Thyroxine Treatment During the Perinatal Stage Prevents the Alterations in the ObRb-STAT3 Leptin Signaling Pathway Caused by Congenital Hypothyroidism

2020 ◽  
Vol 52 (11) ◽  
pp. 815-821
Author(s):  
Jorge Tapia-Martínez ◽  
Edgar Cano-Europa ◽  
Vanessa Blas-Valdivia ◽  
Margarita Franco-Colín
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Signaling Pathway ◽  
Congenital Hypothyroidism ◽  
Metabolic Programming ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Thyroxine Treatment ◽  
Pregnancy And Lactation

AbstractThyroid hormone deficiency during crucial stages of development causes congenital hypothyroidism. This syndrome alters hypothalamic pathways involved in long-term bodyweight regulation as ObRb-STAT3 leptin signaling pathway, which is associated with metabolic syndrome. This study aimed to determine if thyroxine treatment during pregnancy and lactation in hypothyroid mothers avoids, in the congenital hypothyroid offspring, the alterations in metabolic programming related to metabolic syndrome and the ObRb-STAT3 leptin signaling pathway in hypothalamus. Twenty-four virgin female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with thyroxine treatment (20 μg/kg/day T4 since pregnancy until lactation). The bodyweight and energy intake, insulin resistance, glucose tolerance, metabolic and hormonal parameters were determined in offspring at 28 weeks after birth. Then, the rats were euthanized to obtain adipose tissue reserves and hypothalamus to measure the expression of ObRb, STAT3, pSTAT3, and SOCS3. Congenital hypothyroidism presented metabolic syndrome such as insulin resistance, glucose tolerance, dyslipidemias, an increase in cardiovascular risk (Castelli I males:166.67%, females: 173.56%; Castelli II males: 375.51%, females: 546.67%), and hypothalamic leptin resistance (SOCS3, Males: 10.96%, females: 25.85%). Meanwhile, the thyroxine treatment in the mothers during pregnancy and lactation prevents the metabolic disturbance. In conclusion, thyroxine treatment during the critical perinatal stage for metabolic programming prevents congenital hypothyroidism-caused metabolic syndrome and hypothalamic leptin resistance.

Congenital Hypothyroidism is Associated With Impairment of the Leptin Signaling Pathway in the Hypothalamus in Male Wistar Animals in Adult Life

2019 ◽  
Vol 51 (05) ◽  
pp. 330-335 ◽  
Author(s):  
Veronica Aiceles ◽  
Flavia Gombar ◽  
Fernanda Cavalcante ◽  
Cristiane Ramos
Keyword(s):  
Signaling Pathway ◽  
Congenital Hypothyroidism ◽  
Weight Control ◽  
Adult Life ◽  
Serum Levels ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Significant Expression ◽  
Body Weight Control ◽  
Post Hoc

AbstractThe goal of this study is to investigate whether congenital hypothyroidism induced by MMI during gestation (G) or gestation plus lactation (GL) would affect the leptin action upon body weight control on hypothalamus. Six to eight pups per group were killed at 90 days of age. For statistical analysis one-way ANOVA followed by the Holm–Sìdak post hoc test was used. Hypothyroidism resulted in a significant increase in leptin serum levels in G 20% and GL 25% (p<0.04). There was a significant expression decrease of OBR in G 45% and GL 63%; pSTAT3 in G 56% and GL 51%; pERK in G 50% and GL 48%; POMC in G 41% and GL 46% (p<0.04), while a significant increase was assigned to SOCS3 in G 52% and GL 170% (p<0.04) protein expression. We can conclude that hypothyroxinemia condition in rats on adulthood results in impairment of the leptin signaling pathway via ObRb-STAT3 in the hypothalamus, which is likely to be involved in the leptin resistance.

scholarly journals Comparison of high-fat and high-carbohydrate diets for obtaining an experimental model of metabolic syndrome

2021 ◽  
Vol 15 (1) ◽  
pp. 3-14
Author(s):  
T. S. Petryn ◽  
◽  
M. R. Nagalievska ◽  
N. O. Sybirna ◽  
◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Pathological Condition ◽  
Male Rats ◽  
Laboratory Animals ◽  
Atherogenic Dyslipidemia ◽  
Chow Diet ◽  
High Fat ◽  
High Carbohydrate

