Caloric restriction (CR) delays the onset of aging and extends lifespan in diverse experimental organisms through an unknown mechanism. In mice, CR induces an extensive remodeling and reprogramming of white adipose tissue (WAT) that may be important in CR's ability to reduce systemic inflammatory tone. A primary event in CR's induction of a metabolically and functionally distinct WAT may involve a novel pathway for mitochondrial adaptation. We hypothesize that metabolic regulators involved in mitochondrial adaptation induce a reprogramming of WAT in response to CR through alterations in PGC-11 processing and function. To test this we will employ a multifaceted approach to investigate the regulation of PGC-11 at molecular, cellular and systemic levels. There are three specific aims:
Specific Aim 1 : To determine the mechanism and functional consequence of GSK32 dependent post-translational modification of PGC-11. The impact of CR in WAT is consistent with a model where reduced GSK32 activity enhances PGC-11 stability. To investigate the molecular basis of this, we will use NIH- 3T3 cells to determine: i) the impact of constitutively active or kinase inactive GSK32 on PGC-11 localization, stability and activity, ii) the identity and requirement for integrity of PGC-11 residues phosphorylated by GSK32, and iii) the significance of the PGC11 destruction box and proteolytic processing consensus sequences in directing PGC-11 turnover and activities.
Specific Aim 2 : To determine the role of PGC-11 and mitochondrial adaptation in adipocyte morphology and function. Factors regulated by CR in WAT also influence adipogenesis of 3T3-L1 preadipocytes, possibly through their impact on PGC-11. To investigate these cellular pathways we will determine: i) the involvement and timing-specific requirement for PGC-11 in adipogenesis, ii) the impact of altered PGC-11 and GSK32 on cell morphology and the adipogenic respiratory transition, and iii) the role of the RNA binding motif of PGC-11 in regulating the pro-respiration splice variant of pyruvate kinase.
Specific Aim 3 : To determine the impact of factors involved in mitochondrial adaptation on WAT and serum factors in mice. We have proposed that CR-induced alterations in GSK32 and SIRT1 act through PGC-11 to implement the metabolic reprogramming observed in WAT from CR mice. We will determine the extent to which GSK32 inhibition (lithium carbonate), SIRT1 activation (resveratrol) or PGC-11 activation (bezafibrate) can mimic the effect of CR on i) WAT gene expression and alternate splicing profiles, ii) serum levels of lipid signaling molecules, and iii) serum levels of adiponectin, leptin, resistin and visfatin. The proposed studies are expected to provide novel mechanistic details of the regulation of PGC-11 and critical insights into WAT remodeling by CR. We expect that the significance of this study will extend to the investigation of diseases that are promoted by deregulation of WAT.
Caloric restriction (CR) represents the most robust dietary intervention to delay the aging process in multiple organisms including mammals. This study investigates the molecular and cellular events induced by CR in white adipose tissue that influence overall metabolism and systemic inflammation. The novel mechanistic insights to be gained from this study are relevant to two major issues facing public health: the increasing population of individuals with age-associated diseases and the prevalence of metabolic disorders associated with obesity.
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