Exposure to the Widely Used Pyrethroid Pesticide Deltamethrin, Does Not Exacerbate High Fat Diet Induced Obesity or Insulin Resistance in C57BL/6J Mice

Abstract Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.

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TAF7L modulates brown adipose tissue formation

eLife ◽

10.7554/elife.02811 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 12

Author(s):

Haiying Zhou ◽

Bo Wan ◽

Ivan Grubisic ◽

Tommy Kaplan ◽

Robert Tjian

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Core Promoter ◽

Uncoupling Protein ◽

Dna Looping ◽

Chromatin Interactions ◽

Brown Adipose ◽

Important Regulator

Brown adipose tissue (BAT) plays an essential role in metabolic homeostasis by dissipating energy via thermogenesis through uncoupling protein 1 (UCP1). Previously, we reported that the TATA-binding protein associated factor 7L (TAF7L) is an important regulator of white adipose tissue (WAT) differentiation. In this study, we show that TAF7L also serves as a molecular switch between brown fat and muscle lineages in vivo and in vitro. In adipose tissue, TAF7L-containing TFIID complexes associate with PPARγ to mediate DNA looping between distal enhancers and core promoter elements. Our findings suggest that the presence of the tissue-specific TAF7L subunit in TFIID functions to promote long-range chromatin interactions during BAT lineage specification.

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In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid

Biochemical Journal ◽

10.1042/bj3170827 ◽

1996 ◽

Vol 317 (3) ◽

pp. 827-833 ◽

Cited By ~ 83

Author(s):

Pere PUIGSERVER ◽

Francisca VÁZQUEZ ◽

María L. BONET ◽

Catalina PICÓ ◽

Andreu PALOU

Keyword(s):

Retinoic Acid ◽

Cultured Cells ◽

Uncoupling Protein ◽

Primary Cultures ◽

Brown Adipocyte ◽

Brown Adipose ◽

Adipocyte Cell ◽

Differentiation Stage

The effects of retinoic acid (RA) isomers (all-trans-RA and 9-cis-RA) on the appearance of uncoupling protein (UCP; thermogenin), the only unequivocal molecular marker of the brown adipocyte differentiated phenotype, have been investigated in primary cultures of brown adipocytes, in the brown adipocyte cell line HIB 1B and directly in intact mice. The results obtained with cultured cells indicate that retinoids function as inducers of the appearance of UCP and, at the same time, partially inhibit brown adipocyte cell proliferation. The two RA isomers displayed similar effectiveness as UCP inducers, their effect being comparable with that triggered by noradrenaline, so far considered to be the main modulator of UCP gene expression. The effectiveness of retinoids as UCP inducers was dependent on the stage of brown adipocyte differentiation, being maximal in confluent primary cells and in the medium–late differentiation stage of HIB 1B cells. Corroborating the results obtained in vitro, we show that administration of all-trans-RA or 9-cis-RA to mice leads to an increase in their brown adipose tissue specific UCP content. 9-cis-RA treatment also prevented the loss of UCP on cold deacclimation. To our knowledge, this is the first report of a stimulatory effect of retinoid compounds on UCP induction in vivo.

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Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity

Nutrition Research Reviews ◽

10.1017/s0954422416000159 ◽

2016 ◽

Vol 29 (2) ◽

pp. 234-248 ◽

Cited By ~ 71

Author(s):

Katherine Gil-Cardoso ◽

Iris Ginés ◽

Montserrat Pinent ◽

Anna Ardévol ◽

Mayte Blay ◽

...

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Mucosal Barrier ◽

Low Grade ◽

Protective Effects ◽

Barrier Integrity ◽

Diet Induced Obesity

AbstractDiet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

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Crude Extracts fromLycium barbarumSuppress SREBP-1c Expression and Prevent Diet-Induced Fatty Liver through AMPK Activation

BioMed Research International ◽

10.1155/2014/196198 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Wang Li ◽

Yan Li ◽

Qing Wang ◽

Yi Yang

Keyword(s):

