Brown adipose tissue (BAT) is unique in its ability to acutely turn on uncoupling, leading to nutrient consumption and thermogenesis. As such, expansion of BAT is considered a potential strategy to reduce obesity in humans. New approaches to increase BAT mass have been developed, however the ability of fully differentiated BAT to dissipate energy by thermogenesis still remains dependent on adrenergic stimulation. Therefore, to obtain therapeutic benefit, expansion of BAT must be complemented by new approaches to activate BAT uncoupling and energy dissipation. Our studies indicate that in addition to lipolysis, adrenergic stimulation induces acute and robust changes to mitochondrial network architecture. These changes to mitochondria increase the ability of free fatty acids (FFA) to induce uncoupling and energy dissipation. We hypothesize that changes to mitochondrial dynamics serve as an amplification pathway for norepinephrine-induced uncoupling by enhancing the ability of FFA to activate UCP1 and by recruiting PTP as a secondary uncoupling mechanism. To address this hypothesis we will (i) study NE-unique changes to mitochondrial dynamics in the mouse brown adipocytes (BA) and human brite (brown in white) adipocytes, and determine the molecular mediators of these effects, (ii) quantify the extent to which mitochondrial dynamics acts as an amplification and sensitization pathway for energy dissipation in human brite and mouse BA in vitro and in vivo, and (iii) determine the mechanism by which changes to mitochondrial dynamics amplifies energy expenditure and increases sensitivity of BAT to FFA. This study will demonstrate that mitochondrial dynamics is a potential therapeutic point of intervention through which activation of BA uncoupling can be achieved at plasma levels of fatty acids, in the absence of adrenergic stimulation. Two pharmacological approaches to target mitochondrial dynamics will also be tested as a proof of concept for this approach, verifying the impact of changes to mitochondrial dynamics on BA uncoupling and energy dissipation.

Public Health Relevance

Brown adipose tissue constitute an effective mechanism through which the organism waste energy by heat production. In this proposal we describe a novel mechanism for energy expenditure in the brown adipocyte as our results indicate that this new mechanism is activated by adrenaline and serves as an amplification pathway for energy dissipation. Pharmacological activation of this pathway may offer an approach to bypass the need for adrenaline.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099618-01A1
Application #
8697536
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$366,563
Indirect Cost
$154,063
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118