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Investigating Molecular Pathways Controlling Resistance to Obesity and NAFLD in Plin2-Null Mice
Başlık:
Investigating Molecular Pathways Controlling Resistance to Obesity and NAFLD in Plin2-Null Mice
Yazar:
Libby, Andrew Eric, author.
ISBN:
9780438003088
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (159 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: James L. McManaman Committee members: Andrew P. Bradford; Robert H. Eckel; Miguel Lanaspa Garcia; Moshe Levi; David J. Orlicky; Hugo R. Rosen.
Özet:
Obesity and its associated disorder, non-alcoholic fatty liver disease (NAFLD), comprise serious public health challenges in the modern world. Despite intense study, current treatments for obesity and NAFLD have proven largely ineffective. Perilipin-2 (Plin2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in obesity and NAFLD. Mice lacking whole-body Plin2 (Plin2-null) are resistant to obesity and fatty liver formation compared to wild type (WT) mice when placed on a 30-week high fat diet. Nevertheless, the molecular mechanisms by which Plin2-null animals resist weight gain and NAFLD remain poorly understood. To explore these mechanisms, WT and Plin2-null mice were placed on a Western or control diet for 30 weeks. Consistent with previous studies, Plin2 deletion prevented obesity and insulin resistance in Western diet fed mice, and dramatically reduced hepatic triglyceride and cholesterol content. Biochemical studies reveal that PLIN2 deletion suppressed genes involved in hepatic de novo lipogenesis and cholesterol biosynthetic pathways in Plin2-null mice. GC-MS lipidomics demonstrates that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. Compared to WT mice on western diet, Plin2-null animals also exhibit profound histological browning and robust induction of the thermogenic program in their subcutaneous white adipose tissue at room temperature. The degree of browning in Plin2-null animals is dependent on the type of diet they are placed on, with diets high in simple carbohydrates eliciting the most robust browning responses. To study this observation, mice were placed on a high sucrose diet for 6 weeks. Plin2-null mice on this diet developed profound browning and exhibited elevated markers of adipose tissue insulin sensitivity. Our findings indicate that diet-mediated beiging in Plin2-null mice is likely due to enhanced FGF21 production by the liver, which may also explain reduced intake of sugar-containing diets and increased glucose tolerance that has been observed. These data suggest that resistance to obesity and NAFLD in Plin2-null mice may be due to reduced food intake, increased energy expenditure in white adipose tissue, and alterations in the hepatic lipidome that suppress carbohydrate-driven lipid synthesis.
Notlar:
School code: 1639
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680700.1) | 680700-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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