Abstract
Sustained β3 adrenergic receptor (ADRB3) activation simultaneously upregulates fatty acid synthesis and oxidation in mouse brown, beige, and white adipose tissues; however, the cellular basis of this dual regulation is not known. Treatment of mice with the ADRB3 agonist CL316,243 (CL) increased expression of fatty acid synthase (FASN) and medium chain acyl-CoA dehydrogenase (MCAD) protein within the same cells in classic brown and white adipose tissues. Surprisingly, in inguinal adipose tissue, CL-upregulated FASN and MCAD in distinct cell populations: high MCAD expression occurred in multilocular adipocytes that co-expressed UCP1+, whereas high FASN expression occurred in paucilocular adipocytes lacking detectable UCP1. Genetic tracing with UCP1-cre, however, indicated nearly half of adipocytes with a history of UCP1 expression expressed high levels of FASN without current expression of UCP1. Global transcriptomic analysis of FACS-isolated adipocytes confirmed the presence of distinct anabolic and catabolic phenotypes, and identified differential expression of transcriptional pathways known to regulate lipid synthesis and oxidation. Surprisingly, paternally-expressed genes of the non-classical gene imprinted network were strikingly enriched in anabolic phenotypes, suggesting possible involvement in maintaining the balance of metabolic phenotypes. The results indicate that metabolic heterogeneity is a distinct property of activated beige/brite adipocytes that might be under epigenetic control.
Highlights
Sustained β3 adrenergic receptor (ADRB3) activation simultaneously upregulates fatty acid synthesis and oxidation in mouse brown, beige, and white adipose tissues; the cellular basis of this dual regulation is not known
We previously reported that chronic ADRB3 activation simultaneously upregulates de novo fatty acid synthesis and oxidation in brown, beige, and white adipose tissues[9]
To compare the induction of proteins involved in thermogenesis, FA mitochondrial oxidation, FA synthesis and re-esterification by ADRB3 activation, we examined expression levels of UCP1, medium-chain specific acyl-CoA dehydrogenase (MCAD), fatty acid synthase (FASN), and GYK in inguinal WAT, gonadal WAT and interscapular BAT from mice treated with CL for 7 days
Summary
Sustained β3 adrenergic receptor (ADRB3) activation simultaneously upregulates fatty acid synthesis and oxidation in mouse brown, beige, and white adipose tissues; the cellular basis of this dual regulation is not known. Global transcriptomic analysis of FACS-isolated adipocytes confirmed the presence of distinct anabolic and catabolic phenotypes, and identified differential expression of transcriptional pathways known to regulate lipid synthesis and oxidation. While it is well known that adrenergic stimulation increases catabolic metabolism in brown and white adipose tissues[3,8], it is not widely appreciated that chronic activation upregulates de novo fatty acid synthesis, which allows cells to meet oxidative demand with enhanced synthesis[9,10,11]. We previously reported that chronic pharmacological activation of ADRB3 simultaneously upregulates fatty acid synthesis and oxidation in brown, beige/brite, and white adipose tissues[9]. The presence of anabolic and catabolic phenotypes within the inguinal adipose tissue organ suggests the potential for functional interactions between cells that synthesize and export fatty acids and those that oxidize them
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