Abstract
Brown adipose tissue (BAT) thermogenesis is an emerging target for prevention and treatment of obesity. Mitochondria are the heat generators of BAT. Yet, there is no noninvasive means to image the temporal dynamics of the mitochondrial activity in BAT in vivo. Here, we report a technology for quantitative monitoring of principal kinetic components of BAT adaptive thermogenesis in the living animal, using the PET imaging voltage sensor 18F-fluorobenzyltriphenylphosphonium (18F-FBnTP). 18F-FBnTP targets the mitochondrial membrane potential (ΔΨm)—the voltage analog of heat produced by mitochondria. Dynamic 18F-FBnTP PET imaging of rat’s BAT was acquired just before and during localized skin cooling or systemic pharmacologic stimulation, with and without administration of propranolol. At ambient temperature, 18F-FBnTP demonstrated rapid uptake and prolonged steady-state retention in BAT. Conversely, cold-induced mitochondrial uncoupling resulted in an immediate washout of 18F-FBnTP from BAT, which was blocked by propranolol. Specific variables of BAT evoked activity were identified and quantified, including response latency, magnitude and kinetics. Cold stimulation resulted in partial washout of 18F-FBnTP (39.1%±14.4% of basal activity). The bulk of 18F-FBnTP washout response occurred within the first minutes of the cold stimulation, while colonic temperature remained nearly intact. Drop of colonic temperature to shivering zone did not have an additive effect. The ß3-adrenergic agonist CL-316,243 elicited 18F-FBnTP washout from BAT of kinetics similar to those caused by cold stimulation. Thus, monitoring ΔΨm in vivo using 18F-FBnTP PET provides insights into the kinetic physiology of BAT. 18F-FBnTP PET depicts BAT as a highly sensitive and rapidly responsive organ, emitting heat in short burst during the first minutes of stimulation, and preceding change in core temperature. 18F-FBnTP PET provides a novel set of quantitative metrics highly important for identifying novel therapeutic targets at the mitochondrial level, for developing means to maximize BAT mass and activity, and assessing intervention efficacy.
Highlights
The recent discovery of metabolically active brown adipose tissue (BAT) depots in human adults [1,2,3,4,5] has opened new avenues for the search of therapeutic approaches to the prevention and treatment of obesity and comorbidities
We report a technology for quantitative monitoring of principal kinetic components of Brown adipose tissue (BAT) adaptive thermogenesis in the living animal, using the PET imaging voltage sensor 18Ffluorobenzyltriphenylphosphonium (18F-FBnTP). 18F-FBnTP targets the mitochondrial membrane potential (ΔΨm)—the voltage analog of heat produced by mitochondria
The effect of localized skin cooling on 18F-FBnTP retention in BAT was studied using 90-min dynamic PET scan (Protocol III, n = 6). 18F-FBnTP was administered IV, and the first 20 or 30 min of the dynamic scan were acquired while the animal was kept warm, using heating lamp
Summary
The recent discovery of metabolically active brown adipose tissue (BAT) depots in human adults [1,2,3,4,5] has opened new avenues for the search of therapeutic approaches to the prevention and treatment of obesity and comorbidities (e.g., diabetes, heart disease). The absence of BAT [18,19,20] or UCP1 [21,22] resulted in metabolic inefficiency leading to obesity, hyperphagia and insulin resistance [22]. Activation of BAT resulted in a significant decrease of triglycerides in blood, which otherwise would be stored in the body as white fat lipids [24]
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