Program Enrichment

Mitochondrial Dynamics and Stress response pathways in metabolic diseases

The prevalence of obesity and associated comorbidities, such as diabetes and cardiovascular disease, have increased dramatically over the last several decades. Activation of brown adipose tissue (BAT) function has emerged as a promising therapeutic strategy to increase energy expenditure and counteract weight gain. Recent evidence in mice and humans suggest a role for BAT in regulating the secretion of endocrine factors or BATokines, such as fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), that may promote cardiometabolic health. Our work in mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1) in BAT demonstrated that mitochondrial stress induces the integrated stress response (ISR), which is required to improve metabolic fitness in these mice, partially via FGF21 secretion as a BATokine. We also demonstrated that the ISR is induced in BAT in response to cold. Our research program aims to understand the role of the ISR in the regulation of BAT-mediated systemic metabolic adaptations in response to cold, diet-induced obesity and mitochondrial stress. Our current research projects focus on: 1. Investigating the role of PKR-like ER kinase (PERK) as an upstream regulator of ISR activation in BAT; 2. The role of the activating transcription factor 4 (ATF4), the main effector of the ISR, in BAT thermogenesis and metabolic homeostasis. 3. The role of GDF15 in the regulation of BAT-mediated metabolic protection. We believe these studies have the potential of identifying new pathways that can be targeted to induce BAT’s thermogenic activity and secretome, to counteract obesity and its comorbidities.