Fatty Liver ◽

High Fat Diet ◽

Uncoupling Protein ◽

Expression Profiles ◽

Liver Steatosis ◽

High Fat ◽

Lycium Barbarum ◽

Brown Adipose

Lycium barbarumpolysaccharide (LBP) is well known in traditional Chinese herbal medicine that, has beneficial effects. Previous study reported that LBP reduced blood glucose and serum lipids. However, the underlying LBP-regulating mechanisms remain largely unknown. The main purpose of this study was to investigate whether LBP prevented fatty liver through activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of sterol regulatory element-binding protein-1c (SREBP-1c). Male C57BL/6J mice were fed a low-fat diet, high-fat diet, or 100 mg/kg LBP-treatment diet for 24 weeks. HepG2 cells were treated with LBP in the presence of palmitic acid. In our study, LBP can improve body compositions and lipid metabolic profiles in high-fat diet-fed mice. Oil Red O stainingin vivoandin vitroshowed that LBP significantly reduced hepatic intracellular triacylglycerol accumulation. H&E staining also showed that LBP can attenuate liver steatosis. Hepatic genes expression profiles demonstrated that LBP can activate the phosphorylation of AMPK, suppress nuclear expression of SREBP-1c, and decrease protein and mRNA expression of lipogenic genesin vivoorin vitro. Moreover, LBP significantly elevated uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α) expression of brown adipose tissue. In summary, LBP possesses a potential novel treatment in preventing diet-induced fatty liver.

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Evaluation of Active Brown Adipose Tissue by the Use of Hyperpolarized [1-13C]Pyruvate MRI in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19092597 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2597 ◽

Cited By ~ 5

Author(s):

Mette Riis-Vestergaard ◽

Peter Breining ◽

Steen Pedersen ◽

Christoffer Laustsen ◽

Hans Stødkilde-Jørgensen ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Fdg Pet ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Protein Levels ◽

Positron Emission ◽

Brown Adipose

The capacity to increase energy expenditure makes brown adipose tissue (BAT) a putative target for treatment of metabolic diseases such as obesity. Presently, investigation of BAT in vivo is mainly performed by fluoro-d-glucose positron emission tomography (FDG PET)/CT. However, non-radioactive methods that add information on, for example, substrate metabolism are warranted. Thus, the aim of this study was to evaluate the potential of hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging (HP-MRI) to determine BAT activity in mice following chronic cold exposure. Cold (6 °C) and thermo-neutral (30 °C) acclimated mice were scanned with HP-MRI for assessment of the interscapular BAT (iBAT) activity. Comparable mice were scanned with the conventional method FDG PET/MRI. Finally, iBAT was evaluated for gene expression and protein levels of the specific thermogenic marker, uncoupling protein 1 (UCP1). Cold exposure increased the thermogenic capacity 3–4 fold (p < 0.05) as measured by UCP1 gene and protein analysis. Furthermore, cold exposure as compared with thermo-neutrality increased iBAT pyruvate metabolism by 5.5-fold determined by HP-MRI which is in good agreement with the 5-fold increment in FDG uptake (p < 0.05) measured by FDG PET/MRI. iBAT activity is detectable in mice using HP-MRI in which potential changes in intracellular metabolism may add useful information to the conventional FDG PET studies. HP-MRI may also be a promising radiation-free tool for repetitive BAT studies in humans.

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Brown preadipocyte transplantation locally ameliorates obesity

Archives of Plastic Surgery ◽

10.5999/aps.2020.02257 ◽

2021 ◽

Vol 48 (4) ◽

pp. 440-447

Author(s):

Kento Takaya ◽

Naruhito Matsuda ◽

Toru Asou ◽

Kazuo Kishi

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Uncoupling Protein ◽

Tissue Loss ◽

Whole Body ◽

Obese Mouse ◽

Fat Pad ◽

Brown Adipose

Background Brown adipose tissue (BAT) is a potential target for anti-obesity treatments. Previous studies have shown that BAT activation causes an acute metabolic boost and reduces adiposity. Furthermore, BAT and BAT-derived cell transplantation reportedly help treat obesity by regulating glucose and fatty acid metabolism. However, since BAT transplantation leads to whole-body weight loss, we speculated that earlier approaches cause a generalized and unnecessary fat tissue loss, including in breast and hip tissues.Methods We transplanted white adipose tissue-derived or BAT-derived preadipocytes prepared from C57BL/6 mice into one side of the inguinal fat pads of an obese mouse model (db/ db mice) to examine whether it would cause fat loss at the peri-transplant site (n=5 each). The same volume of phosphate-buffered saline was injected as a control on the other side. Six weeks after transplantation, the inguinal fat pad was excised and weighed. We also measured the concentrations of glucose, triglycerides, fatty acids, and total cholesterol in the peripheral blood.Results BAT-derived preadipocytes showed abundant mitochondria and high levels of mitochondrial membrane uncoupling protein 1 expression, both in vivo and in vitro, with a remarkable reduction in weight of the inguinal fat pad after transplantation (0.17±0.12 g, P=0.043). Only free fatty acid levels tended to decrease in the BAT-transplanted group, but the difference was not significant (P=0.11).Conclusions Our results suggest that brown adipocytes drive fat degradation around the transplantation site. Thus, local transplantation of BAT-derived preadipocytes may be useful for treating obesity, as well as in cosmetic treatments.