Introduction. Metabolic syndrome is a cluster of metabolic abnormalities that includes hypertension, central obesity, insulin resistance and atherogenic dyslipidemia. Given the wide geographical distribution and growing number of people suffering from this disease, there is an urgent need in developing animal models that would accurately reproduce the development of all symptoms of human metabolic syndrome (insulin resistance, dyslipidemia, obesity and hypertension). The most cost-effective method related to the real causes of metabolic syndrome is the use of different types of diets. Materials and Methods. The study was performed on white outbred male rats about 6 months old and weighing 300–400 g. The metabolic syndrome was induced by high-fat and high-carbohydrate diets. The lipid-enriched diet involved the consumption of regular chow diet for laboratory animals with additional fat content (40 % by weight of chow). The source of additional lipids was olive oil, which is rich in monounsaturated fatty acids (MUFAs). Animals on the diet enriched in carbohydrates together with regular chow diet for laboratory animals consumed 10 % fructose solution instead of drinking water. Glucose tolerance tests were conducted and areas under the glycemic curves were calculated. We determined the content of glycated hemoglobin and glucose concent­ration, the concentration of low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and cholesterol in the blood plasma of rats. Results. The development of metabolic syndrome induced by an excessive consumption of carbohydrates and lipids for 42 days was accompanied by impaired glucose tolerance, increased glycosylated hemoglobin, triglycerides and cholesterol concentrations, as well as a decreased HDL content. An increase in the concentrations of LDL and activity of paraoxonase were found due to the induction of the pathological condition by an excessive fat intake, while a high carbohydrate diet caused a decrease in paraoxonase activity. Conclusions. The use of fructose for 42 days causes the most pronounced manifestations of the studied pathology. The use of this model will allow determining the biochemical and molecular changes that accompany the development of this pathological condition. It will also facilitate the development and evaluation of the effectiveness of new therapeutic approaches to the treatment of metabolic syndrome.

scholarly journals Consumption of added sugars and development of metabolic syndrome components among a sample of youth at risk of obesity

2014 ◽  
Vol 39 (4) ◽  
pp. 512-512 ◽  
Author(s):  
JiaWei Wang
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
Diet Quality ◽  
Healthy Eating Index ◽  
Added Sugar ◽  
Added Sugars ◽  
Sugar Intake

Previous evidence showed controversial links between added sugar intake, diet quality, and increasing prevalence of metabolic syndrome (MetS) components (abdominal adiposity, dysglycemia, elevated blood pressure, reduced high-density lipoprotein cholesterol (HDL-C), and hypertriglyceridemia) in youth, and most studied only its liquid source of sugar-sweetened beverages (SSB). To better understand the extent of the detrimental effects of added sugars from both liquid and solid sources to diets in terms of nutrient and food intake and metabolic consequences in children, 3 studies were undertaken to (i) quantify the associations of added sugar intake with overall diet quality and adiposity indicators; (ii) assess whether excess weight and glucose tolerance status modifies the associations between consumption of added sugars and MetS components; and (iii) evaluate whether consumption of added sugars predicts the development of MetS components over time. Data for these studies were obtained from the Quebec Adiposity and Lifestyle Investigation in Youth cohort. Caucasian children (8 to 10 years at baseline, N = 630) with at least 1 obese biological parent were recruited from 1040 Quebec primary schools and followed-up 2 years later (N = 564). Dietary intake, including added sugars (liquid vs. solid) and Canadian Healthy Eating Index (HEI-C) was assessed in three 24-h recalls at baseline. Adiposity indicators included measured height and weight for body mass index (BMI), BMI z score, waist circumference (WC), and fat mass (by dual-energy X-ray absorptiometry). Plasma glucose and insulin were measured at fasting and by oral glucose tolerance tests to calculate the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda IS index (Matsuda-ISI). Systolic blood pressure (SBP), concentration of triglycerides and HDL-C were measured by standard instruments. Multivariate linear regression models were used, adjusting for age, sex, pubertal status (by Tanner stage), energy intake, fat mass, and physical activity (by 7-day accelerometer). The main findings include the following: (i) Higher consumption of added sugars from SSB or solid sources was associated with lower nutrient density and lower HEI-C. Positive associations with adiposity indicators were observed with consumption of added sugars from liquid sources only. (ii) Higher SSB consumption was associated with higher HOMA-IR and higher SBP among overweight children (≥85th BMI percentile), as well as higher SBP and higher WC among children with impaired glucose tolerance. These associations with metabolic indicators were not observed among children whose BMI was below 85th percentile. (iii) No association with added sugar intake was observed for 2-year changes in adiposity, but higher consumption of added sugars from liquid sources was associated with higher fasting glucose, higher fasting insulin, higher HOMA-IR, and lower Matsuda-ISI. In conclusion, this thesis suggested that consumption of added sugars from both solid and liquid sources was associated with a lower overall diet quality, but only added sugars from liquid sources was associated with adiposity indicators. Cross-sectional links with higher levels of SSB intake and MetS components were more evident among overweight/obese and glucose-intolerant children. Consumption of added sugars from liquid sources was not associated with changes in adiposity over 2 years, but was clearly associated with development of impaired glucose homeostasis and insulin resistance. This thesis presents further evidence on the nutritional and metabolic consequences of consuming added sugar from liquid and solid sources.

