Apoptosis Through Targeted Activation of Caspase8 (“ATTAC-mice”): Novel Mouse Models of Inducible and Reversible Tissue Ablation

Trujillo, María E.; Pajvani, Utpal B.; Scherer, Philipp E.

doi:10.4161/cc.4.9.2030

Cited by 28 publications

(24 citation statements)

References 35 publications

(37 reference statements)

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“…In adults, for example, diet-induced obesity overwhelms the WAT stores, and fat accumulates in ectopic organs, such as liver and skeletal muscle, causing insulin resistance. This is illustrated nicely in the "fatless mouse" models as well as in patients with lipodystrophy; in the latter, in the absence of WAT, fat is stored in the liver and muscle, leading to severe insulin resistance (38)(39)(40)(41)(42)(43)(44)(45). With transplantation of wild-type WAT into this model, lipids dissipate from the liver and deposit in fat pads, and insulin resistance resolves.…”

Section: Discussionmentioning

confidence: 83%

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Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

McCurdy¹,

Bishop²,

Williams³

et al. 2009

J. Clin. Invest.

420

562

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Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.

show abstract

Section: Discussionmentioning

confidence: 83%

“…For example, in humans and nonhuman primates (NHPs), the development of WAT occurs during the third trimester (36,37). It is well accepted that WAT is critical for storage of excess lipids and that a lack of WAT results in whole-body insulin resistance and susceptibility to fatty liver in adult humans (38)(39)(40)(41)(42)(43)(44)(45).…”

Section: Introductionmentioning

confidence: 99%

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

McCurdy¹,

Bishop²,

Williams³

et al. 2009

J. Clin. Invest.

420

562

View full text Add to dashboard Cite

show abstract

“…Notably, the infl ammasome proteins were found neither in the adipocytes of control mice nor in the adipocytes or CLSs of FAT-ATTAC mice ( Fig. 9E ), a transgenic model of apoptotic adipocyte death ( 19,33 ).…”

Section: Discussionmentioning

confidence: 99%

“…That NLRP3-dependent caspase-1 activation and production of infl ammatory cytokines play a prominent role in metabolic syndrome has recently been confi rmed in mice lacking NLRP3, ASC, or caspase-1, which are resistant to the development of high-fat diet-induced obesity and insulin resistance ( 42 ). adipocyte apoptosis is induced through forced dimerization of a caspase-8 fusion protein ( 19,33 ), disclosed an analogous sequence of morphological events: apoptotic adipocytes fi rst exhibit organelle alterations; then they lose perilipin immunoreactivity, degenerate, and recruit neutrophils and lymphocytes; and fi nally, they are resorbed by macrophages in CLSs ( 36 ). Thus, the death of hypertrophic adipocytes appears to be a major event triggering macrophage recruitment and CLS formation in both genetic obesity and in the adipose tissue-specifi c apoptosis model.…”

Section: Nlrp3 Infl Ammasome Is Activated In Hypertrophic Adipocytes mentioning

confidence: 99%

Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis

Giordano¹,

Murano²,

Mondini³

et al. 2013

Journal of Lipid Research

Self Cite

243

171

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“…An excess of apoptosis can lead to lipodystrophic metabolic changes. 21 However, induction of moderate amounts of adipocyte apoptosis in obese mice has shown metabolic improvement, 22 suggesting that modulation of fat homeostasis by regulating differentiation and apoptosis might represent an instrument for controlling fat pad mass in the body. Interestingly, PPARg can have proapoptotic functions in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia

et al. 2014

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Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2Dadip mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2 Dadip mice. At the molecular level, Fra-2 directly binds to the PPARc2 promoter and represses PPARc2 expression. Deletion of Fra-2 leads to increased PPARc2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.

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Apoptosis Through Targeted Activation of Caspase8 (“ATTAC-mice”): Novel Mouse Models of Inducible and Reversible Tissue Ablation

Cited by 28 publications

References 35 publications

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia

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