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Role of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00119.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. E363-E372 ◽

Cited By ~ 45

Author(s):

Ruidan Xue ◽

Yun Wan ◽

Shuo Zhang ◽

Qiongyue Zhang ◽

Hongying Ye ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Brown Fat ◽

Brown Adipocyte ◽

White Adipocyte ◽

Brown Adipose ◽

And Function ◽

Brown Adipogenesis

There are two different types of fat present in mammals: white adipose tissue, the primary site of energy storage, and brown adipose tissue, which is specializes in energy expenditure. Factors that specify the developmental fate and function of brown fat are poorly understood. Bone morphogenic proteins (BMPs) play an important role in adipogenesis. While BMP4 is capable of triggering commitment of stem cells to the white adipocyte lineage, BMP7 triggers commitment of progenitor cells to a brown adipocyte lineage and activates brown adipogenesis. To investigate the differential effects of BMPs on the development of adipocytes, C3H10T1/2 pluripotent cells were pretreated with BMP4 and BMP7, followed by different adipogenic induction cocktails. Both BMP4 and BMP7 unexpectedly activated a full program of brown adipogenesis, including induction of the brown fat-defining marker uncoupling protein-1 (UCP1), increasing the expression of early regulators of brown fat fate PRDM16 (PR domain-containing 16) and induction of mitochondrial biogenesis and function. Implantation of BMP4-pretreated C3H10T1/2 cells into nude mice resulted in the development of adipose tissue depots containing UCP1-positive brown adipocytes. Interestingly, BMP4 could also induce brown fat-like adipocytes in both white and brown preadipocytes, thereby decreasing the classical brown adipocyte marker Zic1 and increasing the recently identified beige adipocyte marker TMEM26. The data indicate an important role for BMP4 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro and offers a potentially new therapeutic approach for the treatment of obesity.

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Impact of glycosylphosphatidylinositol-specific phospholipase D on hepatic diacylglycerol accumulation, steatosis, and insulin resistance in diet-induced obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00319.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. E239-E250 ◽

Cited By ~ 6

Author(s):

Shigeki Masuda ◽

Yuya Fujishima ◽

Norikazu Maeda ◽

Yuri Tsugawa-Shimizu ◽

Yuto Nakamura ◽

...

Keyword(s):

Insulin Resistance ◽

Phospholipase D ◽

Mrna Level ◽

Nonalcoholic Fatty Liver ◽

Diet Induced Obesity ◽

Hepatic Insulin Signaling ◽

Rat Primary Hepatocytes ◽

Relationship Of

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme that specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI-PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in the liver. GPI-PLD mRNA was most highly expressed in the liver, and the hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet. Furthermore, diacylglycerol (DAG) content was significantly decreased, and PKCε activity was suppressed in the livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI-PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (R = 0.37, P = 0.0006) and triglyceride (R = 0.34, P = 0.001) levels in male subjects with metabolic syndrome. In conclusion, upregulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in the liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and the progression of NAFLD.

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DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

10.2337/figshare.14319725 ◽

2021 ◽

Author(s):

Lin Shuai ◽

Bo-Han Li ◽

Hao-Wen Jiang ◽

Lin Yang ◽

Jia Li ◽

...

Keyword(s):

Energy Homeostasis ◽

Adipocyte Differentiation ◽

Metabolic Diseases ◽

Diet Induced Obesity ◽

Beige Adipocytes ◽

Thermogenic Adipocytes ◽

And Function ◽

H3k79 Methylation

Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. Here, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing -1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis in vivo. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis in vitro. Mechanistically, DOT1L epigenetically regulates the BAT-selective gene program through modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.

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GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity

10.2337/figshare.17026628 ◽

2021 ◽

Author(s):

Qiongya Zhao ◽

Ting Luo ◽

Feng Gao ◽

Yinxu Fu ◽

Bin Li ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Metabolic Diseases ◽

Chain Complex ◽

Complex Activity ◽

Insulin Resistant ◽

Mitochondrial Homeostasis ◽

Dna Release

GRP75, defined as a major component of both mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in HFD-fed mice, and induction of Grp75 in mice could prevent HFD induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than MAM communication: GRP75 was negatively associated with respiratory-chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus trigger cytosolic mitochondrial DNA release and activate the cGAS/STING-dependent pro-inflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.

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