Abstract 81: Pharmacological Inhibition of Calpain Attenuates Adipose Tissue Apoptosis, Macrophage Accumulation and Inflammation in Diet-induced Obese Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Venkateswaran Subramanian ◽  
Anju Balakrishnan ◽  
Deborah A Howatt ◽  
Jessica J Moorleghen ◽  
Wendy S Katz
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Obese Mice ◽  
Tissue Macrophage ◽  
Pharmacological Inhibition ◽  
Adipose Tissue Macrophage ◽  
Insulin Tolerance ◽  
Calpain Inhibition ◽  
Macrophage Accumulation

Background and Objective Obesity is associated with low-grade chronic inflammation and apoptosis that contributes to development of insulin resistance and other metabolic complications. Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not defined. Calpains are calcium-dependent neutral cysteine proteases that are essential for multiple cellular functions, such as cytoskeletal remodeling and apoptotic cell death. Recent studies have demonstrated that activated calpain promotes adipocyte differentiation in vitro, and enhances macrophage recruitment during nephropathy. However, the functional role of calpain activation in adipose tissue macrophage accumulation and obesity remains to be elucidated. The purpose of this study was to define whether pharmacological inhibition of calpain influences diet-induced obesity and adipose tissue macrophage accumulation in mice. Methods and Results Male C57BL/6 mice (8 weeks old; n=10 per group) were fed either low (10% kcal) or high (60% kcal) fat diet for 12 weeks. Calpeptin, a calpain inhibitor (2.5 mg/kg/day) or vehicle (DMSO) was administered daily by osmotic mini-pumps for 12 weeks. Calpeptin administration did not influence high fat diet induced body weight and fat mass gain throughout the study. Calpain inhibition had no effect on glucose and insulin tolerance in obese mice. However, calpain inhibition highly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as evident by TUNEL, Picro Sirius and CD68 immunostaining. Real-time PCR analysis showed that calpain inhibition significantly suppressed inflammatory cytokines (TNFα, IL-6, MCP-1, F4/80) expression in adipose tissue (P<0.05 vs vehicle). In addition, Oil Red O staining revealed that calpain inhibition also suppressed accumulation of hepatic fat. Conclusion Pharmacological inhibition of calpain attenuated macrophage accumulation, adipocyte apoptosis, fibrosis and inflammation in diet-induced obese mice without influencing body weight gain and insulin tolerance.

scholarly journals Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice

Diabetes ◽  
2012 ◽  
Vol 61 (10) ◽  
pp. 2495-2505 ◽  
Author(s):  
C. E. McCurdy ◽  
S. Schenk ◽  
M. J. Holliday ◽  
A. Philp ◽  
J. A. Houck ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Obese Mice ◽  
Tissue Macrophage ◽  
Adipose Tissue Macrophage ◽  
Macrophage Accumulation

332-OR: Pharmacological Inhibition of CREBZF Improves Insulin Resistance by Altering Activation of Macrophage in Adipose Tissue of Diet-Induced Obese Mice

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 332-OR
Author(s):  
YUXIAO LIU ◽  
ZHIMIN HU ◽  
ZHENGSHUAI LIU ◽  
WEITONG SU ◽  
ZENGPENG ZHENG ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Obese Mice ◽  
Pharmacological Inhibition

Abstract 17023: Adipose Tissue Specific Temporal Deletion of Ager Induces Weight Loss in Diet Induced Obese Mice and Improves Glucose Homeostasis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Robin Wilson ◽  
Lakshmi Arivazhagan ◽  
Henry Ruiz ◽  
Jay Pendse ◽  
Laura Frye ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Fasting Glucose ◽  
Obese Mice ◽  
Gene Encoding ◽  
Low Fat Diet ◽  
Insulin Tolerance ◽  
Specific Deletion

