup of 34 women, subcutaneous adipose tissue biopsy was carried out for the analysis of mRNA expression levels of adiponectin, suppressor of cytokine signaling 3 (SOCS-3), tumor necrosis factor alpha (TNF-alpha), pentraxine 3 (PTX-3), angiotensinogen and angiotensin-converting enzyme, and a blood sample was also taken from this group for the measurement of circulating adiponectin, interleukin-6, TNF-alpha and PTX-3. Microalbuminuria was defined as albumin/creatinine ratio >or=3.5 mg mmol(-1). Real-time PCR was used to quantify mRNA., Results: Six percent of obese women had microalbuminuria. When dividing the whole cohort into three groups according to AER changes (decrease, stability and increase), we noted that 2 h glucose, insulin and HOMA-IR significantly decreased (P<0.05 for all) only in women who had a decrease in AER, whereas BMI and waist circumference significantly decreased in all the three groups (P<0.05). At baseline, higher AER was associated to significantly higher adipose tissue mRNA expression levels of SOCS-3 and PTX-3 (P<0.05) and to higher TNF-alpha and angiotensinogen expression., Conclusions: In obese women, weight loss alone is not sufficient to induce the AER decrease that occurs only with a concomitant improvement in glucose homeostasis. The adipose tissue gene expression profile seems to favor the early renal impairment often seen in obese subjects.

Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.

Objective: To investigate the influence of the Trp64Arg polymorphism in the beta 3-adrenoreceptor gene on adipocytokines, insulin resistance and weight loss secondary to a low fat versus a low carbohydrate diet., Methods: A population of 193 obese patients was analyzed. A nutritional evaluation was performed at the beginning and at the end of a 2-month period in which subjects received 1 of 2 hypocaloric diets., Results: 172 (89.1%; 44 males, 128 females) subjects had the genotype Trp64/Trp64 (wild-type group) and 21 subjects (10.9%; 4 males, 17 females) had Trp64/Arg64 (mutant-type group). In the wild-type group BMI, weight, fat mass, waist circumference, systolic blood pressure, glucose, triglycerides, insulin, homeostasis model assessment (HOMA) and leptin decreased significantly regardless of the diet. In the mutant-type group, this was the case for BMI, weight, waist circumference, fat mass and leptin levels. Only leptin levels have a significant decrease in the wild-type group (diet I 13.7%, diet II 26.3%, p < 0.05 for both). In the mutant group, leptin decreased as well (diet I 22.5%, diet II 30.1%, p < 0.05 for both)., Conclusion: The metabolic effect of mild weight reduction by 2 hypocaloric diets is greatest in subjects homozygous for the normal beta 3-adrenoreceptor gene. Improvement in glucose, insulin and HOMA is better than in the mutant-type group., (2009 S. Karger AG, Basel.)

Aim: The Gly482Ser missense mutation of the transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) has been involved in insulin function impairments, with conflicting results. The current study investigated the relationships of carrying this polymorphism with insulin resistance (IR) during a short-term weight-loss and the subsequent weight follow-up., Methods: The Gly482Ser was genotyped in 180 Spanish volunteers [body mass index: 31.4+/-3.2kg/m(2); age: 35+/-5 years]. Specific phenotypical measurements were determined at baseline, following an 8-week low-calorie diet (LCD) as well as after 6-month and 1-year of follow-up., Results: At baseline the Ser482Ser genotype was associated with higher HOMA-IR and insulin concentrations than the other genotypes (p<0.05), which was accompanied by an increased higher risk of IR (OR: 2.97; 95% CI: 1.24-7.15). After following the LCD, such increased risk of insulin insensitivity in Ser482Ser carriers was toned down (p>0.05). This outcome was sustained after 6-month and 1-year of follow-up (p>0.05)., Conclusions: These data show an increased risk of IR in obese carrying the rs8192673 Ser482Ser genotype. This risk was markedly reduced by an energy-restricted diet, which was sustained 6 months and 1 year after the diet therapy. This observation allows identifying obese subjects who might personally profit most from an energy-restrictive treatment concerning insulin response and lead to more individualized prognostic and therapeutic decisions.

