Role of Fat Metabolism in Cellular Differentiation

Biswas, Dipsikha (2017) Role of Fat Metabolism in Cellular Differentiation. PhD thesis, C U.

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    Supervisors

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    Chakrabarti, Partha

    Abstract

    The metabolic phenotype of a cell can change in response to substrate availability and the metabolic demands of proliferation, growth and cell survival. The adaptation of the cellular metabolism to suit the developmental stages or during unrestricted proliferation is known as metabolic remodelling. The major shift in the metabolism occurs between the choices of the fuel; accordingly the cell’s metabolic phenotype could either be preferentially glycolytic or oxidative. Cellular differentiation entails a shift in the metabolic phenotype as the energy demands and requisites for raw materials reduce once the cells are committed to a specific lineage. Previous studies have speculated a shift towards oxidative phosphorylation as the major metabolic phenotype in the differentiated cells. Adipose triglyceride lipase (ATGL) is the ratelimiting enzyme for triacylglycerol (TG) catabolism and is considered to be a key driver of the oxidative phosphorylation (OXPHOS). However, the role of fat metabolism has been relatively unexplored in the context of metabolic switching during differentiation. This study thus aimed to unravel the role of ATGL catalyzed lipolysis in metabolic rewiring during differentiation. The study was further expanded to investigate the effect of the ATGL in driving the skeletal muscle mitochondrial metabolism and its implication in muscle frailty or sarcopenia. Initially, several in vitro models of differentiation of the mesenchymal lineage were screened for the metabolic shift towards an oxidative phenotype and it was found to be dependent on ATGL.Mouse placental differentiation was chosen for further studies and ATGL induction was found to be concomitant with increased fatty acid oxidation (FAO) and oxygen consumption rates (OCR) and paralleled the PPARγ expression patterns; although the key glycolytic enzyme, hexokinase II and the lactate levels were not significantly repressed suggesting that glycolysis is not completely dispensable.Next, the role of ATGL mediated lipid metabolism was investigated in another cellular differentiation system, the skeletal muscle. Myogenesis, marked by the fusion of myoblasts into myotubes, parallels mitochondrial biogenesis which is regulated via a transcriptional program driven by PPARα and its coactivator PPAR-γ coactivator-1α (PGC1α). However, the role of ATGL dependent lipolysis in skeletal muscle mitochondrial metabolism was poorly understood. ATGL was exclusively induced during differentiation and it was demonstrated by genetic as well as pharmacological interventions in both in vitro and in vivo systems, to be a transcriptional target of PPARα. However, augmented expression of ATGL did not alter the effects of PPARα or its agonist fenofibrate dependent lipid metabolism and insulin sensitivity. Both in vitro and in vivo, ectopic expression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) without alteration in mitochondrial content. Over expression of ATGL rendered PPARα and PGC1α redundant and they are unable to function upon depletion of ATGL. Further, in middle aged rats, fenofibrate induced ATGL expression selectively in the oxidative soleus muscle, where PPARα- ATGL pathway sustained mitochondrial oxidative function. In conclusion, ATGL driven lipid catabolism is instrumental in driving the oxidative phosphorylation during cellular differentiation and is indispensable for the function of the PPARa mediated mitochondrial oxidative program in the skeletal muscle.

    Item Type: Thesis (PhD)
    URI: http://www.eprints.iicb.res.in/id/eprint/2628
    Subjects: Cell Biology & Physiology
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 28 Apr 2017 11:29
    Last Modified: 28 Apr 2017 11:32
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