Browsing by Subject "Adipose tissue"

Now showing 1 - 3 of 3
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    Examining Cellular Senescence and Brown Adipose-Like Features of Cardiac Adipose Tissue in Female Mice
    (2024) Nguyen, Katie; Carey, Anna; Camell, Christina
    Cardiovascular disease (CVD) is an age- and obesity-associated disease that is the leading cause of death in the world. During aging, white adipose tissue (AT) expands and becomes more inflammatory, driving systemic changes to lipid metabolism and increasing CVD risk. Senescent cells accumulate in white AT with age and secrete pro-inflammatory cytokines, chemokines, and proteases that constitute the senescence-associated secretory phenotype (SASP) and contribute to chronic inflammation and disease during aging. Epicardial and pericardial AT are beige, thermogenic tissues that surround the heart and can produce heat through metabolic activation by β3 adrenergic stimulation. The thermogenic capacity of other AT depots (i.e., subcutaneous and brown) declines with age, but it is unknown if thermogenic capacity and senescence in epicardial and pericardial AT changes with age. Therefore, we measured markers of senescence (p16, p21, Il6, Il1b) and thermogenesis (Ucp1, Ppargc1α) in epicardial and pericardial AT in young and old female mice. The old mice exhibited a basal reduction in Ucp1 and Ppargc1α expression in both tissues compared to the young, suggesting that basal thermogenesis declines with age. In contrast, β3 adrenergic stimulation induced greater expression of Ucp1 in old pericardial AT compared to young. Senescence factors including p16 and p21 increased in the AT from old mice compared to the young, indicating increased senescence in old pericardial and epicardial AT. However, cytokine expression was unchanged or reduced with age. Notably, epicardial AT showed greater p16 and loss of thermogenic markers compared to pericardial AT during aging, suggesting differential aging of these tissues. Ultimately, our results showed that cardiac AT thermogenesis is impaired basally, but not under stimulation, and may be more senescent during aging. Additionally, epicardial AT shows greater age-related metabolic dysfunction. These data provide more insight into the heterogeneity of adipose tissue depots, which will benefit research in CVD.
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    Identification of the transcription factor ZEB1 as a novel modulator of adiposity.
    (2009-09) Saykally, Jessica Nicole
    Obesity and its subsequent metabolic disorders have become global health problems. While this is largely due to environmental influences, the propensity to gain weight also has a significant genetic component. In an effort to identify genes that contribute to obesity, several genome-wide scans on obese patient populations have been performed. One consistent location that displayed linkage to obesity is chromosome 10p11-12. A likely candidate gene within this region is the TCF8 gene, which encodes the ZEB1 transcription factor. To test whether TCF8 is an anti-obesity gene, DNA from obese patients was genotyped using single nucleotide polymorphisms throughout the TCF8 genetic locus. Logarithm of the odds for linkage of TCF8 to childhood obesity was high in two regions. Sequencing of a subset of the patient DNAs revealed a polymorphism that results in an amino acid change within the coding region of 50% of the patients. More tests will be required to determine whether the polymorphism has a functional consequence. In addition, TCF8+/- and wild type (WT) C57BL/6 mice were fed a high fat diet or regular chow diet for 20 weeks and their body weights, body composition, and metabolic parameters measured. TCF8 +/- female mice were significantly heavier on both diets due to an increase in fat. Increased adipose mass was the result of increased adipocyte size and was sufficient to cause metabolic consequences. Interestingly, this phenotype was not observed in male or female mice treated with the specific anti-estrogen Faslodex, suggesting that ZEB1 is mediating some of estrogen’s anti-obesity effects. Expression of several known estrogen-regulated genes important in lipolysis and lipogenesis measured in TCF8 +/- and WT suggests that ZEB1 modulates the flux of lipids in adipocytes. This thesis identifies TCF8 as an anti-obesity gene in mice and potentially in humans. Loss of one copy of the TCF8 gene is sufficient to increase adiposity and subsequent metabolic consequences. This is a novel observation as no one has previously proposed a role for ZEB1 in adipose tissue. In addition, this data contributes to our understanding of sexual dimorphism in metabolism.
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    Understanding the role of Lipocalin 2 as an important regulator of energy metabolism
    (2013-03) Zhang, Yuanyuan
    Lipocalin 2 (Lcn2) is a recently identified adipose tissue-derived cytokine which functions in innate immunity, inflammation, and insulin resistance. Nonetheless, the metabolic regulation and function of adipose Lcn2 is not completely understood. Herein, we investigated how adipose Lcn2 expression is regulated by metabolic challenges and nutrient signals, as well as how Lcn2 deficiency affects whole-body energy metabolism and lipid homeostasis. We found that Lcn2 mRNA expression was significantly upregulated during fasting and cold exposure in mice. Insulin stimulated Lcn2 expression and secretion in 3T3-L1 adipocytes in a dose-dependent manner, which was enhanced by glucose and attenuated by aspirin treatment. Multiple fatty acids also induced Lcn2 expression and secretion in adipocytes. The regulation of adipose Lcn2 by metabolic challenges and nutrient signals indicated a potential role of Lcn2 in energy metabolism. Next, we explored the metabolic consequences of Lcn2 deficiency in mice under high fat diet (HFD) conditions. We found that Lcn2 deficiency potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance in mice. Moreover, Lcn2 knockout (KO) mice exhibited impaired adaptive thermogenesis and cold intolerance. Further studies showed that Lcn2 deficiency reduced the efficiency of cold-induced mitochondrial oxidation of lipids and blunted cold-induced activation of Uncoupling Protein 1 and expression of thermogenic and angiogenic genes, leading to lipid accumulation and thermogenic dysfunction of brown adipocytes. Interestingly, the administration of PPARgamma agonist effectively improved HFD-induced insulin resistance in Lcn2 KO mice without increasing body weight, subcutaneous fat mass, or lipid accumulation in liver. PPARgamma agonist administration also fully prevented cold-intolerant phenotype in Lcn2 KO mice. Our results indicate that Lcn2 plays a critical role in the regulation of lipid homeostasis and thermogenic activation via a possible mechanism of modulating PPARgamma activation.