GQ-16, a TZD-Derived Partial PPARγ Agonist, Induces the Expression of Thermogenesis-Related Genes in Brown Fat and Visceral White Fat and Decreases Visceral Adiposity in Obese and Hyperglycemic Mice

Coêlho, Michella Soares; Lima, Caroline Lourenço de; Royer, Carine; Silva, Janaina B.; Oliveira, Fernanda Cerqueira Barroso; Christ, Camila G.; Pereira, Sidney Alcântara; Báo, Sônia Nair; Lima, Manfredo; Pitta, M. G. R.; Pitta, Ivan R.; Neves, Francisco A. R.; Amato, Angélica Amorim

doi:10.1371/journal.pone.0154310

Cited by 31 publications

(49 citation statements)

References 43 publications

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“…Decreased insulin resistance and reduced hyperglycemia have been observed in humans [64,65] and in obese mice [66–68] following treatment with rosiglitazone. The major clinical side effect of rosiglitazone is significant weight gain [69,70].…”

Section: Discussionmentioning

confidence: 99%

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Peterson¹,

Jackson²,

Zimmerman³

et al. 2017

PLoS ONE

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The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Conclusion: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

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Section: Discussionmentioning

confidence: 99%

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Peterson¹,

Jackson²,

Zimmerman³

et al. 2017

PLoS ONE

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show abstract

“…Activation of PPARγ by synthetic ligand rosiglitazone induces expression of genes specific for brown adipocytes and mitochondrial biogenesis in white adipocyte cell lines and murine WAT through the activation of the PRDM16 pathway [ 2 , 125 ]. In addition, treatment with partial PPARγ agonist (GQ-16) reduced high fat diet-induced weight gain in mice that was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, as well as, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT [ 126 ]. Consistently, AT in mice with PPARγ knockout has reduced capacity to generate ATP that translates to a lower metabolic rate [ 127 ].…”

Section: Pharmacological Interventions Aiming At White Adipose Tismentioning

confidence: 99%

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

Kuryłowicz

Puzianowska-Kuźnicka

2020

IJMS

148

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The ongoing obesity pandemic generates a constant need to develop new therapeutic strategies to restore the energy balance. Therefore, the concept of activating brown adipose tissue (BAT) in order to increase energy expenditure has been revived. In mammals, two developmentally distinct types of brown adipocytes exist; the classical or constitutive BAT that arises during embryogenesis, and the beige adipose tissue that is recruited postnatally within white adipose tissue (WAT) in the process called browning. Research of recent years has significantly increased our understanding of the mechanisms involved in BAT activation and WAT browning. They also allowed for the identification of critical molecules and critical steps of both processes and, therefore, many new therapeutic targets. Several non-pharmacological approaches, as well as chemical compounds aiming at the induction of WAT browning and BAT activation, have been tested in vitro as well as in animal models of genetically determined and/or diet-induced obesity. The therapeutic potential of some of these strategies has also been tested in humans. In this review, we summarize present concepts regarding potential therapeutic targets in the process of BAT activation and WAT browning and available strategies aiming at them.

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“… 19 , 20 , 21 , 22 , 23 Similarly to visceral obesity, BAT was also reported to be inversely related to metabolic risk. 13 , 17 , 24 , 25 …”

Section: Introductionmentioning

confidence: 99%

Association of proton density fat fraction in adipose tissue with imaging-based and anthropometric obesity markers in adults

et al. 2017

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Background/Objectives:The purpose of this study was to examine the relationship of the proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), of supraclavicular and gluteal adipose tissue with subcutaneous and visceral adipose tissue (SAT and VAT) volumes, liver fat fraction and anthropometric obesity markers. The supraclavicular fossa was selected as a typical location where brown adipocytes may be present in humans and the gluteal region was selected as a typical location enclosing primarily white adipocytes.Subjects/Methods:In this cross-sectional study, 61 adults (44 women, median age 29.3 years, range 21–68 years) underwent an MRI examination of the neck and the abdomen/pelvis (3T, Ingenia, Philips Healthcare). PDFF maps of the supraclavicular and gluteal adipose tissue and the liver were generated. Volumes of SAT and VAT were calculated and supraclavicular and subcutaneous fat were segmented using custom-built post-processing algorithms. Body mass index (BMI), waist circumference and waist-to-height ratio were recorded. Statistical analysis was conducted using the Student's t-test and Pearson correlation analysis.Results:Mean supraclavicular PDFF was 75.3±4.7% (range 65.4–83.8%) and mean gluteal PDFF was 89.7±2.9% (range 82.2-94%), resulting in a significant difference (P<0.0001). Supraclavicular PDFF was positively correlated with VAT (r=0.76, P<0.0001), SAT (r=0.73, P<0.0001), liver PDFF (r=0.42, P=0.0008) and all measured anthropometric obesity markers. Gluteal subcutaneous PDFF also correlated with VAT (r=0.59, P<0.0001), SAT (r=0.63, P<0.0001), liver PDFF (r=0.3, P=0.02) and anthropometric obesity markers.Conclusions:The positive correlations between adipose tissue PDFF and imaging, as well as anthropometric obesity markers suggest that adipose tissue PDFF may be useful as a biomarker for improving the characterization of the obese phenotype, for risk stratification and for selection of appropriate treatment strategies.

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GQ-16, a TZD-Derived Partial PPARγ Agonist, Induces the Expression of Thermogenesis-Related Genes in Brown Fat and Visceral White Fat and Decreases Visceral Adiposity in Obese and Hyperglycemic Mice

Cited by 31 publications

References 43 publications

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

Association of proton density fat fraction in adipose tissue with imaging-based and anthropometric obesity markers in adults

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