Inflammation during obesity and aging contributes to impairments in adipose tissue leading to poor metabolic health. Consequently, obesity induces an inflammatory environment within adipose tissue that is associated with an irreversible cell cycle arrest known as cellular senescence. Likewise, this inflammatory environment is detrimental to the generation of new adipocytes, impairing the physiological role of white adipose tissue and damaging metabolic health. However, there is substantial evidence that reducing dietary protein intake, without reducing caloric intake, protects against HFD-induced obesity, improves glucose homeostasis, increases energy expenditure, and remodels adipose tissue. Our lab recently discovered that the effects of dietary protein restriction (DPR) require increases in the beneficial metabolic hormone Fibroblast Growth Factor 21 (FGF21), and that FGF21 mediates improvements in metabolic health by acting directly within the brain. Importantly, our data suggest that a key FGF21-dependent effect of protein restriction is the remodeling of white adipose tissue, and we hypothesize that this adipose tissue remodeling is a primary mediator of the improvements in metabolic health and lifespan. However, the specific changes that occur in adipose tissue which contribute to the beneficial metabolic effects of protein restriction are not well defined. Considering that obesity is associated with profound changes in adipose tissue, and that white adipose tissue is a critical endocrine mediator of energy expenditure and insulin sensitivity, it is likely that diet interventions such as DPR will reduce the metabolic insult cellular senescence and its markers, such as p16INK4a and the senescence-associated secretory phenotype (SASP), in adipose tissue. The goal of the current proposal is to determine if remodeling of adipose tissue by DPR reduces senescent cells, therefore reducing the SASP in WAT. This pilot and feasibly grant will test the central hypothesis that dietary protein restriction protects against the detrimental effects of senescent cells during obesity.
The goal of the current supplemental Pennington/Louisiana NORC proposal is to determine if remodeling of adipose tissue by dietary protein restriction reduces senescent cells in the adipose tissue, therefore reducing the senescence-associated secretory phenotype leading to impaired metabolic health. This pilot and feasibly grant from a minority early stage investigator will test the central hypothesis that dietary protein restriction protects against the detrimental effects of senescent cells during obesity.
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