title: Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats.
abstract: Activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) present potential new therapies for obesity and type 2 diabetes. Here, we examined the effects of β3-adrenergic stimulation on tissue-specific uptake and storage of free fatty acids (FFA) and its implications for whole body FFA metabolism in diet-induced obese rats using a multi-radiotracer technique. Male Wistar rats were high fat-fed for 12 wk and administered β3-agonist CL316,243 (CL, 1 mg·kg-1·day-1) or saline via osmotic minipumps during the last 3 wk. The rats were then fasted and acutely infused with a tracer mixture ([14C]palmitate and the partially metabolized R-[3H]bromopalmitate) under anesthesia. CL infusion decreased body weight gain and fasting plasma glucose levels. While core body temperature was unaffected, infrared thermography showed an increase in tail heat dissipation following CL infusion. Interestingly, CL markedly increased both FFA storage and utilization in interscapular and perirenal BAT, whereas the flux of FFA to skeletal muscle was decreased. In this rat model of obesity, only sporadic populations of beige adipocytes were detected in the epididymal WAT depot of CL-infused rats, and there was no change in FFA uptake or utilization in WAT following CL infusion. In summary, β3-agonism robustly increased FFA flux to BAT coupled with enhanced utilization. Increased BAT activation most likely drove the increased tail heat dissipation to maintain thermostasis. Our results emphasize the quantitative role of brown fat as the functional target of β3-agonism in obesity.
authors: Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden.
authors: Amy
authors: A
authors: Warner
authors: Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden.
authors: Ann
authors: A
authors: Kjellstedt
authors: Discovery Sciences, Transgenics, AstraZeneca Gothenburg, Sweden.
authors: Alba
authors: A
authors: Carreras
authors: Pathology, Drug Safety and Metabolism, AstraZeneca Gothenburg, Sweden; and.
authors: Gerhard
authors: G
authors: Böttcher
authors: Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden.
authors: Xiao-Rong
authors: XR
authors: Peng
authors: University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Patrick
authors: P
authors: Seale
authors: Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden.
authors: Nicholas
authors: N
authors: Oakes
authors: Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden; daniel.linden@astrazeneca.com.
authors: Daniel
authors: D
authors: Lindén
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002250:Carbon Radioisotopes; D059305:Diet, High-Fat; D004149:Dioxoles / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013817:Thermography; D014316:Tritium; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D002250:Carbon Radioisotopes; D004149:Dioxoles; D005230:Fatty Acids, Nonesterified; D010168:Palmitates; D022702:Receptors, Adrenergic, beta-3; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D014316:Tritium; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
keywords: CL316,243; brown adipose tissue; diabetes; free fatty acids; obesity; β3-adrenergic receptor