302-LB: Mild Mitochondrial Stress in POMC Neurons Promotes Thermogenesis in Inguinal White Adipose Tissues and Prevents Diet-Induced Obesity

Mild mitochondrial stress in POMC neurons promotes thermogenesis in inguinal white adipose tissues and prevents diet-induced obesity. Normal mitochondrial dynamics and functions in hypothalamic neurons are pivotal in the maintenance of systemic energy homeostasis. CRIF1 has been identified as a mito-ribosomal protein which critically mediates incorporation of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) polypeptides into the inner mitochondrial membrane. Complete loss of CRIF1 in neurons causes severe OXPHOS dysfunction and leads to a neuronal death. To study the impact of mitochondrial stress in hypothalamic proopiomelanocortin (POMC) neurons, we generated a mice model lacking CRIF1 expression specifically in the POMC neurons using cre-lox system. Both male and female POMC-cre; CRIF1f/f mice developed obesity since the 10-15 weeks of age due to a gradual loss of POMC neurons. Unexpectedly, energy expenditure and thermogenesis were enhanced in POMC-cre; CRIF1+/f mice compared to their wild littermates. Moreover, they were resistance to diet-induced obesity when exposed to a high fat diet (HFD) before the 10 weeks of age. For the mechanism of enhanced thermogenesis, we found increased UCP1 expression and brown adipocyte-like cells in the inguinal subcutaneous white adipose tissue (ingWAT), so called "browning of subcutaneous fat depot." More strikingly, the expression of mitochondrial unfolded protein response (UPRmt) markers was significantly increased in the ingWAT of POMC-cre; CRIF1+/f mice. These findings strongly suggest that mild mitochondrial stress in POMC neurons causes mitochondrial stress response in the remote organ (ingWAT) via unidentified cell-non-autonomous mechanisms, leading to increased thermogenic activity in this fat depot. Disclosure S. Kim: None. S. Min: None. G. Kang: None. J. Kim: None. J. Choi: None. M. Kim: None. Funding National Research Foundation of Korea (NRF-2013M3C7A1056024)