Pioglitazone Enhances β-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues

Pharmacology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Shaimaa El-Fayoumi ◽  
Rehab Mansour ◽  
Amr Mahmoud ◽  
Ahmed Fahmy ◽  
Islam Ibrahim
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Resistance Index ◽  
Chow Diet ◽  
Oral Antidiabetic Agent ◽  
Insulin Sensitizer ◽  
Standard Chow Diet ◽  
High Fructose

<b><i>Introduction:</i></b> Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. <b><i>Methods:</i></b> Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. <b><i>Results:</i></b> The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. <b><i>Conclusion:</i></b> To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

scholarly journals Effects of food pattern change and physical exercise on cafeteria diet-induced obesity in female rats

2012 ◽  
Vol 108 (8) ◽  
pp. 1511-1518 ◽  
Author(s):  
Jéferson F. Goularte ◽  
Maria B. C. Ferreira ◽  
Gilberto L. Sanvitto
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Physical Exercise ◽  
Energy Intake ◽  
Liver Weight ◽  
Cafeteria Diet ◽  
Chow Diet ◽  
Diet Induced Obesity ◽  
Visceral Adipose

Obesity affects a large number of people around the world and appears to be the result of changes in food intake, eating habits and physical activity levels. Changes in dietary patterns and physical exercise are therefore strongly recommended to treat obesity and its complications. The present study tested the hypothesis that obesity and metabolic changes produced by a cafeteria diet can be prevented with dietary changes and/or physical exercise. A total of fifty-six female Wistar rats underwent one of five treatments: chow diet; cafeteria diet; cafeteria diet followed by a chow diet; cafeteria diet plus exercise; cafeteria diet followed by a chow diet plus exercise. The duration of the experiment was 34 weeks. The cafeteria diet resulted in higher energy intake, weight gain, increased visceral adipose tissue and liver weight, and insulin resistance. The cafeteria diet followed by the chow diet resulted in energy intake, body weight, visceral adipose tissue and liver weight and insulin sensitivity equal to that of the controls. Exercise increased total energy intake at week 34, but produced no changes in the animals' body weight or adipose tissue mass. However, insulin sensitivity in animals subjected to exercise and the diet was similar to that of the controls. The present study found that exposure to palatable food caused obesity and insulin resistance and a diet change was sufficient to prevent cafeteria diet-induced obesity and to maintain insulin sensitivity at normal levels. In addition, exercise resulted in normal insulin sensitivity in obese rats. These results may help to develop new approaches for the treatment of obesity and type 2 diabetes mellitus.

scholarly journals Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

2009 ◽  
Vol 201 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Camilla Alexanderson ◽  
Elias Eriksson ◽  
Elisabet Stener-Victorin ◽  
Malin Lönn ◽  
Agneta Holmäng
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Female Rats ◽  
Whole Body ◽  
Low Grade ◽  
Expression Of Genes ◽  
Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

scholarly journals The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-γ target genes, in dogs

2007 ◽  
Vol 98 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Constance Gayet ◽  
Veronique Leray ◽  
Masayuki Saito ◽  
Brigitte Siliart ◽  
Patrick Nguyen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Visceral Adipose

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-γ (PPARγ) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARγ and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARγ, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARγ, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARγ expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARγ mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

scholarly journals Disruption of GIP/GIPR Axis in Human Adipose Tissue Is Linked to Obesity and Insulin Resistance

2014 ◽  
Vol 99 (5) ◽  
pp. E908-E919 ◽  
Author(s):  
Victòria Ceperuelo-Mallafré ◽  
Xavier Duran ◽  
Gisela Pachón ◽  
Kelly Roche ◽  
Lourdes Garrido-Sánchez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stem Cells ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Human Adipose Tissue ◽  
Fat Cells ◽  
Model Assessment ◽  
Adipose Derived Stem Cells ◽  
Obese Patients ◽  
Insulin Sensitizer

Context: Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear. Objective: Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance. Design: GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients. Results: GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR. Conclusions: GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.

scholarly journals A minor role for lipocalin 2 in high-fat diet-induced glucose intolerance

