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 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 Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. E676-E693 ◽  
Author(s):  
Valentina Caracciolo ◽  
Jeanette Young ◽  
Donna Gonzales ◽  
Yingchun Ni ◽  
Stephen J. Flowers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Zinc Finger Protein ◽  
Inflammatory Responses ◽  
Adipose Tissue Inflammation ◽  
Obese Mice ◽  
Tissue Inflammation ◽  
Mrna Binding

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKβ and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

scholarly journals Peripancreatic adipose tissue protects against high-fat-diet-induced hepatic steatosis and insulin resistance in mice

2020 ◽  
Vol 44 (11) ◽  
pp. 2323-2334
Author(s):  
Belén Chanclón ◽  
Yanling Wu ◽  
Milica Vujičić ◽  
Marco Bauzá-Thorbrügge ◽  
Elin Banke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Obese Mice ◽  
High Fat ◽  
Insulin Levels ◽  
Fat Depots ◽  
Fat Depot

Abstract Background/objectives Visceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice. Subjects/methods Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4–5/group), cellular composition (FACS analysis, n = 5–6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6–10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5–11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8–10/group). Results We found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many “non-adipocytes” such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05). Conclusions PAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

scholarly journals PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice

2010 ◽  
Vol 9 (1) ◽  
pp. 64 ◽  
Author(s):  
Anna Foryst-Ludwig ◽  
Martin Hartge ◽  
Markus Clemenz ◽  
Christiane Sprang ◽  
Katharina Heß ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
T Lymphocyte ◽  
Obese Mice

Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone

Bone ◽  
2018 ◽  
Vol 115 ◽  
pp. 68-82 ◽  
Author(s):  
J.A.C. Guedes ◽  
J.V. Esteves ◽  
M.R. Morais ◽  
T.M. Zorn ◽  
D.T. Furuya
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Obese Mice

scholarly journals URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and BAT whitening in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y Tanaka ◽  
T Nagoshi ◽  
A Yoshii ◽  
Y Oi ◽  
H Takahashi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Critical Role ◽  
Selective Inhibition ◽  
Selective Inhibitor ◽  
Obese Mice ◽  
Alcoholic Fatty Liver ◽  
Brown Adipose

Abstract Background Accumulating evidence suggests that high uric acid is strongly associated with obesity and metabolic syndrome and drives the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidney, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. Objectives We hypothesizes that URAT1 plays an important role in obesity-induced metabolic disorders, and URAT1-selective inhibitor treatment ameliorates systemic insulin resistance, NAFLD and adipose tissue dysfunction using diet-induced obese mice. Methods Mice fed a high-fat diet (HFD) for 16 to 18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. Results Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than kidney. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis, as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (Ccl2 and TNFα), all of which were attenuated by dotinurad. Likewise, HFD significantly increased URAT1 expression in BAT, resulting in the lipid accumulation (whitening of BAT) and increased production of tissue reactive oxygen species, which were reduced by dotinurad via UCP1 activation. Conclusions A novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome, and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model

Antioxidants ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 40 ◽  
Author(s):  
Shailendra P. Singh ◽  
Menachem Greenberg ◽  
Yosef Glick ◽  
Lars Bellner ◽  
Gaia Favero ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gene Therapy ◽  
Adipose Tissue ◽  
Vascular Function ◽  
Therapeutic Approach ◽  
Vascular Dysfunction ◽  
Cellular Respiration ◽  
Heme Oxygenase 1 ◽  
Obese Mice ◽  
Mice Model

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

scholarly journals The effect of oxytetracycline on insulin resistance in obese mice

1974 ◽  
Vol 142 (3) ◽  
pp. 465-475 ◽  
Author(s):  
Nicole Bégin-Heick ◽  
Michel Bourassa ◽  
H. M. C. Heick
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Blood Glucose ◽  
Insulin Receptor ◽  
Lipid Content ◽  
Food Restriction ◽  
Obese Mice ◽  
Receptor Sites ◽  
Chronic Food Restriction

1. Chronic oxytetracycline treatment was found to improve the insulin resistance of the obese–hyperglycaemic mouse. 2. The improved response to insulin was accompanied by decreased concentrations of circulating insulin and glucose, by a decrease in the lipid content of the liver and by an increase in the insulin-receptor sites of the liver and adipose tissue. 3. The increase in insulin-receptor sites preceded the fall in blood glucose. 4. Comparable studies done on food-restricted animals indicated that although chronic food restriction corrected the hyperinsulinaemia it did not restore the insulin-receptor sites or the hyperglycaemia.

Sign in / Sign up

Export Citation Format

Share Document