scholarly journals The Role of Insulin-Like Growth Factor (IGF) Binding Protein-2 in the Insulin-Mediated Decrease in IGF-I Bioactivity

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5192-5192
Author(s):  
Ayman M. Arafat ◽  
Martin O. Weickert ◽  
Jan Frystyk ◽  
Joachim Spranger ◽  
Christof Schöfl ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Igf System ◽  
Igf I ◽  
Igf Binding

ABSTRACT Context: Insulin interacts with the GH-IGF system by a reciprocal regulation of IGF-binding proteins (IGFBP) and GH, which in turn regulate insulin sensitivity via bioactive IGF-I. This network is linked to metabolic syndrome and cardiovascular diseases. Objective: We evaluated the effect of glucose and insulin on IGFBP-1-4, particularly IGFBP-2, in the regulation of bioactive IGF-I and its relation to insulin resistance. Setting: The study was conducted at an endocrinology center. Research Design and Methods: Twenty-four healthy subjects (12 men; aged 21–72 yr; body mass index 25.9 ± 0.9 kg/m2) and 19 subjects with impaired glucose tolerance (IGT; eight men; aged 26–71 yr; body mass index 28.9 ± 1.2 kg/m2 ) were prospectively studied using oral glucose tolerance test and hyperinsulinemic euglycemic clamp. Results: During the clamp, insulin decreased IGF-I bioactivity in both IGT subjects and controls (−16.2 ± 2.8 and −13.9 ± 3.3%, respectively; P &lt; 0.01). In addition, insulin increased IGFBP-2 and GH and decreased IGFBP-1 and -4 but did not alter total IGF-I, IGF-II, or IGFBP-3 levels. During the oral glucose tolerance test, GH and IGFBP-1 were markedly suppressed. Subjects with IGT showed more pronounced insulin resistance and lower GH, IGFBP-1, and IGFBP-2 levels (P &lt; 0.05). In multiple regression analysis, IGFBP-2 was an independent predictor of insulin sensitivity (β = 0.36, P &lt; 0.05) and IGF-I bioactivity (β = −0.5, P &lt; 0.05). Conclusions: Our data indicate that insulin acutely decreases IGF-I bioactivity through differential modulation of IGFBPs. Furthermore, IGFBP-2 plays a central role in the insulin-IGF system cross talk and is closely linked to insulin resistance, thereby providing a further explanation for its association with the metabolic syndrome.

scholarly journals Effect of the rs997509 Polymorphism on the Association between Ectonucleotide Pyrophosphatase Phosphodiesterase 1 and Metabolic Syndrome and Impaired Glucose Tolerance in Childhood Obesity

2009 ◽  
Vol 94 (1) ◽  
pp. 300-305 ◽  
Author(s):  
Nicola Santoro ◽  
Grazia Cirillo ◽  
Maria Grazia Lepore ◽  
Alfonsina Palma ◽  
Alessandra Amato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Confidence Interval ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Odds Ratio ◽  
Rare Allele ◽  
Common Allele ◽  
Obese Children

Abstract Context: Variants on the nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP-1) gene have been associated with obesity and insulin resistance. Because insulin resistance is a pivotal factor in the development of metabolic syndrome (MS) and impaired glucose tolerance (IGT), we aimed to test the association between the K121Q and rs997509 ENPP-1 variants with obesity, MS and IGT in obese children and adolescents. Methods: We screened 809 children, 409 obese and 400 lean controls. Obese subjects underwent a standard oral glucose tolerance test, whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) were calculated. Results: No difference in prevalence for K121Q and rs997509 polymorphisms between obese and controls (P &gt; 0.05) were observed. Obese children carrying the rs997509 rare allele showed higher insulin (P = 0.001), HOMA (P &lt; .001) and lower WBISI values (P = 0.04) compared with common allele homozygous. A similar observation was done for K121Q variant, with 121Q allele carriers showing higher insulin (P = 0.03) and HOMA (P = 0.04) values than 121K homozygotes. Moreover, subjects carrying the rs997509 rare allele had higher risk of MS (odds ratio 2.4, 95% confidence interval: 1.3–4.3) and IGT (odds ratio 4.7, 95% confidence interval: 1.9–11.4) than common allele homozygotes. Evaluating combined effects of both polymorphisms, which are in strong linkage disequilibrium, we showed that the effect on insulin sensitivity was due to the rs997509 T variant. Conclusion: We conclude that the ENPP1 rs997509T allele can predispose obese children to MS and IGT and that this variant might drive the association between the ENPP1 121Q allele and insulin resistance.

scholarly journals Intracellular pH Regulation of Skeletal Muscle in the Milieu of Insulin Signaling

