scholarly journals Fabp4-Cre-mediated Sirt6 deletion impairs adipose tissue function and metabolic homeostasis in mice

2017 ◽  
Vol 233 (3) ◽  
pp. 307-314 ◽  
Author(s):  
Xiwen Xiong ◽  
Cuicui Zhang ◽  
Yang Zhang ◽  
Rui Fan ◽  
Xinlai Qian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Knockout Mice ◽  
Genome Stability ◽  
Weight Maintenance ◽  
Critical Role ◽  
Gene Promoter ◽  
Metabolic Homeostasis ◽  
Brown Adipose

SIRT6 is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis and anti-inflammation. However, its function in the adipose tissue is not well understood. To examine the metabolic function of SIRT6 in the adipose tissue, we generated two mouse models that are deficient in Sirt6 using the Cre-lox approach. Two commonly used Cre lines that are driven by either the mouse Fabp4 or Adipoq gene promoter were chosen for this study. The Sirt6-knockout mice generated by the Fabp4-Cre line (Sirt6f/f:Fabp4-Cre) had a significant increase in both body weight and fat mass and exhibited glucose intolerance and insulin resistance as compared with the control wild-type mice. At the molecular levels, the Sirt6f/f:Fabp4-Cre-knockout mice had increased expression of inflammatory genes including F4/80, TNFα, IL-6 and MCP-1 in both white and brown adipose tissues. Moreover, the knockout mice showed decreased expression of the adiponectin gene in the white adipose tissue and UCP1 in the brown adipose tissue, respectively. In contrast, the Sirt6 knockout mice generated by the Adipoq-Cre line (Sirt6f/f:Adipoq-Cre) only had modest insulin resistance. In conclusion, our data suggest that the function of SIRT6 in the Fabp4-Cre-expressing cells in addition to mature adipocytes plays a critical role in body weight maintenance and metabolic homeostasis.

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 Cold-inducible Klf9 regulates thermogenesis of brown and beige fat

2020 ◽  
Author(s):  
Ada Admin ◽  
Heng Fan ◽  
Yujie Zhang ◽  
Jun Zhang ◽  
Qiyuan Yao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Critical Role ◽  
Fasting Blood Glucose ◽  
Gene Promoter ◽  
Cold Sensitivity ◽  
Cellular Respiration ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Beige Fat

Promoting development and function of brown and beige fat may represent an attractive treatment of obesity. In the present study, we show that fat Klf9 expression is markedly induced by cold exposure and a β-adrenergic agonist. Moreover, Klf9 expression levels in human white adipose tissue (WAT) are inversely correlated with adiposity, and Klf9 overexpression in primary fat cells stimulates cellular thermogenesis, which is <a>Ucp1</a>-dependent. Fat-specific Klf9 transgenic mice gain less weight and have smaller fat pads due to increased thermogenesis of brown and beige fat. Moreover, Klf9 transgenic mice displayed lower fasting blood glucose levels, improved glucose tolerance and insulin sensitivity under the high-fat diet condition. Conversely, Klf9 mutation in brown adipocytes reduces the expression of thermogenic genes, causing a reduction in cellular respiration. Klf9-mutant mice exhibited obesity and cold sensitivity due to impairments in the thermogenic function of fat. Finally, fat Klf9 deletion inhibits the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, Cold-inducible Klf9 stimulates expression of <a>PGC-1α</a>, a master regulator of fat thermogenesis, by a direct binding to its gene promoter region, subsequently promoting energy expenditure. The present study reveals a critical role for Klf9 in mediating thermogenesis of brown and beige fat.

Abstract 605: Bone Morphogenetic Protein Inhibitors Play Important Roles in Brown and White Adipogenesis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Ana M Blazquez-Medela ◽  
Medet Jumabay ◽  
Kristina I Bostrom
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Body Fat ◽  
Lipid Accumulation ◽  
Adipogenic Differentiation ◽  
Critical Role ◽  
Matrix Gla Protein ◽  
Brown Adipocyte ◽  
Brown Adipose ◽  
Time Point

Adipose tissue is intimately connected to the development of metabolic syndrome, type 2 diabetes and cardiovascular disease. The near pandemic increase in incidence and prevalence of obesity makes it necessary to understand adipose regulation in order to develop strategies against obesity and its comorbidities. Adipose tissue performs a variety of functions. White adipose tissue (WAT) is responsible for energy storage, hormone production and organ protection, whereas brown adipose tissue (BAT) has a key role in thermogenesis. Previous studies have shown the importance of Bone Morphogenetic Proteins (BMPs) in the differentiation of brown and white adipocytes. BMP4 has been linked to both brown and white adipogenesis and BMP7 is essential for brown adipogenesis. Nevertheless, the role of the BMP inhibitors, which modulate the actions of BMPs, has not yet been elucidated. Our hypothesis is that the BMP inhibitors play important roles in the adipogenic process. Using two different mice models -Matrix Gla Protein (Mgp) KO and Noggin fat-specific KO- we found that the absence of Mgp resulted in dramatic adipose changes, suggesting a critical role in the separation of white and brown adipocytes. Adipocyte-specific deletion of Noggin, however, suggested a role in modulating the size and lipid accumulation in fully differentiated adipocytes. The absence of Mgp led to a reduction in body fat and body weight (3-12 animals per group and time point) whereas the absence of Noggin caused an increase in body fat and body weight (4-18 animals per time point and body weight). Tissue culture experiments using white and brown adipocyte progenitor cells showed specific temporal patterns of the BMPs and BMP-inhibitors that were consistent with the mouse findings. In conclusion, BMP inhibitors are essential in distinguishing brown and white adipogenic differentiation. We hypothesize that MGP is critical in the initial separation, whereas Noggin regulates cell size and lipid accumulation.

Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice

2009 ◽  
Vol 297 (1) ◽  
pp. E184-E193 ◽  
Author(s):  
Josep Mercader ◽  
Joan Ribot ◽  
Incoronata Murano ◽  
Søren Feddersen ◽  
Saverio Cinti ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Fat Diet ◽  
Retinoblastoma Protein ◽  
Brown Adipocyte ◽  
Wild Type ◽  
High Fat ◽  
Brown Adipose

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. Rb+/− mice had body weight and adiposity indistinguishable from that of wild-type (Rb+/+) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, Rb+/− mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)γ as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, Rb+/− mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPARα in liver and of PPARδ in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances.

scholarly journals Activin A Plays a Critical Role in Adipose Tissue Wasting in the Progression of Cancer Cachexia

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A40-A40
Author(s):  
Yi Luan ◽  
Mikyoung You ◽  
Pauline C Xu ◽  
Tom Thompson ◽  
So-Youn Kim
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Cancer Progression ◽  
Cancer Cachexia ◽  
Critical Role ◽  
Activin A ◽  
Adipose Tissues ◽  
Female Mice ◽  
Brown Adipose

Abstract Background: Nearly 50% of cancer patients suffer from cancer cachexia, a wasting syndrome with atrophy of white adipose tissue (WAT) and skeletal muscle. Cachexia leads to negative energy balance, limits cancer therapies, and reduces survival rate. It is characterized by body weight loss due to negative nutrients and energy balance from involuntary reduced food intake and abnormal metabolic conditions such as insulin resistance and hypertriglyceridemia. Cancer-driven factors such as activin A and IL-6 (interlukein-6) contribute to the occurrence of cachexia symptoms during cancer progression. While the importance of muscle atrophy has been emphasized in cachexia research, the underlying mechanism of adipose tissue wasting remains unclear. One proposed theory is that WAT switches to brown adipose tissue (BAT), characterized by the high expression level of UCP1 (uncoupling protein 1). Hypothesis: We hypothesize that activin A plays a critical role in adipose tissue wasting during cancer cachexia progression. Experiment: GDF9-iCre+; PIK3CA* female mice which shows cachexia symptoms in cancer progression were sacrificed before and after cachexia development. In addition, we injected FST288, an antagonist to activin A, for two weeks during cancer cachexia development. We harvested and analyzed multi-sites adipose tissues (gonadal, subcutaneous, interscapular and perirenal), muscle and liver. Serum activin A and IL-6 were measured using ELISA kits. DEXA and calorimetry analyses were performed, as well as immunohistochemistry, qPCR and western blotting assay. Results:GDF9-iCre+; PIK3CA* female mice started to display bilateral ovarian tumors around postnatal day (PD) 60, lose body weight around PD70 and became cachexia condition around PD80 with an increased level of serum activin A. Along with that, other body organs including liver, pancreas, muscle, and adipose tissues became dramatically small in mass. Our data proved that cachexia progression is correlated with the level of activin A rather than IL-6 in serum of GDF9-iCre+; PIK3CA* female mice. As serum activin A increased, adipocytes lost lipids and had distinct browning phenotypes in some adipocytes within WAT. Interestingly, calorimetry analysis did not display an increase in energy expenditure in cachectic mice although browning was evident in WAT. However, treatment with FST288 during cancer progression kept body weight and WAT in GDF9-iCre+; PIK3CA* female mice. Most of all, FST288 protected the size and lipid droplets of adipose tissues against WAT wasting during cachexia development. Conclusion: The progression of cancer cachexia impacts adipose tissues. Injection of FST288 supports the key role of activin A in the progress of cachexia. FST288 prevented adipose tissue wasting and cachexia development, revealing another evidence of the efficacy of activin A antagonist in preventing cancer cachexia development.

scholarly journals Cold-inducible Klf9 regulates thermogenesis of brown and beige fat

2020 ◽  
Author(s):  
Ada Admin ◽  
Heng Fan ◽  
Yujie Zhang ◽  
Jun Zhang ◽  
Qiyuan Yao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Critical Role ◽  
Fasting Blood Glucose ◽  
Gene Promoter ◽  
Cold Sensitivity ◽  
Cellular Respiration ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Beige Fat