Introduction: The incidence of obesity and its comorbidities is increasing at an alarming rate in US and around the globe. Our previous studies showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and insulin resistance (IR), as global Ager (gene encoding RAGE) and adipocyte-specific Ager- deleted mice fed a high fat diet (HFD) showed protection from weight gain and IR. However, the role of Ager deletion in mice with established obesity, switched to low fat diet has not been tested. We hypothesize that temporal adipocyte-specific deletion of Ager in obese mice could enhance weight loss and improves glucose homeostasis. Methods: Mice with conditional adipocyte-specific Ager deletion were generated by breeding Ager flox/flox mice with AdipoQ ERT2 Cre recombinase mice resulting in Ager flox/flox / AdipoQ ERT2 Cre (+) and Cre (-) animals. Mice were fed HFD (60% kcal/fat) for 20 weeks starting at 8 weeks of age to establish obesity and were then treated with tamoxifen (TAM) (75 mg/kg per day x 3 alternative days) to induce deletion of Ager . After 4 weeks of TAM treatment, mice were switched to standard chow for 7 weeks and body weight was monitored regularly. Fasting glucose, insulin and glucose tolerance was measured. Results: After 7 weeks of switching to standard chow following TAM, Cre (+) lost significantly more body weight whereas Cre (-) mice showed no significant weight loss over 7 weeks. Furthermore, Cre (+) mice exhibited significantly higher food intake, lower fasting glucose, lower epididymal and inguinal white adipose tissue weights, and improved glucose and insulin tolerance compared to Cre (-) mice. Conclusions: Temporal adipocyte-specific deletion of Ager in mice with established obesity promotes weight loss and improves glucose homeostasis. RAGE may act as a novel therapeutic target in obesity.

scholarly journals Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice

2007 ◽  
Vol 117 (10) ◽  
pp. 2877-2888 ◽  
Author(s):  
Takashi Nomiyama ◽  
Diego Perez-Tilve ◽  
Daisuke Ogawa ◽  
Florence Gizard ◽  
Yue Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Macrophage Infiltration ◽  
Tissue Macrophage ◽  
Adipose Tissue Macrophage

scholarly journals Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance

2015 ◽  
Vol 21 (3) ◽  
pp. 403-416 ◽  
Author(s):  
Michael J. Kraakman ◽  
Helene L. Kammoun ◽  
Tamara L. Allen ◽  
Virginie Deswaerte ◽  
Darren C. Henstridge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
High Fat ◽  
Tissue Macrophage ◽  
Macrophage Recruitment ◽  
Adipose Tissue Macrophage ◽  
Improve Insulin Resistance

scholarly journals Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

2021 ◽  
Author(s):  
Omar Sharif ◽  
Julia Stefanie Brunner ◽  
Ana Korosec ◽  
Rui Martins ◽  
Alexander Jais ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Immune Cell ◽  
Metabolic Effects ◽  
Sphingolipid Metabolism ◽  
Protective Effects ◽  
Tissue Macrophage ◽  
Insulin Tolerance ◽  
Ceramide Synthesis

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated ATM-expressed TREM2 promoted health. Here, we identified that in mice TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in TREM2’s systemic protective effects on metabolic health.

scholarly journals Adipose tissue macrophage burden, systemic inflammation, and insulin resistance

2020 ◽  
Vol 319 (2) ◽  
pp. E254-E264 ◽  
Author(s):  
Qingyi Jia ◽  
Maria E. Morgan-Bathke ◽  
Michael D. Jensen
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Multivariate Regression ◽  
Metabolic Parameters ◽  
Model Assessment ◽  
Adipocyte Size ◽  
Tissue Macrophage ◽  
Adipose Tissue Macrophage

Adipose tissue inflammation, as defined by macrophage accumulation, is proposed to cause insulin resistance and systemic inflammation. Because the strength of this relationship for humans is unclear, we tested whether adipose tissue macrophage (ATM) burden is correlated with these health indicators. Using immunohistochemistry, we measured abdominal subcutaneous CD68+ (total ATM), CD14+ (proinflammatory/M1), and CD206+ (anti-inflammatory/M2) ATM in 97 volunteers (BMI 20–38 kg/m2, in addition to body composition, adipocyte size, homeostasis model assessment of insulin resistance, ADIPO-IR, adipose tissue insulin resistance measured by palmitate, plasma lipids, TNF, and IL-6 concentrations. There were several significant univariate correlations between metabolic parameters to IL-6 and ATM per 100 adipocytes, but not ATM per gram tissue; adipocyte size was a confounding variable. We used matching strategies and multivariate regression analyses to investigate the relationships between ATM and inflammatory/metabolic parameters independent of adipocyte size. Matching approaches revealed that the groups discordant for CD206 but concordant for adipocyte size had significantly different fasting insulin and IL-6 concentrations. However, groups discordant for adipocyte size but concordent for ATM differeded in that visceral fat, plasma triglyceride, glucose, and TNF concentrations were greater in those with large adipocytes. Multivariate regression analysis indicated that indexes of insulin resistance and fasting triglycerides were predicted by body composition; the predictive value of ATM per 100 adipocytes or per gram tissue was variable between males and females. We conclude that the relationship between ATM burden and metabolic/inflammatory variables is confounded by adipocyte size/body composition and that ATM do not predict insulin resistance, systemic inflammation, or dyslipidemia. ATM may primarily play a role in tissue remodeling rather than in metabolic pathology.

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