TY - JOUR
T1 - Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing
AU - Gonzalez-Hurtado, Elsie
AU - Lee, Jieun
AU - Choi, Joseph
AU - Wolfgang, Michael J.
N1 - Funding Information:
This work was supported in part by a National Institutes of Health grant R01NS072241 and American Diabetes Association grant # 1-16-IBS-313 to M. J. W. E. G. H. was supported by the Johns Hopkins PREP grant R25GM109441.
Publisher Copyright:
© 2017 The Authors
PY - 2018/1
Y1 - 2018/1
N2 - Objective To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation. Methods Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A−/−), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue. Results Chronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2A−/− mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2A−/− adipose tissue albeit to a lesser extent in Cpt2A−/− mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2A−/− mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2A−/− BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2A−/− mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss. Conclusion Mitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.
AB - Objective To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation. Methods Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A−/−), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue. Results Chronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2A−/− mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2A−/− adipose tissue albeit to a lesser extent in Cpt2A−/− mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2A−/− mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2A−/− BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2A−/− mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss. Conclusion Mitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.
KW - Adipose macrophage
KW - Adrenergic signaling
KW - Brown adipose tissue
KW - Cold induced thermogenesis
KW - Fatty acid oxidation
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U2 - 10.1016/j.molmet.2017.11.004
DO - 10.1016/j.molmet.2017.11.004
M3 - Article
C2 - 29175051
AN - SCOPUS:85034956824
SN - 2212-8778
VL - 7
SP - 45
EP - 56
JO - Molecular Metabolism
JF - Molecular Metabolism
ER -