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2910
Author(s):  
Dheeraj Kumar Posa ◽  
Shahid P. Baba
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Signaling Pathway ◽  
Intracellular Ph ◽  
Cross Talk ◽  
Insulin Signaling ◽  
Insulin Signaling Pathway ◽  
Glycolytic Pathway ◽  
Insulin Responses

Type 2 diabetes (T2D), along with obesity, is one of the leading health problems in the world which causes other systemic diseases, such as cardiovascular diseases and kidney failure. Impairments in glycemic control and insulin resistance plays a pivotal role in the development of diabetes and its complications. Since skeletal muscle constitutes a significant tissue mass of the body, insulin resistance within the muscle is considered to initiate the onset of diet-induced metabolic syndrome. Insulin resistance is associated with impaired glucose uptake, resulting from defective post-receptor insulin responses, decreased glucose transport, impaired glucose phosphorylation, oxidation and glycogen synthesis in the muscle. Although defects in the insulin signaling pathway have been widely studied, the effects of cellular mechanisms activated during metabolic syndrome that cross-talk with insulin responses are not fully elucidated. Numerous reports suggest that pathways such as inflammation, lipid peroxidation products, acidosis and autophagy could cross-talk with insulin-signaling pathway and contribute to diminished insulin responses. Here, we review and discuss the literature about the defects in glycolytic pathway, shift in glucose utilization toward anaerobic glycolysis and change in intracellular pH [pH]i within the skeletal muscle and their contribution towards insulin resistance. We will discuss whether the derangements in pathways, which maintain [pH]i within the skeletal muscle, such as transporters (monocarboxylate transporters 1 and 4) and depletion of intracellular buffers, such as histidyl dipeptides, could lead to decrease in [pH]i and the onset of insulin resistance. Further we will discuss, whether the changes in [pH]i within the skeletal muscle of patients with T2D, could enhance the formation of protein aggregates and activate autophagy. Understanding the mechanisms by which changes in the glycolytic pathway and [pH]i within the muscle, contribute to insulin resistance might help explain the onset of obesity-linked metabolic syndrome. Finally, we will conclude whether correcting the pathways which maintain [pH]i within the skeletal muscle could, in turn, be effective to maintain or restore insulin responses during metabolic syndrome.

Tesaglitazar, a dual PPARα/γ agonist, ameliorates glucose and lipid intolerance in obese Zucker rats

2005 ◽  
Vol 289 (4) ◽  
pp. R938-R946 ◽  
Author(s):  
Nicholas D. Oakes ◽  
Pia Thalén ◽  
Therese Hultstrand ◽  
Severina Jacinto ◽  
Germán Camejo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Therapeutic Effects ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Mass Load ◽  
Obese Zucker Rats

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor α/γ agonist, tesaglitazar, 3 μmol·kg−1·day−1 for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.

scholarly journals The joint effect of congenital hypothyroidism and hypercaloric diet consumption as triggers of type 2 diabetes mellitus

2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Jorge Alberto Tapia-Martínez ◽  
Margarita Franco-Colín ◽  
Vanessa Blas-Valdivia ◽  
Edgar Cano-Europa
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Cardiovascular Risk ◽  
Glucose Tolerance ◽  
Congenital Hypothyroidism ◽  
Hypercaloric Diet

Introduction Congenital hypothyroidism affects metabolic and thyroid programming, having a deleterious effect on bodyweight regulation promoting metabolic diseases. This work aimed to demonstrate the development of type 2 diabetes mellitus (T2D) in animals with congenital hypothyroidism, only by the consumption of a mild hypercaloric diet in the extrauterine stage. Methods Two groups of female Wistar rats (n  = 9): euthyroid and hypothyroid were used. Hypothyroidism was induced by a thyroidectomy with parathyroid reimplantation. Male offsprings post-weaning were divided into four groups (n  = 10): euthyroid, hypothyroid, euthyroid + hypercaloric diet, and hypothyroid + hypercaloric diet. The hypercaloric diet consisted of ground commercial feed plus 20% lard and was administered until postnatal week 40. Bodyweight and energy intake were monitored weekly. Also, metabolic and hormonal markers related to cardiovascular risk, insulin resistance, and glucose tolerance were analyzed at week 40. Then, animals were sacrificed to perform the morphometric analysis of the pancreas and adipose tissue. Results T2D was developed in animals fed a hypercaloric diet denoted by the presence of central obesity, hyperphagia, hyperglycemia, dyslipidemia, glucose tolerance, insulin resistance and hypertension, as well as changes in the cytoarchitecture of the pancreas and adipose tissue related to T2D. The results show that congenital hypothyroid animals had an increase in metabolic markers and an elevated cardiovascular risk. Conclusions Congenital hypothyroid animals develop T2D, having the highest metabolic disturbances and a worsened clinical prognosis than euthyroid animals.

Sign in / Sign up

Export Citation Format

Share Document