2011 ◽  
Vol 301 (5) ◽  
pp. E825-E835 ◽  
Author(s):  
Lucy S. Jun ◽  
C. Parker Siddall ◽  
Evan D. Rosen
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Phenotype ◽  
Chow Diet ◽  
High Fat

Adipose tissue controls energy homeostasis and systemic insulin sensitivity through the elaboration of a series of cytokines and hormones, collectively termed “adipokines.” We and others have identified Lcn2 as a novel adipokine, but its exact role in obesity-induced insulin resistance remains controversial. The aim of this study was to examine the metabolic phenotype of Lcn2−/− mice to clarify the role of Lcn2 in metabolism. Male and female Lcn2−/− and wild-type (WT) littermates were placed on either chow or high-fat diet (HFD) to characterize their metabolic phenotype. Studies included body weight and body composition, glucose and insulin tolerance tests, and adipokine expression studies in serum and in white adipose tissue (WAT). Neither chow nor HFD cohorts showed any differences in body weight or body composition. Chow-fed Lcn2−/− mice did not exhibit any difference in glucose homeostasis compared with WT mice. Fasting serum glucose levels were lower in the chow-fed Lcn2−/− mice, but this finding was not seen in the HFD cohort. Serum adiponectin, leptin, resistin, and RBP4 levels were not different between WT and Lcn2−/− on chow diet. HFD-fed male Lcn2−/− mice did display a small improvement in glucose tolerance, but no difference in insulin sensitivity was seen in either male or female Lcn2−/− mice on HFD. We conclude that the global ablation of Lcn2 has a minimal effect on obesity-associated glucose intolerance but does not appear to affect either age- or obesity-mediated insulin resistance in vivo.

Serum Myostatin is Upregulated in Obesity and Correlates with Insulin Resistance in Humans

2018 ◽  
Vol 127 (08) ◽  
pp. 550-556 ◽  
Author(s):  
Melina Amor ◽  
Bianca K. Itariu ◽  
Veronica Moreno-Viedma ◽  
Magdalena Keindl ◽  
Alexander Jürets ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Obese Group ◽  
Sensitivity Indices

AbstractObesity and type 2 diabetes mellitus have reached an epidemic level, thus novel treatment concepts need to be identified. Myostatin, a myokine known for restraining skeletal muscle growth, has been associated with the development of insulin resistance and type 2 diabetes mellitus. Yet, little is known about the regulation of myostatin in human obesity and insulin resistance. We aimed to investigate the regulation of myostatin in obesity and uncover potential associations between myostatin, metabolic markers and insulin resistance/sensitivity indices. Circulating active myostatin concentration was measured in the serum of twenty-eight severely obese non-diabetic patients compared to a sex and age matched lean and overweight control group (n=22). Insulin resistance/sensitivity was assessed in the obese group. Skeletal muscle and adipose tissue specimens from the obese group were collected during elective bariatric surgery. Adipose tissue samples from lean and overweight subjects were collected during elective abdominal surgery. Myostatin concentration was increased in obese compared to lean individuals, while myostatin adipose tissue expression did not differ. Muscle myostatin gene expression strongly correlated with expression of metabolic genes such as IRS1, PGC1α, SREBF1. Circulating myostatin concentration correlated positively with insulin resistance indices and negatively with insulin sensitivity indices. The best correlation was obtained for the oral glucose insulin sensitivity index. Our results point to an interesting correlation between myostatin and insulin resistance/sensitivity in humans, and emphasize its need for further evaluation as a pharmacological target in the prevention and treatment of obesity-associated metabolic complications.

scholarly journals Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans

2019 ◽  
Vol 316 (5) ◽  
pp. E866-E879 ◽  
Author(s):  
Stephan Sachs ◽  
Simona Zarini ◽  
Darcy E. Kahn ◽  
Kathleen A. Harrison ◽  
Leigh Perreault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Matrix Proteins ◽  
Muscle Insulin Resistance ◽  
Intermuscular Adipose Tissue ◽  
Skeletal Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Sensitivity

