Authors
Nam, MinwooFaculty Advisor
John F. Keaney, Jr.Academic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
Division of Cardiovascular MedicineDocument Type
Doctoral DissertationPublication Date
2017-01-11Keywords
Brown adipose tissuethermogenic gene program
mitochondria
mitochondrial retrograde signaling
PPARgamma
calcium
Animal Experimentation and Research
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
In murine and human brown adipose tissue (BAT), mitochondria are powerful generators of heat. Emerging evidence has suggested that the actions of mitochondria extend beyond this conventional biochemical role. In mouse BAT and cultured brown adipocytes, impaired mitochondrial respiratory capacity is accompanied by attenuated expression of Ucp1, a key thermogenic gene, implying a mitochondrial retrograde signaling. However, few have investigated this association in the context of mitochondria-nucleus communication. Using mice with adipose-specific ablation of LRPPRC, a regulator of respiratory capacity, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to transcriptional and metabolic reprogramming of BAT. Impaired respiratory capacity triggers down-regulation of thermogenic and oxidative genes, promoting a storage phenotype in BAT. This retrograde regulation functions by interfering with promoter-specific recruitment of PPARg. In addition, cytosolic calcium may mediate the retrograde signal from mitochondria to nucleus. These data are consistent with a model whereby BAT connects its respiratory capacity to thermogenic gene expression, which in turn contributes to determining its metabolic commitment. Additionally, we find that augmented respiratory capacity activates the thermogenic gene program in inguinal (subcutaneous) white adipose tissue (IWAT) from adipose-specific LRPPRC transgenic mice. When fed a high-fat diet at thermoneutrality, these mice exhibit metabolic improvements as shown by reduced fat mass and improved insulin sensitivity. Furthermore, there is increased recruitment of brown-like adipocytes in IWAT and thus energy expenditure is significantly increased, providing a potential explanation for protection from obesity. These data suggest that augmented respiratory capacity promotes ‘browning’ of IWAT, which has beneficial effects on obesity and diabetes.DOI
10.13028/M2NP4FPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32263Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2NP4F