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Dopaminergic and adrenergic receptors synergistically stimulate browning in 3T3-L1 white adipocytes

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Abstract

The browning of white adipose tissue (WAT) has attracted considerable attention in the scientific community as a popular strategy for enhancing energy expenditure to combat obesity. As a part of this strategy, β3-adrenergic receptor (β3-AR) is the most widely studied receptor that mediates thermogenesis. Parenthetically, further studies in search for additional receptors expressed in adipocytes that can mediate thermogenesis has been appearing, and this paper reports that dopaminergic receptor 1 (DRD1) and β3-AR synergistically stimulate browning in 3T3-L1 white adipocytes. qRT-PCR and immunoblot analysis methods were applied to evaluate the effects of DRD1 on the target proteins downstream of β3-AR and other markers involved in lipid metabolism, mitochondrial biogenesis, and browning events. These results show that DRD1 is expressed in epididymal WAT (eWAT), brown adipose tissue (BAT), and inguinal WAT (iWAT) of normal and high-fat-fed mice, and a deficiency of DRD1 downregulates the expression of brown adipocyte-specific proteins. Silencing of DRD1 affected lipid metabolic activity in 3T3-L1 adipocytes by reducing mitochondrial biogenesis as well as levels of lipolytic and fat oxidative marker proteins in a similar pattern to β3-AR. Moreover, mechanistic studies showed that the depletion of DRD1 downregulates β3-AR and its downstream molecules, suggesting both receptors might synergistically stimulate browning. Parallel to the UCP1-dependent thermogenesis, the depletion of DRD1 also downregulates the expression of core proteins responsible for UCP1-independent thermogenesis. Overall, DRD1 mediates β3-AR-dependent 3T3-L1 browning and UCP1-independent thermogenesis.

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Abbreviations

ACC:

Acyl-CoA carboxylase

ACO:

Acyl-coenzyme A oxidase 1

AMPK:

AMP-activated protein kinase

ATF2:

Activating transcription factor 2

ATGL:

Adipose triglyceride lipase

α1-AR:

Alpha 1 adrenergic receptor

β3-AR:

Beta-3 adrenergic receptor

C/EBP:

CCAAT/enhancer-binding protein/encoding gene

COX-4:

Cyclooxygenase-4

CPT1:

Carnitine palmitoyltransferase 1

CYT-C:

Cytochrome C

CKmt:

Mitochondrial creatine kinase

DRD1:

Dopamine receptor D1

FAS:

Fatty acid synthase

HSL:

Hormone-sensitive lipase

ERK:

Extracellular signal-regulated kinase

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator 1α

p38 MAPK:

P38 mitogen-activated protein kinase

PKA:

Protein kinase A

PPAR:

Peroxisome proliferator-activated receptor

PRDM16:

PR domain containing 16

RyR2:

Ryanodine receptor 2

SERCA:

Sarco/endoplasmic reticulum Ca2+ ATPase

UCP1:

Uncoupling protein 1

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Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT, No. 2019R1A2C2002163).

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Authors and Affiliations

  1. Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea

    Kiros Haddish & Jong Won Yun

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  1. Kiros Haddish
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Contributions

Kiros Haddish performed experimental design, conducted experiments, analyzed the data, performed statistical analyses, wrote the manuscript, and conducted a molecular docking study and Jong Won Yun carried out scientific support, wrote the manuscript, critically reviewed the manuscript and experimental design, and approved the manuscript version to be published. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Jong Won Yun.

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Ethics approval

All the procedures were performed according to the guidelines approved by the National Institutes of Health. All animal experiments were approved by the Committee for Laboratory Animal Care and Use of Daegu University (DUIACC-2021–001-0310–001).

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The authors declare no competing interests.

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Key points

• Deficiency of DRD1 downregulates the expression of browning markers.

• Silencing of DRD1 reduces lipolytic and mitochondrial biogenesis markers.

• DRD1 and β3-AR synergistically regulate white fat browning.

• Deficiency of DRD1 reduces ATP-dependent thermogenesis.

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Supplementary file2 (DOCX 25 KB)

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Haddish, K., Yun, J.W. Dopaminergic and adrenergic receptors synergistically stimulate browning in 3T3-L1 white adipocytes. J Physiol Biochem 79, 117–131 (2023). https://doi.org/10.1007/s13105-022-00928-y

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