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

scholarly journals Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes

2019 ◽  
Vol 104 (8) ◽  
pp. 3327-3336 ◽  
Author(s):  
Diana Barb ◽  
Fernando Bril ◽  
Srilaxmi Kalavalapalli ◽  
Kenneth Cusi
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Growth Factor ◽  
Liver Biopsy ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth

Abstract Context The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed. Objective To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD). Design and Setting Cross-sectional study in a university hospital. Patients Interventions and Main Outcome Measures Patients with a body mass index &gt;25 (n = 187) underwent: (i) euglycemic hyperinsulinemic clamp to assess tissue-specific insulin resistance (IR); (ii) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification, (iii) liver biopsy (if NAFLD present; n = 146); and (iv) fasting plasma FGF21 levels. Methods and Results Patients were divided into three groups: (i) No NAFLD (n = 41); (ii) No nonalcoholic steatohepatitis (NASH) (patients with isolated steatosis or borderline NASH; n = 52); and (iii) NASH (patients with definite NASH; n = 94). Groups were well-matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both P &lt; 0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r = −0.17, P = 0.006) and skeletal muscle (r = −0.23, P = 0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453 ± 262 pg/mL) when compared with the No NASH (341 ± 198 pg/mL, P = 0.03) or No NAFLD (325 ± 289 pg/mL, P = 0.02) groups. Plasma FGF21 increased with the severity of necroinflammation (P = 0.02), and most significantly with worse fibrosis (P &lt; 0.001), but not with worsening steatosis (P = 0.60). Conclusions Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.

scholarly journals Expression of macrophage genes within skeletal muscle correlates inversely with adiposity and insulin resistance in humans

2018 ◽  
Vol 43 (2) ◽  
pp. 187-193 ◽  
Author(s):  
Dongmei Liu ◽  
Flor Elisa Morales ◽  
Heidi. B. IglayReger ◽  
Mary K. Treutelaar ◽  
Amy E. Rothberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Muscle Tissue ◽  
Skeletal Muscle Tissue ◽  
Obese Patients ◽  
Weight Loss Intervention

Local inflammation in obese adipose tissue has been shown to contribute to insulin resistance; however, the role of macrophage infiltration within skeletal muscle is still debatable. This study aimed to evaluate the association of skeletal muscle macrophage gene expression with adiposity levels and insulin sensitivity in obese patients. Twenty-two nondiabetic obese patients and 23 healthy lean controls were included. Obese patients underwent a 3-month weight loss intervention. Macrophage gene expression in skeletal muscle (quantitative real-time polymerase chain reaction), body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (homeostatic model assessment (HOMA) and oral glucose tolerance test) were compared between groups and their associations were analyzed. To validate skeletal muscle findings, we repeated the analyses with macrophage gene expression in adipose tissue. Expression levels of macrophage genes (CD68, CD11b, CD206, CD16, CD40, and CD163) were lower in skeletal muscle tissue of obese versus lean participants. Macrophage gene expression was also found to be inversely associated with adiposity, fasting insulin, and HOMA (r = −0.4 ∼ −0.6, p < 0.05), as well as positively associated with insulin sensitivity (r = 0.4 ∼ 0.8, p < 0.05). On the other hand, adipose tissue macrophage gene expression showed higher levels in obese versus lean participants, presenting a positive association with adiposity levels. Macrophage gene expression, in both skeletal and adipose tissue samples, was only minimally affected by the weight loss intervention. In contrast with the established positive relationship between adiposity and macrophage gene expression, an unexpected inverse correlation between these 2 variables was observed in skeletal muscle tissue. Additionally, muscle macrophage gene expression was inversely correlated with insulin resistance.

scholarly journals Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity

2016 ◽  
Vol 310 (3) ◽  
pp. E190-E199 ◽  
Author(s):  
Young-Min Park ◽  
R. Scott Rector ◽  
John P. Thyfault ◽  
Terese M. Zidon ◽  
Jaume Padilla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Capacity ◽  
Tissue Specific ◽  
Subcutaneous White Adipose Tissue ◽  
Brown Adipose ◽  
Glucose Clearance

High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats ( n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-3H]glucose was used to determine glucose clearance, whereas 2-[14C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR ( P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR ( P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR ( P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.

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