Promoting development and function of brown and beige fat may represent an attractive treatment of obesity. In the present study, we show that fat Klf9 expression is markedly induced by cold exposure and a β-adrenergic agonist. Moreover, Klf9 expression levels in human white adipose tissue (WAT) are inversely correlated with adiposity, and Klf9 overexpression in primary fat cells stimulates cellular thermogenesis, which is <a>Ucp1</a>-dependent. Fat-specific Klf9 transgenic mice gain less weight and have smaller fat pads due to increased thermogenesis of brown and beige fat. Moreover, Klf9 transgenic mice displayed lower fasting blood glucose levels, improved glucose tolerance and insulin sensitivity under the high-fat diet condition. Conversely, Klf9 mutation in brown adipocytes reduces the expression of thermogenic genes, causing a reduction in cellular respiration. Klf9-mutant mice exhibited obesity and cold sensitivity due to impairments in the thermogenic function of fat. Finally, fat Klf9 deletion inhibits the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, Cold-inducible Klf9 stimulates expression of <a>PGC-1α</a>, a master regulator of fat thermogenesis, by a direct binding to its gene promoter region, subsequently promoting energy expenditure. The present study reveals a critical role for Klf9 in mediating thermogenesis of brown and beige fat.

Characterization of MCH-mediated obesity in mice

2003 ◽  
Vol 284 (5) ◽  
pp. E940-E945 ◽  
Author(s):  
Masahiko Ito ◽  
Akira Gomori ◽  
Akane Ishihara ◽  
Zenjun Oda ◽  
Satoshi Mashiko ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Critical Role ◽  
Acid Oxidation ◽  
Intracerebroventricular Infusion ◽  
Brown Adipose ◽  
Ad Libitum ◽  
Lipogenic Activity

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitum-fed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.

scholarly journals Adipose tissue insulin resistance due to loss of PI3K p110α leads to decreased energy expenditure and obesity

2014 ◽  
Vol 306 (10) ◽  
pp. E1205-E1216 ◽  
Author(s):  
Victoria L. B. Nelson ◽  
Ya-Ping Jiang ◽  
Kathleen G. Dickman ◽  
Lisa M. Ballou ◽  
Richard Z. Lin
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Insulin Signaling ◽  
Uncoupling Protein ◽  
Critical Role ◽  
Liver Steatosis ◽  
Cellular Respiration ◽  
Brown Adipose

Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear. Using Cre recombinase driven by the aP2 promoter, we created mice that lack the class 1A PI3K catalytic subunit p110α or p110β specifically in the white and brown adipose tissue. The loss of p110α, not p110β, resulted in increased adiposity, glucose intolerance and liver steatosis. Mice lacking p110α in adipose tissue exhibited a decrease in energy expenditure but no change in food intake or activity compared with control animals. This low energy expenditure is a consequence of low cellular respiration in the brown adipocytes caused by a decrease in expression of key mitochondrial genes including uncoupling protein-1. These results illustrate a critical role of p110α in the regulation of energy expenditure through modulation of cellular respiration in the brown adipose tissue and suggest that compromised insulin signaling in adipose tissue might be involved in the onset of obesity.

The Important Roles of Matrix Metalloproteinases in the Pathophysiology of Obesity

2017 ◽  
Vol 68 (7) ◽  
pp. 1481-1484 ◽  
Author(s):  
Radu Mihail Mirica ◽  
Mihai Ionescu ◽  
Alexandra Mirica ◽  
Octav Ginghina ◽  
Razvan Iosifescu ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Matrix Metalloproteinases ◽  
English Language ◽  
Critical Role ◽  
Animal Experiments ◽  
Hdl Cholesterol ◽  
Tissue Growth ◽  
Basement Membranes ◽  
Body Weight Reduction

Obesity involves the growth of adipose tissue cells (adipocytes and preadipocytes), as well as microvascular endothelial cells. Matrix metalloproteinases (MMPs) are relevant ezymes for the modulation of extracellular matrix (ECM) and adipocyte and preadipocytes differentiation. They are elevated in obese patients, generating abnormal ECM metabolism.[1]. This article proposes a thorough study of literature with focus on the important roles of matrix metalloproteinases in the pathophysiology of obesity. The article represents a narrative review based on an English-language PubMed research of the medical literature regardind important aspects of the proposed aim. MMP-2 activity was signi�cantly higher than MMP-9, both activities were detectable. MMP-9 was strongly correlated with body weight parameters before surgery, as well as after significant body weight reduction as a result of bariatric surgery. Concerning MMP-2 and MMP-9 they are also involved in the turnover of basement membranes both those of adipose tissue and endothelial. MMP-9 levels were moderately correlated with HDL cholesterol levels. Taken together, the present data suggest that changes in ECM through MMP-mediated degradation might play a critical role in the adipocyte differentiation process. These findings are detected both in clinical trials and in laboratory animal experiments. It is then tempting to speculate that the adipocyte-derived MMPs might represent a new pharmacological target for the inhibition of adipose tissue growth by inhibiting adipose differentiation as well as angiogenic process.

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