Mahdaviani 2014 Abstract MiP2014
|Hormone‐induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure.|
Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis . The brown adipocyte is a unique system to study the relationship between mitochondrial architecture and bioenergetic function. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically‐induced changes in energy expenditure. Brown pre-adipocyes were harvested from 4-week-old wild-type male C57BL6/J mice and differentiated in culture. Oxygen consumption was measured using Seahorse XF24. Mitochondrial membrane potential was measured using TMRE and Zeiss LSM 710 confocal microscope. Measurements were taken before and after activation with NE (1 uM) and FFA (palmitate or oleate, 0.4 mM).
The sympathetic neurotransmitter norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE‐mediated Drp1 phosphorylation was dependent on protein kinase‐A (PKA) activity , whereas Opa1 cleavage required mitochondrial depolarization, mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold‐exposed mice. Mitochondrial uncoupling, induced by NE in brown adipocytes, was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure.
These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Taken together these data reveal that adrenergically‐induced changes of mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
• O2k-Network Lab: SE Stockholm Wikstroem J
Labels: MiParea: Respiration, mt-Structure;fission;fusion, mt-Membrane
Organism: Mouse Tissue;cell: Fat, Other cell lines
Regulation: Coupling efficiency;uncoupling
Event: A2, Oral MiP2014
1-Dep Medicine, Boston Univ School Medicine, MA, USA; 2-Dep Mol Biosc, Wenner-Gren Inst, Stockholm Univ, Sweden; 3-Dep Clinical Biochem, Fac Medicine, Ben Gurion Univ Negev, Beer-Sheva, Israel; 4-Dep Medicine and Dr. Pinchas Bornstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 5-Dep Exp Clinical Med, Univ Ancona, Italy, 6-Center for Nanoscales System, Harvard Univ, Cambridge, MA, USA. - [email protected]
References and acknowledgements
Supported by T32 Cardiovascular Biology training grant.
- Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359
- Chang CR, Blackstone C (2007) Drp1 phosphorylation and mitochondrial regulation. EMBO Rep 8: 1088–9; author reply 1089–90