Background and Objective: An accumulating body of evidence shows that modest weight loss (5%) through dietary changes and exercices is an effective means for managing obesity-associated disorders. As far as we kow, nobody has described the dietary response in insulin resistance and adipocytokines, analyzing the G308A variant of the tumor necrosis factor alpha (TNF-alpha) gene. The aim of our study was to investigate the influence of G308A polymorphism in the TNF-alpha gene on insulin resistance and weight loss secondary to a hypocaloric diet in obese patients., Patients and Method: A population of 69 obese -body mass index (BMI) > 30 kg/m2- non diabetic outpatients was analyzed in a prospective way. Before and after 3 months of life style modification program, tetrapolar electrical bioimpedance, blood pressure, a serial assessment of nutritional intake with 3 days written food records and biochemical analysis were performed. The lifestyle modification program consisted of a hypocaloric diet 1,520 kcal., Results: Sixty-nine patients completed the follow-up during 3 months, with a weight loss (standard deviation) of 2.96 (3.4) kg (3.3%). Fifty two patients (13 males and 39 females) (75.3%) had the genotype G308/G308 (wild group) with an average age of 44.9 (16.8) years, and 17 patients (5 males and 12 females) (24.7%) had the genotype G308/A308 (mutant group) with an average age of 48.3 (15.2) years, without statistical differences. In mutant type group, BMI, body weight and waist circumference decreased. Mutant type group had higher basal and after treatment weight than wild group., Conclusions: Weight loss is associated with different changes depending of TNF-alpha genotype. Carries of G308G variant of TNF-* gene have a better metabolic response than A308 obeses.

Context: It is unknown whether genetic factors that play an important role in body weight homeostasis influence the response to laparoscopic adjustable gastric banding (LAGB)., Objective: We investigated the impact of common polymorphisms in four candidate genes for insulin resistance on weight loss after LAGB., Design: The design was a 6-month follow-up study., Setting: The study setting was hospitalized care., Patients: A total of 167 unrelated morbidly obese subjects were recruited according to the following criteria: age, 18-66 yr inclusive; and body mass index greater than 40 kg/m2 or greater than 35.0 kg/m2 in the presence of comorbidities., Intervention: LAGB was used as an intervention., Main Outcome Measure: Measure of correlation between weight loss and common polymorphisms in candidate genes for insulin resistance and obesity was the main outcome measure., Results: The following single nucleotide polymorphisms were detected by digestion of PCR products with appropriate restriction enzymes: Gly972Arg of the insulin receptor substrate-1 gene, Pro12Ala of the proliferator-activated receptor-gamma gene, C-174G in the promoter of IL-6 gene, and G-866A in the promoter of uncoupling protein 2 gene. Baseline characteristics including body mass index did not differ between the genotypes. At the 6-month follow-up after LAGB, carriers of G-174G IL-6 genotype had lost more weight than G-174C or C-174C genotype (P = 0.037), and carriers of A-866A uncoupling protein 2 genotype had lost more weight as compared with G-866G (P = 0.018) and G-866A (P = 0.035) genotype, respectively. Weight loss was lower in carriers of Gly972Arg insulin receptor substrate-1 genotype than Gly972Gly carriers, but not statistically significant (P = 0.06). No difference between carriers of Pro12Ala and Pro12Pro proliferator-activated receptor-gamma genotype was observed., Conclusions: These data demonstrate that genetic factors, which play an important role in the regulation of body weight, may account for differences in the therapeutic response to LAGB.

Apolipoprotein (APO) C1 is a 6.6-kDa protein present in plasma and associated with lipoproteins. Using hyperinsulinemic-euglycemic clamp tests, we previously found that in APOC1 transgenic mice, the whole-body insulin-mediated glucose uptake is increased concomitant with a decreased fatty acid uptake. These latter results are confirmed in the present study, showing that APOC1 transgenic mice exhibit a 50% reduction in the uptake of the fatty acid analog 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid in white adipose tissue stores. We next investigated whether APOC1 overexpression can modulate the initiation and/or development of obesity and insulin resistance. When crossbred on the genetically obese ob/ob background, APOC1 transgenic mice were fully protected from the development of obesity compared with ob/ob only mice, as reflected by a strong reduction in body weight (21 +/- 4 vs. 44 +/- 7 g), total adipose tissue stores (15 +/- 3 vs. 25 +/- 3% body wt), and average adipocyte size (7,689 +/- 624 vs. 15,295 +/- 1,289 microm(2)). Although less pronounced, APOC1 overexpression also reduced body weight on a wild-type background, solely due to a reduction in adipose tissue. Furthermore, despite elevated plasma free fatty acid and triglyceride levels, APOC1 overexpression significantly improved insulin sensitivity in ob/ob mice, as demonstrated by a strong reduction in plasma glucose and insulin levels, as well as a better performance in the glucose tolerance test. In conclusion, a marked reduction in the uptake of fatty acids into adipocytes may underlie the protection from obesity and insulin resistance in transgenic mice overexpressing human APOC1.